Archive for February, 2020

As amphibians go, axolotls are pretty cute. These salamanders sport a Mona Lisa half-smile and red, frilly gills that make them look dressed up for a party. You might not want them at your soiree, though: Theyre also cannibals. While rare now in the wild, axolotls used to hatch en masse, and it was a salamander-eat-salamander world. In such a harsh nursery, they evolved or maybe kept the ability to regrow severed limbs.

Their regenerative powers are just incredible, says Joshua Currie, a biologist at the Lunenfeld-Tanenbaum Research Institute in Toronto whos been studying salamander regeneration since 2011. If an axolotl loses a limb, the appendage will grow back, at just the right size and orientation. Within weeks, the seam between old and new disappears completely.

And its not just legs: Axolotls can regenerate ovary and lung tissue, even parts of the brain and spinal cord.

The salamanders exceptional comeback from injury has been known for more than a century, and scientists have unraveled some of its secrets. It seals the amputation site with a special type of skin called wound epithelium, then builds a bit of tissue called the blastema, from which sprouts the new body part. But until recently, the fine details of the cells and molecules needed to create a leg from scratch have remained elusive.

With the recentsequencingandassemblyof the axolotls giant genome, though, and thedevelopment of techniques to modify the creatures genes in the lab,regeneration researchers are now poised to discover those details. In so doing, theyll likely identify salamander tricks that could be useful in human medicine

Already, studies are illuminating the cells involved, and defining the chemical ingredients needed. Perhaps, several decades from now, people, too, might regrow organs or limbs. In the nearer future, the findings suggest possible treatments for ways to promote wound-healing and treat blindness.

The idea of human regeneration has evolved from an if to a when in recent decades, says David Gardiner, a developmental biologist at the University of California, Irvine. Everybody now is assuming that its just a matter of time, he says. But, of course, theres still much to do.

In a working limb, cells and tissues are like the instruments in an orchestra: Each contributes actions, like musical notes, to create a symphony. Amputation results in cacophony, but salamanders can rap the conductors baton and reset the remaining tissue back to order and all the way back to the symphonys first movement, when they first grew a limb in the embryo.

The basic steps are known: When a limb is removed, be it by hungry sibling or curious experimenter, within minutes the axolotls blood will clot. Within hours, skin cells divide and crawl to cover the wound with a wound epidermis.

Next, cells from nearby tissues migrate to the amputation site, forming a blob of living matter. This blob, the blastema, is where all the magic happens, said Jessica Whited, a regenerative biologist at Harvard University, in a presentation in California last year. It forms a structure much like the developing embryos limb bud, from which limbs grow.

This movie shows immune cells, labeled to glow green, moving within a regenerating axolotl fingertip. Scientists know that immune cells such as macrophages are essential for regeneration: When they are removed, the process is blocked.

Finally, cells in the blastema turn into all the tissues needed for the new limb and settle down in the right pattern, forming a tiny but perfect limb. This limb then grows to full size. When all is done, you cant even tell where the amputation occurred in the first place, Whited tellsKnowable Magazine.

Scientists know many of the molecular instruments, and some of the notes, involved in this regeneration symphony. But its taken a great deal of work.

As Currie started as a new postdoc with Elly Tanaka, a developmental biologist at the Research Institute of Molecular Pathology in Vienna, he recalls wondering, Where do the cells for regeneration come from? Consider cartilage. Does it arise from the same cells as it does in the developing embryo, called chondrocytes, that are left over in the limb stump? Or does it come from some other source?

To learn more, Currie figured out a way to watch individual cells under the microscope right as regeneration took place. First, he used a genetic trick to randomly tag the cells he was studying in a salamander with a rainbow of colors. Then, to keep things simple, he sliced off just a fingertip from his subjects. Next, he searched for cells that stuck out say, an orange cell that ended up surrounded by a sea of other cells colored green, yellow and so on. He tracked those standout cells, along with their color-matched descendants, over the weeks of limb regeneration. His observations, reported in the journalDevelopmental Cellin 2016,illuminated several secrets to the regeneration process.

Regenerative biologist Joshua Currie labeled the cells in axolotls with a rainbow of colors, so that he could follow their migration after he amputated the tip of the salamanders fingertips. In this image, three days after amputation, the skin (uncolored) has already covered the wound. (Credit: Josh Currie)

For one thing, cell travel is key. Cells are really extricating themselves from where they are and crawling to the amputation plane to form this blastema, Currie says. The distance cells will journey depends on the size of the injury. To make a new fingertip, the salamanders drew on cells within about 0.2 millimeters of the injury. But in other experiments where the salamanders had to replace a wrist and hand, cells came from as far as half a millimeter away.

More strikingly, Currie discovered that contributions to the blastema were not what hed initially expected, and varied from tissue to tissue. There were a lot of surprises, he says.

Chondrocytes, so important for making cartilage in embryos, didnt migrate to the blastema (earlier in 2016, Gardiner and colleaguesreported similar findings). And certain cells entering the blastema pericytes, cells that encircle blood vessels were able to make more of themselves, but nothing else.

The real virtuosos in regeneration were cells in skin called fibroblasts and periskeletal cells, which normally surround bone. They seemed to rewind their development so they could form all kinds of tissues in the new fingertip, morphing into new chondrocytes and other cell types, too.

To Curries surprise, these source cells didnt arrive all at once. Those first on the scene became chondrocytes. Latecomers turned into the soft connective tissues that surround the skeleton.

How do the cells do it? Currie, Tanaka and collaborators looked at connective tissues further, examining the genes turned on and off by individual cells in a regenerating limb. In a 2018Sciencepaper, the team reported thatcells reorganized their gene activation profileto one almost identical, Tanaka says, to those in the limb bud of a developing embryo.

Muscle, meanwhile, has its own variation on the regeneration theme. Mature muscle, in both salamanders and people, contains stem cells called satellite cells. These create new cells as muscles grow or require repair. In a 2017 study inPNAS, Tanaka and colleagues showed (by tracking satellite cells that were made to glow red) that most, if not all, ofmuscle in new limbs comes from satellite cells.

If Currie and Tanaka are investigating the instruments of the regeneration symphony, Catherine McCusker is decoding the melody they play, in the form of chemicals that push the process along. A regenerative biologist at the University of Massachusetts Boston, she recently published arecipe of sorts for creating an axolotl limb from a wound site. By replacing two of three key requirements with a chemical cocktail, McCusker and her colleagues could force salamanders to grow a new arm from a small wound on the side of a limb, giving them an extra arm.

Using what they know about regeneration, researchers at the University of Massachusetts tricked upper-arm tissue into growing an extra arm (green) atop the natural one (red). (Credit: Kaylee Wells/McCusker Lab)

The first requirement for limb regeneration is the presence of a wound, and formation of wound epithelium. But a second, scientists knew, was a nerve that can grow into the injured area. Either the nerve itself, or cells that it talks to, manufacture chemicals needed to make connective tissue become immature again and form a blastema. In their 2019 study inDevelopmental Biology, McCusker and colleagues guided byearlier work by a Japanese team used two growth factors, called BMP and FGF, to fulfill that step in salamanders lacking a nerve in the right place.

The third requirement was for fibroblasts from opposite sides of a wound to find and touch each other. In a hand amputation, for example, cells from the left and right sides of the wrist might meet to correctly pattern and orient the new hand. McCusckers chemical replacement for this requirement was retinoic acid, which the body makes from vitamin A. The chemical plays a role in setting up patterning in embryos and has long been known to pattern tissues during regeneration.

In their experiment, McCuskers team removed a small square of skin from the upper arm of 38 salamanders. Two days later, once the skin had healed over, the researchers made a tiny slit in the skin and slipped in a gelatin bead soaked in FGF and BMP. Thanks to that cocktail, in 25 animals the tissue created a blastema no nerve necessary.

About a week later, the group injected the animals with retinoic acid. In concert with other signals coming from the surrounding tissue, it acted as a pattern generator, and seven of the axolotls sprouted new arms out of the wound site.

The recipe is far from perfected: Some salamanders grew one new arm, some grew two, and some grew three, all out of the same wound spot. McCusker suspects that the gelatin bead got in the way of cells that control the limbs pattern. The key actions produced by the initial injury and wound epithelium also remain mysterious.

Its interesting that you can overcome some of these blocks with relatively few growth factors, comments Randal Voss, a biologist at the University of Kentucky in Lexington. We still dont completely know what happens in the very first moments.

If we did know those early steps, humans might be able to create the regeneration symphony. People already possess many of the cellular instruments, capable of playing the notes. We use essentially the same genes, in different ways, says Ken Poss, a regeneration biologist at the Duke University Medical Center in Durham who describednew advances in regeneration, thanks to genetic tools, in the 2017Annual Review of Genetics.

Regeneration may have been an ability we lost, rather than something salamanders gained. Way back in our evolutionary past, the common ancestors of people and salamanders could have been regenerators, since at least one distant relative of modern-day salamanders could do it. Paleontologists have discovered fossils of300-million-year-old amphibians with limb deformities typically created by imperfect regeneration.Other members of the animal kingdom, such as certain worms, fish and starfish, can also regenerate but its not clear if they use the same symphony score, Whited says.

These fossils suggest that amphibians calledMicromelerpetonwere regenerating limbs 300 million years ago. Thats because the fossils show deformities, such as fused bones, that usually occur when regrowth doesnt work quite right. (Credit: Nadia B Frbisch et al./Proceedings of the Royal Society B, 2014)

Somewhere in their genomes, all animals have the ability, says James Monaghan, a regeneration biologist at Northeastern University in Boston. After all, he points out, all animals grow body parts as embryos. And in fact, people arent entirely inept at regeneration. We can regrow fingertips, muscle, liver tissue and, to a certain extent, skin.

But for larger structures like limbs, our regeneration music falls apart. Human bodies take days to form skin over an injury, and without the crucial wound epithelium, our hopes for regeneration are dashed before it even starts. Instead, we scab and scar.

Its pretty far off in the future that we would be able to grow an entire limb, says McCusker. I hope Im wrong, but thats my feeling.

She thinks that other medical applications could come much sooner, though such as ways to help burn victims. When surgeons perform skin grafts, they frequently transfer the top layers of skin, or use lab-grown skin tissue. But its often an imperfect replacement for what was lost.

Thats because skin varies across the body; just compare the skin on your palm to that on your calf or armpit. The tissues that help skin to match its body position, giving it features like sweat glands and hair as appropriate, lie deeper than many grafts. The replacement skin, then, might not be just like the old skin. But if scientists could create skin with better positional information, they could make the transferred skin a better fit for its new location.

Monaghan, for his part, is thinking about regenerating retinas for people who have macular degeneration or eye trauma. Axolotls can regrow their retinas (though, surprisingly, their ability to regenerate the lens is limited to hatchlings). He is working with Northeastern University chemical engineer Rebecca Carrier, whos been developing materials for use in transplantations. Her collaborators are testing transplants in pigs and people, but find most of the transplanted cells are dying. Perhaps some additional material could create a pro-regeneration environment, and perhaps axolotls could suggest some ingredients.

Carrier and Monaghan experimented with the transplanted pig cells in lab dishes, and found they were more likely to survive and develop into retinal cells if grown together with axolotl retinas. The special ingredientseems to be a distinct set of chemicals that exist on axolotl, but not pig, retinas.Carrier hopes to use this information to create a chemical cocktail to help transplants succeed. Even partially restoring vision would be beneficial, Monaghan notes.

Thanks to genetic sequencing and modern molecular biology, researchers can continue to unlock the many remaining mysteries of regeneration: How does the wound epithelium create a regeneration-promoting environment? What determines which cells migrate into a blastema, and which stay put? How does the salamander manage to grow a new limb of exactly the right size, no larger, no smaller? These secrets and more remain hidden behind that Mona Lisa smile at least for now.

10.1146/knowable-012920-1

This article originally appeared in Knowable Magazine, an independent journalistic endeavor from Annual Reviews.

Excerpt from:
What the Axolotl's Limb-Regenerating Capabilities Have to Teach Us - Discover Magazine

Parkinson's disease comes with slowness, rigidity, tremors, and loss of balance due to an insufficiency of the dopamine that coordinates muscle movement. This disease, of which the rate of diagnosis is rising, occurs when the neurons responsible for producing dopamine malfunction or die. About 500,000 Americans are diagnosed with Parkinson's each year.

Most of the time, Parkinson's disease is a condition of the elderly, diagnosed in people 60 and older. However, about 10% of the time, it's detected in people between 21 and 50. "Young-onset Parkinson's is especially heartbreaking because it strikes people at the prime of life," says Michele Tagliati, an author of a new study from Cedars-Sinai.

The study of brain cells from Parkinson's younger victims has found that the misbehaving neurons are present long before diagnosis typically taking some 20 or 30 years to produce detectable symptoms and may even be present prior to birth. The revelation raises hope for combatting Parkinson's because there's already an approved drug that can mitigate the damage done by the troublemaking neurons before the disease ever appears.

The research is published in the journal Nature Medicine.

Image source: Kateryna Kon/Shutterstock

The authors' investigation began with an examination of neurons based on cells from young-onset Parkinson's (YOPD) patients who had no known mutations. From the cells, induced pluripotent stem cells (iPSCs) were generated and differentiated into dishes containing cultures of dopamine neurons. Senior study author Clive Svendsen says, "Our technique gave us a window back in time to see how well the dopamine neurons might have functioned from the very start of a patient's life."

The scientists observed lysosomes within the YOPD neurons malfunctioning. Since lysosomes are counted on as "trash cans" for unnecessary or depleted proteins, the castoff chemicals began to pile up. In particular, substantial accumulations of soluble -synuclein, a protein implicated in different types of Parkinson's, were seen.

Says Svendsen, "What we are seeing using this new model are the very first signs of young-onset Parkinson's,"revealing that, "It appears that dopamine neurons in these individuals may continue to mishandle -synuclein over a period of 20 or 30 years, causing Parkinson's symptoms to emerge."

The researchers also saw unexpectedly high levels of the enzyme protein kinase C in its active form, though what that has to do with Parkinson's, if anything, is unknown.

Image source: sruilk/Shutterstock

The researchers tested a number of drugs on the cultures to see if any might address the observed accumulations of -synuclein. (They performed parallel tests of laboratory mice.) One drug, PEP005, which is already approved by the FDA for treating skin pre-cancers, did effectively reduce the -synuclein buildup, both in the iPSCs and the mice.

Since PEP005 is currently administered in gel form for treating skin, the researchers are now exploring how the drug might be modified so it can be delivered directly to the brain. The team also plans follow-on research to see if their findings apply equally to forms of Parkinson's beyond YOPD.

Related Articles Around the Web

Link:
Can Parkinsons be prevented as it stealthily develops? - Big Think

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Cosmetic Skin Care Market Enhancement And Its growth prospects forecast 2019 to 2026 - Dagoretti News

Image: Nur Yucer, PhD, a project scientist, and Clive Svendsen, PhD, director of the Cedars-Sinai Board of Governors Regenerative Medicine Institute and Professor of Biomedical Sciences and Medicine at Cedars-Sinai. Photo by Cedars-Sinai.

Parkinson's disease is a neurodegenerative disorder that affects predominately dopamine-producing neurons in the brain. Nearly one million will be living with Parkinson's disease in the US this year, according to the Parkinson's Foundation. This is more than the number of people diagnosed with multiple sclerosis, muscular dystrophy and Lou Gehrig's diseasecombined.

About 60,000 Americans are diagnosed with Parkinson's disease each year, and more than 10 million people worldwide are living with it. Incidence of Parkinsons disease increases with age, but an estimated 10 percent of people with Parkinson's disease are diagnosed before age 50. This is called young-onset Parkinson's.

Researchers at Cedars-Sinai, led by Clive Svendsen, PhD, director of the Cedars-Sinai Board of Governors Regenerative Medicine Institute and Professor of Biomedical Sciences and Medicine at Cedars-Sinai, reported in a study published in Nature Medicine that they found that patients who develop young-onset Parkinsons disease may have been born with dysfunctional brain cells that go undetected for decades.

The research team generated special stem cells, known as induced pluripotent stem cells (iPSCs), from cells of patients suffering from young-onset Parkinsons disease. These iPSCswhich can produce any cell type of the human body, all genetically identical to the patients own cellswere used to produce dopamine neurons from each patient to analyze their functions.

Two key abnormalities were observed in these neurons:

- Dr. Clive Svendsen

After testing a number of drugs on the abnormal dopamine neurons, the researchers discovered that a drug called PEP005 (ingenol mebutate) reduced the elevated levels of alpha-synuclein in both the dopamine neurons in the dish and in laboratory mice. A gel formulation of PEP005 is marketed by LEO Pharma as Picato and is FDA-approved for the treatment of actinic keratosis, a scaly skin patch that develops from years of exposure to the sun. According to the Mayo Clinic, a small percentage of actinic keratosis lesions can eventually become skin cancer.

Michele Tagliati, PhD, Director of the Movement Disorders Program and Vice Chair and Professor in the Department of Neurology at Cedars-Sinai, said the research team next will study how PEP005 might be delivered to the brain and whether or not the abnormalities found in young-onset Parkinson's patients also exist in other forms of Parkinsons.

- Dr. Michele Tagliati.

Edward Kim is Managing Editor of Equities.com.

_____

Sources: Equities News, Cedars-Sinai

DISCLOSURE:The views and opinions expressed in this article are those of the authors, and do not represent the views of equities.com. Readers should not consider statements made by the author as formal recommendations and should consult their financial advisor before making any investment decisions. To read our full disclosure, please go to: http://www.equities.com/disclaimer.

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Cedars-Sinai Study Indicates That Parkinson's Disease May Start Before Birth - Equities.com

An intriguing experiment has led researchers to conclude that people who develop early-onset Parkinsons disease between the age of 21 and 50 may have been born with abnormal brain cells that go undetected for decades.

These disordered cells allow gradual accumulation of the -synuclein protein that forms abnormal deposits in the brain, and dysregulated lysosomal proteins that ordinarily play a role in clearing abnormal proteins from cells.

The researchers from Cedars-Sinai Medical Center say they are investigating an FDA approved skin cancer drug they believe might help correct these abnormalities before they become symptomatic.

In other words, they suggest that early-onset Parkinsons the form of the disease that Michael J. Fox was diagnosed with at the age of 29 may be treatable or even prevented. Its an astonishing claim.

To perform the study, the research team generate pluripotent stem cells master cells that can potentially produce any cell or tissue the body needs to repair itself from blood cells of three patients with young-onset Parkinsons disease.

The patients were aged 30-39 and had no known familial history of the disease and no Parkinsons disease mutations.

When generated in the laboratory, these master cells called induced pluripotent stem cells (iPSCs). In their experiment, the Cedars-Sinai researchers described this process as taking adult blood cells back in time to a primitive embryonic state.

The team used the stem cells to produce dopamine neurons from each patient and then cultured them in a dish and analysed the neurons functions.

In Parkinsons patients, brain neurons that make dopamine a neurotransmitter that works to coordinate muscle movement become impaired or die.

Our technique gave us a window back in time to see how well the dopamine neurons might have functioned from the very start of a patients life, said Dr Clive Svendsen, PhD, director of the Cedars-Sinai Board of Governors Regenerative Medicine Institute, and the studys senior author.

According to a statement from Cedars-Sinai, the researchers detected two key abnormalities in the dopamine neurons in the dish:

Dr Svendsen said the experiment allowed the researchers to see the very first signs of young-onset Parkinsons.

It appears that dopamine neurons in these individuals may continue to mishandle alpha-synuclein over a period of 20 or 30 years, causing Parkinsons symptoms to emerge.

The investigators went further, using their iPSC to test a number of drugs that might reverse the lab-born abnormalities.

They found that that one drug, PEP005 already approved by the Food and Drug Administration for treating pre-cancers of the skin reduced the elevated levels of alpha-synuclein in both the dopamine neurons in the dish and in laboratory mice.

The drug also countered another abnormality they found in the patients dopamine neurons elevated levels of an active version of an enzyme called protein kinase C. However, the role of this enzyme version in Parkinsons is not clear.

The drug PEP005 is only available in gel form and the researchers plans to investigate how it might be delivered to the brain to potentially treat or prevent young-onset Parkinsons.

In Parkinsons disease, the symptoms including slowness of movement, rigid muscles, tremors, loss of balance and impaired mood control get worse over time. In most cases, the exact cause of neuron failure is unclear, and there is no known cure.

Just about every week, a new insight into the disease is published. Last week, The New Daily reported on new research that found living less than 50 metres from a major road or less than 150 metres from a highway has been linked to significantly higher incidence of dementia and Parkinsons disease.

In 2018, we published an exciting Australian study that suggested subject to clinical testing the inflammation of the brain that causes so much of the progressive damage in Parkinsons disease (PD) could be halted by taking a single pill each day.

Both these studies might eventually prove to be correct. But its a long wait for the more than 10 million sufferers worldwide and their families.

This latest study could be a game-changer. But it could just as easily wither on the vine. Still, better to take heart than not.

Most patients are 60 or older when they are diagnosed, about 10 per cent are between 21 and 50 years old. .

Young-onset Parkinsons is especially heartbreaking because it strikes people at the prime of life, said Dr Michele Tagliati, director of the Movement Disorders Program, vice chair and professor in the Department of Neurology at Cedars-Sinai, and co-author of the study.

This exciting new research provides hope that one day we may be able to detect and take early action to prevent this disease in at-risk individuals.

See the rest here:
Early onset Parkinsons might begin in the womb: Prevention a possibility - The New Daily

How Mammoth Biosciences is Using Protein Discovery to Unlock the Potential of CRISPR

Its happening again. The world looks on anxiously as new updates emerge almost hourly from China. Just this morning I read in my NY Times Daily Briefing that the death toll from a new coronavirus originating in Wuhan, China, has reached 170, with 7700 people sickened worldwide from the virus. People are asking, is this the next pandemic?

We worry about pandemics because we worry about our ability to stop them and to save lives. Every time a new pandemic, or potential pandemic, emerges, we are reminded that we still dont have an affordable, accessible, rapid and accurate molecular diagnostic test that can be used in the field. Were such a diagnostic to exist, we could more quickly contain the spread of diseases like the new coronavirus, or Ebola, which has killed hundreds of thousands in Africa, or any other disease. It could literally change everything.

The reality is we will continue to see pandemics. Our goal is to build a disposable, portable, ultra-accurate test, similar to a pregnancy test format but molecular, says Trevor Martin, co-founder and CEO of Silicon Valley startup Mammoth Biosciences.

His company is closer to that goal than you might think and theyre doing it with CRISPR.

When you think of CRISPR, you most likely think of gene editing. Youve probably read a dozen articles touting the potential for these molecular scissors to cure diseases such as blindness or cancer. Indeed, clinical trials that began last year have already led to groundbreaking outcomes. But CRISPR can and should be so much more than that.

CRISPR is a microbial immune system, the way by which bacteria fight off viruses, which act by injecting viral DNA into the host genome. And while Cas9 the molecular scissors may be the star of CRISPR, the CRISPR system is actually comprised of several Cas protein families, each of which has its own unique functions. This was this premise upon which Mammoth Biosciences was built: using deep protein discovery focused on CRISPR proteins, identify new proteins and unlock new functions. Its an approach that has paid off.

Our thesis is that novel functions unlock new products, says Martin. From the very beginning the founding of the company [CRISPR] proteins with novel trans-cleavage ability created diagnostics, and that invented this brand new field (CRISPR diagnostics) that people didnt think could exist.

Using CRISPR as a diagnostic tool rather than an editing tool may have been a surprise when Mammoth introduced it to the world two years ago, but Martin says that if we think about CRISPR as a homing beacon instead of just as molecular scissors, the diagnostic applications arent so surprising after all.

[CRISPR] is really a homing beacon, and you can use it to home in on something and then report on it, home in on it and cut it, home in on it and edit a base, activate a gene, destroy a sequence, whatever you want to do. And once you start thinking about it that way, it becomes more obvious whats going on. Diagnostics becomes more clear, but so do other next-generation therapeutic applications, he says.

Mammoths goal is to build out a platform for next-generation CRISPR-based diagnostics and therapeutics. By continuing to search the protein space deeply for new CRISPR proteins with new functions, the company is building a comprehensive toolbox that researchers can use to create new therapeutics and improved diagnostics tools. Their toolbox already contains proteins from the Cas12, Cas13, and Cas14 protein families and it is Cas14 that is especially interesting.

CRISPR proteins can actually be quite large Cas9, for example, is so big that it is difficult to deliver using adenovirus (one of the most common delivery methods for gene editing). The size issue is compounded when considering CRISPR add-ons (like CRISPR prime), which expand upon the scissor function of Cas9 to add precise capabilities like changing one base for another, adding a gene instead of removing a gene, and directed genome targeting. Each add-on makes the CRISPR complex even bigger and harder to deliver.

But Cas14 is unique. It comes from Archaea a close relative to bacteria and its much smaller than other CRISPR proteins like Cas9. It can easily be delivered via adenovirus, it can accommodate CRISPR add-on protein domains, and its small size even makes it effective for delivery using lipid nanoparticles (LNPs). Martin thinks Cas14 can help the field reach the holy grail goal of in vivo gene editing, replacing the current system of removing cells from a patients body, editing them ex vivo in the laboratory, and then re-introducing the edited cells back into the patient.

Cas14 is also the poster child for Mammoths approach to use deep protein discovery for finding novel proteins with novel functions. It is one of the most diverse if not the most diverse of the CRISPR proteins weve discovered so far.

There are potentially many hundreds of [Cas14] proteins, says Martin, which means a ton of functionality that can be uncovered.

And, for some applications, Cas14 can target anywhere in the genome you want it to and has less off-target effects that have led some to worry about the risk to benefit ratio of using CRISPR to treat disease.

Of course, Cas14 is just a start, and its unlikely to be the right tool for everything. Different Cas proteins will be necessary for different applications, and in addition to Mammoths internal work, its their goal to partner deeply with companies to develop their CRISPR proteins and bring them into diagnostic and therapeutic products such as Martins dream rapid diagnostic field test. Mammoth is partnering with UCSF researchers on a coronavirus diagnostic, a partnership that couldnt have come too soon. And, the company recently announced a collaboration with Horizon Discovery to create a new generation of Chinese hamster ovary (CHO) cell line editing tools.

We are not experts in hundreds of disease areas by ourselves but we are the worlds best at developing proteins with these novel functionalities. Like [we did] with CRISPR diagnostics, were now building a platform on the therapeutic side, including working closely with companies with specific expertise to bring products to market, says Martin.

A recent injection of USD $45 million from investors with deep healthcare interests, such as Decheng, Mayfield, Verily, and Brook Byers, will enable the company to double down on their efforts to develop their toolbox of next-generation CRISPR diagnostics and therapeutics. And, recent executive hires bring significant industry expertise to the table from new CBO Peter Nell (co-founder of Casebia, a joint venture between Bayer and CRISPR Therapeutics) and new COO Ted Tisch (a former Synthego executive).

All too often it seems like we arent quite there yet when it comes to the promise of biotechnology. But when it comes to CRISPR, we really are almost there. With Mammoth Biosciences leading the way by providing the next-generation tools needed to fully realize the therapeutic and diagnostic potential of CRISPR, things might turn out a bit different the next time a pandemic rolls around.

Read more from the original source:
The CRISPR Platform for Next-Generation Therapeutics and Diagnostics - SynBioBeta

Written By: Dr. Ananya MukherjeeDepartment of Plant Science and innovationUniversity of Nebraska-Lincoln, USAPhoto Credit: Shutterstock

CRISPR is something you must have come across in your science news feed in the last couple of years or so. Even if you have not, you may have seen the big news that took social media by storm the genome-edited babies in China, Lulu and Nana. One might wonder what is this fuss all about and why is this technique in the news all of a sudden? To make sense of it all its important to delve a little into the history of CRISPR and why it became bigger than any other editing strategies that have been around for a while.

The scientists quest of genome or gene editing is not anything new. For several decades we have been striving to find techniques which will efficiently target genes of interest and make the changes we want them to make but with minimal off-targets. The reason why CRISPR is preferred over other tools is its efficiency, ease of manipulation and most importantly precision. Nearly 33 years ago Francisco Mojica from the University of Alicante, Spain found what we now know as CRISPR or Clusters of Regularly Interspaced Short Palindromic Repeats in E. Coli. Soon after that such regions of repeat DNA were found in another domain Archea as well. However, since then no other organism domain has shown CRISPR like repeats. Although the very fact that these unusual repeat sequences showed up or are conserved in two domains, making them the most widely distributed repeat sequences in prokaryotes. Its hypothesized that these repeats which are part of the bacterial immune system came about to fight the selective pressure created by viruses. In 2005 Alexander Bolotin, French National Institute for Agricultural Research found what we now know as Cas9, a helper enzyme of CRISPR that acts like molecular scissors to make specific edits in DNA. The beauty of CRISPR perhaps is in the fact that the gene we wish to edit doesnt need to be paired with enzymes like in other genetic methods, but Cas9 can be led to the gene via something called a guide RNA.

Soon after in 2007, CRISPR was used for S.thermophilus, which is used in the dairy and yoghurt industry, to resist bacteriophage attacks. Ever since its discovery, there has been no looking back for CRISPR. From agricultural applications like creating genetically edited crops tolerant to drought, crop diseases and higher yield to in-vitro human cells and animal models showing its applications in curing or reversing genetic defects like cystic fibrosis. In a recent article, National Geographic interviewed scientist Zachary Lipman from Cold Spring Harbor who is trying to put in fields high-yield tomatoes. This is not very surprising because since 2013 disease-resistant varieties of tomato are being developed by scientists, showing how far this technique has come. Even abiotic stress such as chill which tomato is very susceptible to, has been tackled with CRISPR by the introduction of genes that can resist cold weather. Essentially it comes down to knowing which gene or group of genes to target so that off-target effect is minimal and the right objective is achieved. Aside from tomato, strawberry, banana, grape, apple, watermelon, and kiwifruit are some more fruits which have been edited by CRISPR. Complex and large genomes such as date palm are now being targeted to be edited by CRISPR to tackle similar growth-related issues in a changing climate. Food crops are being manipulated with the help of CRISPR to produce everything from low gluten wheat to virus-resistant cacao in West Africa that can produce more chocolate. Mushrooms which are known for spoiling easily are being edited to have a longer shelf life. China has scientists working on improving yields in rice. Its no secret that with the boom in population and a changing climate the world is soon going to be in a massive struggle to have enough food for every mouth. With such attempts on a staple food crop, we can benefit in the right direction. These are just some exciting examples. There are lists of agriculture benefits that we have gotten from CRISPR and most of these crops are under varying stages of success.

Gene drives is another new application of CRISPR where a certain favourable trait can be passed down from parent to the next generation and thereby propagate in the entire population such as disease resistance or in agriculture- herbicide or pesticide resistance. In October of this year, David Liu of the Broad Institute of MIT and Harvard and postdoctoral fellow Dr. Andrew Anzalone came up with prime editing, which is a new form of CRISPR Cas9. The beauty of this technique stems from its ability to change the 4 bases of DNA A.T, G and C into any other base as deemed fit. Previous techniques were not as flexible and could not theoretically cure diseases like sickle cell anaemia which requires a specific A to T mutation to correct it. As of now several human trials for CRISPR to treat the disease have been approved and are all on the way. These include sickle cell anaemia to replace the lethal mutation, T cell editing to treat various types of cancer, photoreceptor cell editing to treat Night Blindness and many others. Hence almost every biological system has been affected by the development of CRISPR.

This now brings us to the big CRISPR story which had the world in the crossfire of several debates regarding the ethical concerns of such a fast developing and precise technique like CRISPR. In June 2017 a couple visited Southern University of Science and Technology in Shenzhen China to meet He Jiankui. He, a biophysicist, was attempting to edit an embryo to remove the surface protein CCR5 that HIV uses for establishing infection. In November 2018, twins Lulu and Nana were born with edited genomes and it was known that another woman was also pregnant with a third CRISPR baby. Despite public outrage, He has not admitted to any wrongdoing and has even published a video promotion of the project. This is mainly because sometime in 2017 the US National academy of sciences decided that human trials if strictly regulated are permissible and its up to the governments to decide what can and cannot be done, as reported in Science. Of course, there has been public criticism by Nobel laureates like David Baltimore but there are also scientists who have emailed words of praise to He. He since his controversial appearance in the Hong Kong summit of genome editing in 2018, has been believed to be under house arrest. He was let go from his university position and not made any public appearances since then.

On the face of it, such an edit seems to be a good step in the right direction. After all, any future parent would want his or her kid to be free from certain deadly disease like HIV. The main cause for concerns is the fact that the exact effect of the mutations induced are not known and CRISPR, despite being a sophisticated technique, does have off-target effects. There is no telling if some cells had started to divide in the embryo before the edit was introduced and a mosaic effect may happen in such a case. Taking into consideration all of these dangers, its hard to say if the attempt made was a success or not. However, this is a very slippery slope because designer babies may soon become the future. CRISPR is not without its off-targets and such off-targets in humans can have deadly consequences and may even be inherited as mutations by generations. Editing embryos may not be the best way to eradicate HIV which is more prevalent in the continent of Africa. Editing babies perhaps would be able to slow down HIV in 30 years but by then more techniques will come up to stabilize the spread anyway. There is also the fact that if humans start doing away with all diseases the population boom may be too much for the world to handle climate change and food shortage breathing down our necks. As of now, CRISPR has only grown stronger with a new report showing it can cut and splice whole chromosomes. In the University of Pennsylvania in Philadelphia clinical trials to treat cancer cells have been approved and are underway. The scientific community has no doubt made great strides to use this gene-editing technique positively but only time will tell if the progress of CRISPR continues an upward trajectory both scientifically and ethically.

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The CRISPR Story : From Boon to Bane? - Multidimension Magazine

Top research study on Global Crispr And Crispr-Associated (Cas) Genes Market is an extensive compilation of innovative developments, growth opportunities and revenue analysis of top-tier Crispr And Crispr-Associated (Cas) Genes Industry aspirants. The report states the growth trajectory of Global Crispr And Crispr-Associated (Cas) Genes Market growth during 2020-2026. Key industry aspects like SWOT analysis, Porters five forces analysis, and market statistics are mentioned. Global Crispr And Crispr-Associated (Cas) Genes Industry is expected to reach xx million USD in 2020 and will grow at a CAGR of xx% during 2020-2026.

Know About Crispr And Crispr-Associated (Cas) Genes Market Research Report

The prime manufacturers of Crispr And Crispr-Associated (Cas) Genes Market is as follows:

Mirus Bio LLCAddgeneGE Healthcare DharmaconCaribou BiosciencesTakara Bio USAHorizon Discovery GroupCRISPR THERAPEUTICSThermo Fisher ScientificMerck KGaAEditas MedicineIntellia Therapeutics

The production, regional trade, investment opportunities, mergers & acquisitions and sales channels of Crispr And Crispr-Associated (Cas) Genes Industry are stated. The top manufacturers, product types, applications, and market share is stated. The regional Crispr And Crispr-Associated (Cas) Genes analysis covers North America, Europe, China, Japan, India, South America, Middle East, and Africa and the rest of the world.

Global Crispr And Crispr-Associated (Cas) Genes Research Report offers complete details about industry chain structure, raw materials, pricing analysis, company profiles, and product specifications. The sales analysis, value chain optimization, strategic insights on Crispr And Crispr-Associated (Cas) Genes Industry, product launches and market risks are mentioned in this report. The country-level analysis of Crispr And Crispr-Associated (Cas) Genes Report covers USA, Canada, Mexico, Germany, France, UK, Russia, Italy, China, Japan, India, Korea, Australia, Brazil, Argentina, Colombia, Saudi Arabia, UAE, Egypt, South Africa and rest of the world. Market scope, revenue, information on product services and gross margin status is covered in this report. The import-export scenario, demand-supply, consumer behavior, and complete details on distributors, suppliers, traders, and dealers in Crispr And Crispr-Associated (Cas) Genes Market are stated.

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Key Extracts From Table Of Content:

Section 1: Market Introduction and Overview

Section 2: Product Overview, Classification, Scope

Section 3: Competitive Crispr And Crispr-Associated (Cas) Genes Market scenario based on Top Manufacturers

Section 4: Historic Study of Crispr And Crispr-Associated (Cas) Genes Market Based on Region, Type, Application

Section 5: Company Profiles of Key Crispr And Crispr-Associated (Cas) Genes Players, Market Share, Product Portfolio and Regional Presence

Section 6: Manufacturing Cost Analysis, Key Business Figures, Gross Margin, SWOT Analysis

Section 7: Regional Analysis, Market Status and Prospect From 2015-2026

Section 8: Market Dynamics, Marketing and Sales Channels, Distributors and Customer Analysis

Section 9: Financial Highlights of Crispr And Crispr-Associated (Cas) Genes Market Including Total Revenue, Products, Services, Opportunities, and Market Risk Analysis

Section 10: Global Crispr And Crispr-Associated (Cas) Genes Market Forecast Study, Marketing Channels, Cost Structures, Distributors and Consumer Study

Section 11: Region-wise Forecast Analysis of Sales, Revenue, Growth Rate Till 2026

Section 12: Research Findings, Conclusion, Data Sources, Research Methodology, and Disclaimer

A complete qualitative and competitive assessment of Crispr And Crispr-Associated (Cas) Genes Market is conducted to offer valuable insights. This will enable the market aspirants in shaping their business plans and planning growth strategies. Primary and secondary research techniques like interviews, trade journals, surveys, and reputable paid database sources. A complete historical analysis from 2014-2019 and forecast analysis 2020-2026 with base year as 2019. Our competitive business landscape will help you to gain upper hand in competition.

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Comprehensive Crispr And Crispr-Associated (Cas) Genes Industry Outlook And Growth Trajectory Explained In This Latest Report - Jewish Life News

If you look back and reflect upon the areas of technology that werent conceived, or at least not commonplace, as we rolled into 2010 no iPads, Amazon Echo or Prime, smartwatches, Chromebooks, Uber, 3D printers, Instagram, Bitcoin then you will appreciate that a decade is a long time in tech.

Indeed, when you consider the pact of technological advancement and the theory that it is advancing exponentially, you can be sure that we will see changes just as dramatic, and perhaps more so, by the end of the 2020s.

Making tech predictions is, however, a good way to end up looking foolish. For instance, think about Microsoft CEO Steve Ballmer, who said in 2007, There is no chance that the iPhone is going to get any significant market share.

There are many ways to find out about your future and the direction you should take. But with technology, it can be explosive, with the changes feeling like they happen overnight. Below are some tech ideas which experts believe may be possible and commonplace by 2030:

Mass Use of Flying Jetpacks

Sick of the Memorial Day traffic in Cape Cod? Well, you can beat the rush by using your personal jet pack. YouTube is littered with inventors showing off their fabulous flying machines, but some serious engineers are getting behind the idea. In fact, the main issue is not the mechanics of flying, but the weight of fuel. Get that right, and the answer seems to lie with electricity, and you could be zipping around the Cape with no worries. Moreover, while we view the jetpack as a fun piece of science fiction, its use could have huge benefits for emergency services.

An AI Machine As Your Boss

It sounds like a nightmare dystopian future, but having a robot as your boss is not that far-fetched. A survey of tech and business experts in 2015 found that just under half (45.2%) predicted we would see an AI machine sitting on a board of directors of a corporation by 2025. The premise is that the machines can make wholly logical decisions, based on data analysis, that the human mind cant. While it may seem scary, experts maintain that AI is here to enhance our world, not replace us. We hope they are right.

Your CRISPR Children

CRISPR continuous regularly interspersed short palindromic repeats is really just a fancy name for gene editing. And, the advances in this area are set to cause a huge stir. We are perhaps not quite at the Jurassic Park level yet, but there will be able to do incredible things with it, not all of which will be considered ethical. For instance, it will be possible to edit the DNA sequences of your future children to give them desirable characteristics, just as it will be possible to create a pet lion the size of a house cat. You can see the sense in editing out a hereditary disease, but where do you draw the line?

Live Forever

Want to ensure that you are around for the Red Sox next World Series win should history repeat itself and the team receive another 86-year curse? Well, some very serious scientists believe the abolition of ageing is not that far off. Perhaps not widely available by 2030, although the theory will be firmed up by that time, but almost certainly by the middle of the century. Its a combination of DNA-editing and computers that hold the key, and youll probably get to house yourself within a sleek android body too.

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These Far-Flung Tech Concepts Could Be a Reality by 2030 - Cape Cod Today

CAMBRIDGE, Mass., Feb. 03, 2020 (GLOBE NEWSWIRE) -- TCR2 TherapeuticsInc. (Nasdaq: TCRR), a clinical-stage immunotherapy company developing the next generation of novel T cell therapies for patients suffering from cancer, today announced that it will present a poster at the 2020 Keystone Symposia Conference on Emerging Cellular Therapies: Cancer and Beyond, taking place February 8-10, 2020 in Banff, Canada. The presentation will highlight allogeneic (off-the-shelf) T Cell Receptor Fusion Constructs (TRuC) T cells. In addition to utilizing TCR2s proprietary TRuC-T cell platform, the approach employs CRISPR/Cas9 endonucleases yielding fully functional TRuCs that lack alloreactivity and upregulate activation markers, secrete cytokines and kill tumor cells in an antigen-specific manner.

Presentation details are as follows:Title: Engineering Off-the-Shelf T Cell Receptor Fusion Construct (TRuC) T CellsPoster: 2002Session Title: Q2: Engineering the GenomeSession Date/Time: 7:30pm - 10:00pm M.S.T.

About TCR2 Therapeutics

TCR2Therapeutics Inc.is a clinical-stage immunotherapy company developing the next generation of novel Tcell therapies for patients suffering from cancer.TCR2sproprietary T cell receptor (TCR) Fusion Construct Tcells (TRuC-T cells) specifically recognize and kill cancer cells by harnessing signaling from the entire TCR, independent ofhuman leukocyte antigens (HLA). In preclinical studies, TRuC-T cells have demonstrated superior anti-tumor activity compared to chimeric antigen receptor T cells (CAR-T cells), while exhibiting lower levels of cytokine release. The Companys lead TRuC-T cell product candidate, TC-210, is currently being studied in a Phase 1/2 clinical trial to treat patients with mesothelin-positive non-small cell lung cancer (NSCLC), ovarian cancer, malignant pleural/peritoneal mesothelioma, and cholangiocarcinoma. For more information about TCR2, please visitwww.tcr2.com.

Forward-looking Statements

This press release contains forward-looking statements and information within the meaning of the Private Securities Litigation Reform Act of 1995 and other federal securities laws. The use of words such as "may," "will," "could", "should," "expects," "intends," "plans," "anticipates," "believes," "estimates," "predicts," "projects," "seeks," "endeavor," "potential," "continue" or the negative of such words or other similar expressions can be used to identify forward-looking statements. These forward-looking statements include, but are not limited to, express or implied statements regarding the Companys TRuC-T cells, their potential characteristics, applications and clinical utility, and the potential therapeutic applications of the Companys TRuC-T cell platform.

The expressed or implied forward-looking statements included in this press release are only predictions and are subject to a number of risks, uncertainties and assumptions, including, without limitation: uncertainties inherent in clinical studies and in the availability and timing of data from ongoing clinical studies; whether interim results from a clinical trial will be predictive of the final results of the trial; whether results from preclinical studies or earlier clinical studies will be predictive of the results of future trials; the expected timing of submissions for regulatory approval or review by governmental authorities, including review under accelerated approval processes; orphan drug designation eligibility; regulatory approvals to conduct trials or to market products; TCR2s ability to maintain sufficient manufacturing capabilities to support its research, development and commercialization efforts, whether TCR2's cash resources will be sufficient to fund TCR2's foreseeable and unforeseeable operating expenses and capital expenditure requirements; and other risks set forth under the caption "Risk Factors" in TCR2s most recent Annual Report on Form 10-K, most recent Quarterly Report on Form 10-Q and its other filings with theSecurities and Exchange Commission. In light of these risks, uncertainties and assumptions, the forward-looking events and circumstances discussed in this press release may not occur and actual results could differ materially and adversely from those anticipated or implied in the forward-looking statements. You should not rely upon forward-looking statements as predictions of future events. Although TCR2believes that the expectations reflected in the forward-looking statements are reasonable, it cannot guarantee that the future results, levels of activity, performance or events and circumstances reflected in the forward-looking statements will be achieved or occur.

Moreover, except as required by law, neither TCR2nor any other person assumes responsibility for the accuracy and completeness of the forward-looking statements included in this press release. Any forward-looking statement included in this press release speaks only as of the date on which it was made. We undertake no obligation to publicly update or revise any forward-looking statement, whether as a result of new information, future events or otherwise, except as required by law.

Investor and Media Contact:

Carl MauchDirector, Investor Relations and Corporate Communications(617) 949-5667carl.mauch@tcr2.com

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TCR Therapeutics to Present an Allogeneic Construct at the Keystone Symposia Conference on Emerging Cellular Therapies: Cancer and Beyond - BioSpace

At dusk on January 24th I was walking along the side of the road. There was a lull in traffic and it was wonderfully quiet. Immersed in my own thoughts, this metallic buzzing chirp somehow entered my head.

At dusk on January 24th I was walking along the side of the road. There was a lull in traffic and it was wonderfully quiet. Immersed in my own thoughts, this metallic buzzing chirp somehow entered my head. It came from the open overgrown pasture behind trees. I paused and counted up to fifteen weird chirps before they ended. A minute or two later I heard a faint twittering chip chip whistling sound from high above descending to earth. Seconds later the whistling stopped. At ground level from the hidden field came subdued but excited bird talk. It quickly hushed.

I had just heard, not seen, the sky dance of the woodcock. The male puts on a spectacular courtship display to impress his lady. This guy tried to first catch her attention by issuing piercing peents, launched high into the sky before circling down chirping as wind whistled through his flight feathers, then apparently landed near her and had tried to strike up a conversation. Whats a timberdoodle like you doing in a place like this? He started to repeat the entire process again, but four widely spaced trucks drove past as darkness settled. By the time the noise had ceased, it was dark and still.

The woodcock (Scolopax minor) goes by many curious names: timberdoodle, big-eye, mudbat, bogsucker and night partridge. It is a shore bird that has come inland to live, like the Killdeer. The bird, about the size of a robin, is disguised in russets, browns and blacksnatural camouflage. These hardy birds have long thin bills since they like to slurp down earthworms. Woodcocks are part of the natural food chain, they themselves eaten by hawks, owls and other predators. Unfortunately, their populations are in decline as habitats are being destroyed. by us. Fields sprayed with herbicides and fertilizers to support cattle, tainted water sources and development (houses, roads) are all culprits.

The perfect lead-in to Gardening with the Experts held January 25th at Gordon Cooper Tech Center. The 22nd annual program was presented by the Shawnee Community Beautification Committee. Master Gardener Tom Terry introduced the first speaker, Dr. Yoon Kik Kim, bee savior of Urban Landscaping for Pollinators.

What affects honeybee populations? Small hive beetles make a gooey mess of honey and bees abandon their hive. Varroa mites, comparable to ticks, feed on bee body fat and cause deformed wings and disturbed immune systems. Genetically modified corn and soybean pollen often kill bees. The herbicide Glyphosate (we saw pictures of rats riddled with tumors) destroys the gut bacteria in bees and disrupts their navigation systems. Bees can travel up to three miles from their hive. Dr. Kim noted agricultural chemical researchers for Bayer test adult bees, not the eggs or grubs.

In the Dec/Jan 2020 issue of Mother Earth, Jonathan Lundgren said many pesticides dont kill bees outright, but affect genetics, hormones and microbial allies. Agriculture is reshaping biological communities too fast, and the honeybee is one of the casualties. Lundgren feels no approach will succeed unless agriculture itself is reformed. Healthy soils make healthy plants.

Beekeeper Kim knows all too well the ups and downs of the bee world. He lost most of his bees last year to small hive beetle.

Solutions: Diversify plants to scatter bloom times through spring, summer and fall. Maples bloom February and March, black locusts April to May, alfalfa and Vitex May to frost, white sweet clover April to July (yellow sweet clover later May to July), persimmons May to June, cotton July to frost and buckwheat late summer to frost (buckwheat honey is dark sweet axle grease ). Do not mow when plants are blooming and producing nectar. Dont create green deserts by mowing everything. Develop sustainable environmental laws in Shawnee. Healthy plants make healthy bees.

Gardening in a Box with Larry and Letitia Pierce is an easier way to garden. Benefits: no weeding, boxes are portable and the automatic watering system saves up to 70% in water usage. The gardening boxes seem to encourage robust plants. Larry demonstrated the basic layout of the gardening box. He revealed the false bottom, plastic shelf with two wicking holes, white water tube and overflow hole in side. A small box with float valve controlled the water level of boxes which are linked by tubes.

Leticia knows how important bees are to flowers and proclaimed she was a secret stalker of Dr. Kim! Beautiful color pictures were shown of the January 2019 pepper harvest, Bloody Butcher and Japonica corn, enormous tomato plants and huge cabbages.

The talk ended with this quote by Alice Walker (The Color Purple): In search of my mothers garden, I found my own. A sentiment shared by many. My mothers father always raised a garden. She loved azaleas and patio plants. I go for trees.

Dr. Qing Lana Luo spoke about Rain Gardens for Naturally Resilient Communities and Sustainability. For 17 years she was a park designer of public open spaces and is well qualified to discuss gardens that cleanse and encourage water to infiltrate into the soil. Rain gardens may be in-ground, raised beds, wet, dry, oval, round, free form, with or without curbs.

Rain gardens must have level basins with inflow and overflow components. They are designed to receive runoff from the roof or impervious surfaces and planted areas. Placement must be 10 feet away from a building or house foundation, 100 feet from a wellhead and not in an area with a high-water table.

So, how well does the soil drain? A percolation test can be easily done. Dig a hole 6 inches deep and 6 inches wide, fill with water and measure how fast it drains in 24 hours. Excellent time is 1-6 hours. Passable is from 6-16 hours, but if it takes over 24 hours, find another spot.

Rain gardens act as sponges that mitigate the soil. In a natural system there is 10% runoff and 50% infiltration. Urbanized areas have 55% surface runoff and only 15% infiltration. Rain gardens are important in sustainable stormwater management since they reduce flooding and improve water quality. OSU Fact Sheet HLA-6454 Sustainable Landscapes: Designing a Rain Garden for Residential Property gives the whys, how-to-dos and right plants for the job.

The program finished on a high note. Twenty-four cool gardening ideas had been submitted by attendees. Top tips:

For simple plant food, save the veggie water from lunch or supper (no salt please) and put on plants or garden.

To prevent mosquitoes, add some drops of veggie oil to your birdbath or rain barrel. It will form a protective film over the surface of water. Oil floats.

For the physically impaired gardener who wants to extend or make a new plant bed, consider the Lasagna Garden. Begin with cardboard over grass, cover with leaves, compost, more leaves, aged manure and topsoil.

Some amazing door prizes were given away. The seed swap ended the informative morning. National Seed Swap Day is always the last Saturday in January.

Bee gardens, box gardens, rain gardens. Landscape with nature in mind. Choose one or all three. Spring is coming, so twitters the timberdoodle.

Becky Emerson Carlberg, graduate of Oklahoma State (Plant Pathology) is a teacher, artist, writer as well as certified Oklahoma Master Gardener and Master Naturalist. Contact her at Becscience@att.net.

Originally posted here:
Gardens of the Cross Timbers: Bee, box and rain gardens - Miami News Record

San Diegos first zoo elephants arrived by train in 1923, from San Francisco.

Queenie and Empress walked off a special railroad car and refused to budge. Harry Wegeforth, the zoos founder and a legendary quick-thinker he sometimes stopped his car to snatch wild animals for the collection tried another approach.

Suspecting that the elephants were used to being ridden, he climbed on one, another zoo employee got on the other, and off they went, clomping up Fourth Street, across the Cabrillo Bridge, and onto the zoo grounds in Balboa Park. People stopped what they were doing and stared.

Almost a century later, the worlds largest land mammals still make jaws drop. But nobody rides them to the zoo any more. Many things about their handling and care have changed as the zoo and its sister site, the Safari Park, became leaders in an industry that draws 180 million visitors annually and increasingly prides itself on conservation, not just entertainment.

Much remains unknown about elephants, too witness the death in December at the zoo of 48-year-old Tembo. A sudden change in the African pachyderms condition prompted keepers to euthanize her, according to zoo officials. They said shed been under veterinary care for age-related ailments for a while. Results of a necropsy are pending.

Tembo

(Ken Bohn / San Diego Zoo Global)

Her death came four weeks after another African elephant, MDunda, collapsed and died at the Oakland Zoo. She was 50 and had shown no signs of existing medical issues, albeit her advanced age, the zoo said. A necropsy is under way there, too.

Elephants also die in the wild, of course, and often violently. But their passing in zoos raises thorny questions about what is gained by keeping them captive.

A 2012 investigation by The Seattle Times analyzed the deaths of 321 elephants at accredited zoos in the U.S. over the previous 50 years and found that most died from injury or disease linked to conditions of their captivity. Half of the elephants were dead by the age of 23, well below their expected life spans, according to the report.

The decades-long effort by zoos to preserve and protect elephants is failing, exacerbated by substandard conditions and denial of mounting scientific evidence that most elephants do not thrive in captivity, the newspaper concluded.

The difficulties and cost of keeping elephants healthy, coupled with persistent pressure from animal activists and other critics, have prompted more than 30 North American zoos to shut down their elephant exhibits since the early 1990s, including sites in Detroit, San Francisco, Toronto and other major cities. But zoos in Milwaukee and Atlanta have gone in the other direction, expanding their elephant exhibits or building new ones.

San Diego Zoo Global, the umbrella organization for the zoo and the Safari Park in Escondido, maintains one of the largest herds of elephants outside their natural ranges. The zoos Elephant Odyssey, designed for older animals, has three ages 40, 43, and 56. There are nine at the Safari Parks Elephant Valley, ranging from age 1 to 30.

Behind the scenes, keepers and scientists are studying the animals behaviors and biology in ways they believe have improved the care there and may help sustain populations in Asia, where elephants are considered endangered, and in Africa, where they are threatened. They point to the unusual breeding success of the elephants at the Safari Park so productive that five of them were sent to a zoo in Tucson, Ariz., in 2012 to start a satellite herd. A baby was born there two years later, and the mother is pregnant again.

Such is the nature of the ongoing controversy about elephants in captivity that San Diego Zoo Global has been both praised and scorned for its breeding program. The Association of Zoos and Aquariums gave it an award in 2014 for a truly significant captive propagation effort that clearly enhances the management of the species. Last month, the activist group In Defense of Animals, citing a lack of adequate space and social structures for more babies, placed the Safari Park on its annual list of the Ten Worst Zoos for Elephants.

Krissy Boeche, senior elephant keeper at the San Diego Zoo Safari Park takes a blood sample from Neepo, an eight-year-old African elephant during a physical exam on January 22, 2020.

(Howard Lipin / The San Diego Union-Tribune)

On a recent weekday afternoon in a back corner of the elephant exhibit at the Safari Park, senior keeper Krissy Boeche called Neepo over for a health check.

Hes an 8-year-old African elephant. Like the others, hes been painstakingly trained (with food as the reward) to stand next to metal bars and present various body parts for inspection: feet, trunk, teeth, ears.

On this day, Boeche also drew blood from one of Neepos ears for a new project aimed at better understanding a herpes virus that kills elephants. For a long time, experts believed the EEHV virus was a problem mostly for Asian elephants, but an outbreak last year at the Indianapolis Zoo changed that. Two African elephants, one 6 years old and the other 8, died within weeks of each other.

We realized theres a lot we dont know, said Dr. Lauren Howard, a zoo veterinarian. This is a chance to learn more.

The virus circulates in the Safari Park herd, a normal occurrence. But why does it become active in some elephants and not in others? Regular blood draws and other tests over the next year will help establish baselines, identify risk factors and point the way toward evidence-based care recommendations, Howard said.

Were trying to build up confidence in what we find, not just in one elephant, but the whole herd, Howard said. We want to be able to tell colleagues in the elephant-care community: This is the way you can monitor or manage your elephants to reduce and prevent death from herpes virus.

Zoo workers are also looking for ways to find the virus that might help managers in the wild. Being able to do a blood-draw from an elephant there is difficult, if not impossible, and its dangerous. Can the virus be evaluated instead in saliva or feces, both easier to collect?

Neepo was born at the Safari Park, as were five other current occupants there. In general, zoo managers see births as evidence that animals are thriving.

Mindy Albright, the lead elephant keeper, said newborns also provide opportunities to record various developmental milestones information that can help managers in the wild figure out how old certain elephants are and whether they are healthy. Another study of elephant milk at the park may lead to improvements in formula given to orphaned elephants in Africa.

Umzula-zuli was the San Diego Zoo Safari Parks 13th elephant was born August 13, 2018, which coincidentally is World Elephant Day. The male calf African elephant walking next to his mother, Ndlulamitsi.

(Nelvin C. Cepeda / The San Diego Union-Tribune)

Its exciting that things we do here go back to help elephants in the wild, she said.

Critics like Ed Stewart, co-founder of Performing Animal Welfare Society or PAWS think the money and effort would be better spent preserving and restoring wild habitats, beyond what SD Zoo Global, considered a leader in conservation, is already doing.

Thats the problem we need to solve, he said. The only way to save elephants is to save their habitat. And thats not the work of zoologists. Thats the work of politicians, land-use attorneys, economists.

His group operates three sanctuaries in Northern California, including a 2,300-acre one that houses eight elephants sent there from zoos and circuses. Even at our place, and we have more space than anywhere else, we cant match what the elephants need, he said. Theres no state of the art way to keep elephants in captivity.

He said laudable research is being done on elephants in San Diego, but he questioned the validity of captive breeding.

In some cases, such as the California condor, captive breeding followed by reintroduction to the wild has been credited with saving a species from extinction. But nobody has taken a captive-born elephant and turned it loose in nature, Stewart said, so the main reason zoos breed them is to maintain populations for public display. Entrance fees fund the zoos, and elephants have long been popular with customers. Cute newborns trigger spikes in attendance.

I dont look at a baby elephant standing behind a fence as a success, he said. I think the public thinks if you can breed elephants, theres nothing to worry about. But youre creating animals that will just grow up in captivity and live in a deprived situation. Theres no other way to put it.

Zoo keepers would disagree with the deprived part. Albright said elephants in captivity dont have to scrounge for food or water. Poachers, climate change, fatal interactions with humans moving into previously undeveloped territory life in the wild is no picnic, either.

These guys, she said, nodding at the parks herd, get to relax.

Khosi, a thee-year-old African elephant opens her mouth so Peter Hagopian, an elephant keeper at the San Diego Zoo Safari Park , can get a look at her teeth during a physical exam on January 22, 2020.

(Howard Lipin / The San Diego Union-Tribune)

When the group In Defense of Animals released its yearly Ten Worst Zoos list on Jan. 23, it criticized San Diego Zoo Global for breaking the social bonds between elephants at the Safari Park by moving several to other sites in 2019. Two males were sent to a zoo in Texas, two others to one in Alabama. A fifth elephant went to Zoo Atlanta.

Zoos regularly attempt to justify moves like these by pointing out that wild male elephants leave their families at about age 13, said Laura Bridgeman, director of In Defense of Animals elephant campaign. However, in nature, young males separate gradually from their families they are not suddenly ripped away from them to be transported across the country.

The San Rafael-based group has been compiling the list for 16 years, and the one other time San Diego made it, in 2006, was for moving elephants, too. That came after seven African elephants were brought to the park from Swaziland, where managers said the animals risked being killed because of space constraints in the tiny countrys nature preserves. To make room for the arrivals, the Safari Park sent three of its elephants to the Lincoln Park Zoo in Chicago. All were dead within two years.

Zoo officials have not publicly responded to In Defense of Animals, but the industry moves animals around for a variety of reasons, including breeding and herd compatibility, and its rarely done hastily. The Association of Zoos and Aquariums has a Species Survival Plan that tracks the age, health, genetics and other factors of the roughly 300 elephants currently kept at about 65 accredited zoos in the U.S. The plan guides when and where elephants are moved.

Ongoing research at zoos into nutrition, physiology and reproduction also plays a role in transfers, according to the association.

While the debate about moving elephants around continues, zoos routinely point to another reason for keeping the animals in captivity. One of our main efforts is to inspire all our guests to care about wildlife, Robert Wiese, chief life sciences officer for San Diego Zoo Global, told the Union-Tribune in a 2016 interview. Getting up close to an elephant or feeling a bird swoop over us or seeing a bizarre insect those are opportunities to transform someone so when they go home and hear about wildlife issues they can be ready to act.

The potential audience is huge. According to industry estimates, more people go to zoos and aquariums in the U.S. than attend professional baseball, football, basketball and hockey games combined. A 2018 book, The Ark and Beyond: The Evolution of Zoo and Aquarium Conservation, notes that annual visitors to zoos, aquariums, botanical gardens, nature centers and natural history museums make up a tenth of the people on the planet.

But whether they are motivated to help animals later is an open question. Research has been mixed.

People go to the zoo to laugh, eat popcorn and watch their kids run around, said Lisa Landres, a former elephant keeper at the San Diego Zoo. The amount of people enjoying animals for what they are you could count on one hand.

Landres was a key whistleblower in a notorious elephant-mistreatment incident at the Safari Park (then called the Wild Animal Park) in 1988, which involved trainers disciplining an elephant by hitting her on the head repeatedly with wooden sticks. Landres later became an investigator for the Humane Society of the United States, traveling around the country for more than 10 years to inspect zoos and circuses. What she saw, she said, prompted her to leave that world.

We cant give elephants what they need in captivity, she said. We just cant. A few enlightened zoos have come to the conclusion that if we cant do it properly, we shouldnt do it at all. But too many others just care about the money they can make, the bottom line.

Shed like to see a day when people visit hologram zoos and there are no elephants in captivity. If you want to see one in the flesh, you have to go where they live, she said.

Her wish may come true. In North American zoos as a whole, the populations of Asian and African elephants are not self-sustaining. Previously productive elephants are getting too old to have babies, and there arent yet enough young ones to fill the gap.

But some zoos are more optimistic than others. At the Safari Park, plans are under way to build a new viewing area that will bring visitors closer to the elephant herd.

Read this article:
The elephant in the room: Are zoos suitable homes for the world's largest land mammals? - The San Diego Union-Tribune

Non-profit organisation The Kennel Club and supplier Weatherbys has launched its CombiBreed health tests packages for eight new breeds.

The tests have been created to provide a simplified process for canine genetic health testing for the benefit of both dog breeders and owners, and help to eradicate some of the most concerning genetic disorders facing certain breeds.

The tests are now available for breeds such as Giant Schnauzer, Irish Setter, Jack Russell Terrier, Parson Russell Terrier, Shetland Sheepdog, Spanish Water Dog, Standard Poodle and the Tibetan Terrier.

CombiBreed health tests packages simplify the process of genetic testing by using a single cheek swab to check a dogs DNA for markers associated with a number of different inherited disorders.

The company says by making genetic testing more accessible it will help responsible breeders work towards eradicating these conditions and will encourage first time breeders to make the health of the puppies they breed a priority.

Results from these tests will automatically be registered on the dogs record, and will be freely available on the Kennel Club website, allowing puppy buyers to check if the dog they are thinking of buying has come from health-tested parents

The packages are already available for breeds including: Labrador Retriever, French Bulldog, Cocker Spaniel, English Springer Spaniel, Golden Retriever, German Shepherd, Staffordshire Bull Terrier, Cavalier King Charles Spaniel, Beagle, Border Collie, Chinese Crested and the Australian Shepherd.

Read more:
The Kennel Club and Weatherbys launch CombiBreed all-in-one tests - Pet Gazette

At left, image shows white blood cells (red) from one of the X-CGD clinical trial participants before gene therapy. At right, after gene therapy, white blood cells from the same patient show the presence of the chemicals (blue) needed to attack and destroy bacteria and fungus.

UCLA Broad Stem Cell Research Center/Nature Medicine

University of California - Los Angeles (UCLA) researchers are part of an international team that reported the use of a stem cell gene therapy to treat nine people with the rare, inherited blood disease known as X-linked chronic granulomatous disease, or X-CGD. Six of those patients are now in remission and have stopped other treatments. Before now, people with X-CGDwhich causes recurrent infections, prolonged hospitalizations for treatment, and a shortened lifespanhad to rely on bone marrow donations for a chance at remission.

"With this gene therapy, you can use a patient's own stem cells instead of donor cells for a transplant," said Dr. Donald Kohn, a member of the Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research at UCLA and a senior author of the new paper, published Jan. 28 in the journal Nature Medicine. "This means the cells are perfectly matched to the patient and it should be a much safer transplant, without the risks of rejection."

People with chronic granulomatous disease, or CGD, have a genetic mutation in one of five genes that help white blood cells attack and destroy bacteria and fungus using a burst of chemicals. Without this defensive chemical burst, patients with the disease are much more susceptible to infections than most people. The infections can be severe to life-threatening, including infections of the skin or bone and abscesses in organs such as lungs, liver or brain. The most common form of CGD is a subtype called X-CGD, which affects only males and is caused by a mutation in a gene found on the X-chromosome.

Other than treating infections as they occur and taking rotating courses of preventive antibiotics, the only treatment option for people with CGD is to receive a bone marrow transplant from a healthy matched donor. Bone marrow contains stem cells called hematopoietic, or blood-forming, stem cells, which produce white blood cells. Bone marrow from a healthy donor can produce functioning white blood cells that effectively ward off infection. But it can be difficult to identify a healthy matched bone marrow donor and the recovery from the transplant can have complications such as graft versus host disease, and risks of infection and transplant rejection.

"Patients can certainly get better with these bone marrow transplants, but it requires finding a matched donor and even with a match, there are risks," Kohn said. Patients must take anti-rejection drugs for six to 12 months so that their bodies don't attack the foreign bone marrow.

In the new approach, Kohn teamed up with collaborators at the United Kingdom's National Health Service, France-based Genethon, the U.S. National Institute of Allergy and Infectious Diseases at the National Institutes of Health, and Boston Children's Hospital. The researchers removed hematopoietic stem cells from X-CGD patients and modified the cells in the laboratory to correct the genetic mutation. Then, the patients' own genetically modified stem cellsnow healthy and able to produce white blood cells that can make the immune-boosting burst of chemicalswere transplanted back into their own bodies. While the approach is new in X-CGD, Kohn previously pioneered a similar stem cell gene therapy to effectively cure a form of severe combined immune deficiency (also known as bubble baby disease) in more than 50 babies.

The viral delivery system for the X-CGD gene therapy was developed and fine-tuned by professor Adrian Thrasher's team at Great Ormond Street Hospital, or GOSH, in London, who collaborated with Kohn. The patients ranged in age from 2 to 27 years old; four were treated at GOSH and five were treated in the US, including one patient at UCLA Health.

Two people in the new study died within three months of receiving the treatment due to severe infections that they had already been battling before gene therapy. The seven surviving patients were followed for 12 to 36 months after receiving the stem cell gene therapy. All remained free of new CGD-related infections, and six of the seven have been able to discontinue their usual preventive antibiotics.

"None of the patients had complications that you might normally see from donor cells and the results were as good as you'd get from a donor transplantor better," Kohn said.

An additional four patients have been treated since the new paper was written; all are currently free of new CGD-related infections and no complications have arisen.

Orchard Therapeutics, a biotechnology company of which Kohn is a scientific co-founder, acquired the rights to the X-CGD investigational gene therapy from Genethon. Orchard will work with regulators in the US and Europe to carry out a larger clinical trial to further study this innovative treatment. The aim is to apply for regulatory approval to make the treatment commercially available, Kohn said.

Kohn and his colleagues plan to develop similar treatments for the other forms of CGDcaused by four other genetic mutations that affect the same immune function as X-CGD.

"Beyond CGD, there are also other diseases caused by proteins missing in white blood cells that could be treated in similar ways," Kohn said.

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6 Patients with Rare Blood Disease Doing Well after Gene Therapy Clinical Trial - Lab Manager Magazine

DUBLIN, Jan. 30, 2020 /PRNewswire/ -- The "Gene Therapy Market by Vectors [Non-viral (Oligonucleotides), Viral (Retroviral (Gammaretroviral, Lentiviral)), Adeno-associated], Indication (Cancer, Neurological Diseases), Delivery Method (In Vivo, Ex Vivo), Region - Global Forecast to 2024" report has been added to ResearchAndMarkets.com's offering.

The global gene therapy market is projected to reach USD 13,005.6 million by 2024 from an estimated USD 3,814.9 million in 2019, at a CAGR of 27.8% during the forecast period.

This report provides a detailed picture of the global gene therapy market. It aims at estimating the size and future growth potential of the market across different segments (by vector, indication, delivery method, and region). The report also includes an in-depth competitive analysis of the key market players, along with their company profiles, recent developments, and key market strategies.

High incidence of cancer & other target diseases is a major factor driving the growth of the gene therapy market

The high incidence of cancer and other target diseases, availability of reimbursement, and the launch of new products are the major factors driving the growth of this market. In addition, the strong product pipeline of market players is expected to offer significant growth opportunities in the coming years. However, the high cost of treatment is expected to hamper the market growth to a certain extent in the coming years.

Neurological diseases segment accounted for the largest share of the gene therapy market, by indication, in 2018

Based on indication, the market is segmented into neurological diseases, cancer, hepatological diseases, Duchenne muscular dystrophy, and other indications. The neurological diseases segment accounted for the largest share of the market in 2018. This can be attributed to the increasing number of gene therapy products being approved for the treatment of neurological diseases and the high market penetration of oligonucleotide-based gene therapies.

Viral vectors segment to register the highest growth in the gene therapy market during the forecast period

The gene therapy market, by vector, has been segmented into viral and non-viral vectors. In 2018, the non-viral vectors segment accounted for the largest share of this market. However, the viral vectors segment is estimated to grow at the highest CAGR during the forecast period, primarily due to the increasing demand for CAR T-based gene therapies and the rising incidence of cancer.

North America will continue to dominate the gene therapy market during the forecast period

Geographically, the market is segmented into North America, Europe, the Asia Pacific, and the Rest of the World. In 2018, North America accounted for the largest share of the gene therapy market, followed by Europe. Factors such as the rising prevalence of chronic diseases, high healthcare expenditure, presence of advanced healthcare infrastructure, favorable reimbursement scenario, and the presence of major market players in the region are driving market growth in North America.

Key Topics Covered

1 Introduction

2 Research Methodology 2.1 Research Data2.2 Secondary Data2.2.1 Secondary Source2.3 Primary Data2.4 Market Size Estimation2.4.1 Bottom-Up Approach2.4.2 Bottom-Up Approach for Non-Viral Vectors and Viral Vectors Market2.4.3 Growth Forecast2.5 Market Breakdown and Data Triangulation2.6 Assumptions for the Study

3 Executive Summary

4 Premium Insights 4.1 Gene Therapy Market Overview4.2 North America: Market, By Vector (2018)4.3 Geographical Snapshot of the Market

5 Market Overview 5.1 Introduction5.2 Market Dynamics5.2.1 Drivers5.2.1.1 High Incidence of Cancer and Other Target Diseases5.2.1.2 Product Approvals5.2.1.3 Funding for Gene Therapy Research5.2.2 Opportunities5.2.2.1 Strong Product Pipeline5.2.3 Challenges5.2.3.1 High Cost of Treatments

6 Gene Therapy Market, By Vector 6.1 Introduction6.2 Non-Viral Vectors6.2.1 Oligonucleotides6.2.1.1 North America Accounted for the Largest Share of the Oligonucleotides Segment6.2.2 Other Non-Viral Vectors6.3 Viral Vectors6.3.1 Retroviral Vectors6.3.1.1 Gamma-Retroviral Vectors6.3.1.1.1 The Availability of A Wide Range of Gamma-Retroviral Vectors Supports the Growth of This Market6.3.1.2 Lentiviral Vectors6.3.1.2.1 North America Accounted for the Largest Share of the Lentiviral Vectors Segment6.3.2 Adeno-Associated Virus Vectors6.3.2.1 Possible Applications in In Vivo Applications Have Driven Interest in Adeno-Associated Virus Vectors6.3.3 Other Viral Vectors

7 Gene Therapy Market, By Indication 7.1 Introduction7.2 Neurological Diseases7.2.1 Neurological Diseases Account for the Largest Share of the Market7.3 Cancer7.3.1 Cancer is Expected to Show the Highest Growth in This Market7.4 Hepatological Diseases7.4.1 Increasing Prevalence of Hepatitis B Infections Will Support Market Growth7.5 Duchenne Muscular Dystrophy7.5.1 North America Accounted for the Largest Share of the Dmd Gene Therapy Segment7.6 Other Indications

8 Gene Therapy Market, By Delivery Method 8.1 Introduction8.2 In Vivo Gene Therapy8.3 Ex Vivo Gene Therapy

9 Gene Therapy Market, By Region 9.1 Introduction9.2 North America9.2.1 US9.2.1.1 The US Dominates the Global Market9.2.2 Canada9.2.2.1 Growing Burden of Cancer Will Support Market Growth in Canada9.3 Europe9.3.1 Germany9.3.1.1 Germany Accounted for the Largest Share of the Market in Europe9.3.2 France9.3.2.1 Increasing Cancer Incidence Supports Market Growth9.3.3 UK9.3.3.1 Rising Incidence of Melanoma Will Drive Demand in the UK9.3.4 Italy9.3.4.1 High Incidence of Targeted Diseases and Increasing Per Capita Healthcare Spending Will Drive Market Growth in Italy9.3.5 Spain9.3.5.1 Non-Viral Vectors Dominate the Spanish Market, By Vector9.3.6 Rest of Europe9.4 Asia Pacific9.4.1 Japan9.4.1.1 Japan Dominates the APAC Market for Gene Therapy9.4.2 China9.4.2.1 Rising Prevalence of Cancer and Established Base for Gene Therapy are Supportive Factors in China9.4.3 Rest of APAC9.5 Rest of the World

10 Competitive Landscape 10.1 Overview10.2 Market Share Analysis, 201810.3 Key Strategies10.4 Competitive Leadership Mapping (2018)10.4.1 Visionary Leaders10.4.2 Innovators10.4.3 Dynamic Differentiators10.4.4 Emerging Companies

11 Company Profiles 11.1 Biogen11.2 Gilead Sciences, Inc.11.3 Amgen, Inc.11.4 Novartis AG11.5 Orchard Therapeutics PLC11.6 Spark Therapeutics, Inc. (A Part of Hoffmann-La Roche)11.7 Molmed S.p.A.11.8 Anges, Inc.11.9 Bluebird Bio, Inc.11.10 Human Stem Cells Institute (HSCI)11.11 SIBIONO Genetech Co. Ltd.11.12 Shanghai Sunway Biotech Co. Ltd.11.13 Uniqure N.V.11.14 Gensight Biologics S.A.11.15 Celgene Corporation (A Bristol-Myers Squibb Company)11.16 Cellectis11.17 Sangamo Therapeutics11.18 Mustang Bio11.19 AGTC (Applied Genetic Technologies Corporation)11.20 Poseida Therapeutics, Inc.

For more information about this report visit https://www.researchandmarkets.com/r/h6pehn

Research and Markets also offers Custom Research services providing focused, comprehensive and tailored research.

Media Contact:

Research and Markets Laura Wood, Senior Manager press@researchandmarkets.com

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View original content:http://www.prnewswire.com/news-releases/global-gene-therapy-industry-outlook-2020-2024---strong-product-pipeline-gives-rise-to-lucrative-growth-opportunities-300996293.html

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Global Gene Therapy Industry Outlook 2020-2024 - Strong Product Pipeline Gives Rise to Lucrative Growth Opportunities - P&T Community

After decades of clinical research targeting development of more personalised medicines, the biotechnology sector is now starting to deliver with the first generation of promising new cell and gene therapies.

Whether the optimism about the impact of these therapies plays out as expected or not, advances in this area of research are also having a significant effect on the pace of deal-making in the life sciences sector.

As many investigational cell and gene therapies continue to advance and demonstrate their clinical and commercial potential, companies including smaller biotechnology firms and larger pharmaceutical companies are positioning themselves for opportunities to acquire assets or develop collaborative relationships to take advantage of these new technologies.

Given that development of cell and gene therapies is still in its nascent stages and uncertainties remain about their long-term potential, some industry insiders have questions about the risks involved and how financial deals related to these drugs should be structured.

To better understand deal-making trends related to cell and gene therapies, we conducted an analysis of recent activity in the sector.

We reviewed more than 30 mergers, acquisitions, and licensing agreements executed between 2016-2019 and compared them to deals that were executed for the previous generation of breakthrough therapies, including monoclonal antibodies (mAbs).

In this analysis, we considered a range of factors including the size of the companies involved, target indications, deal structures, terms such as upfront payments and royalties, and the number and clinical stage of assets included in each deal.

One key difference in cell and gene therapy deals is that companies prefer to target partnerships and licensing deals. This shift may be a reflection of the unique challenges in development of these drugs

The review shows that overall the pace of deal-making in cell and gene therapy is faster and occurring much earlier in the drug development process compared to deals seen in the past.

More deals and earlier deals

The pace of deals in the cell and gene therapy sector has been building in momentum since the first of these drugs received regulatory approval nearly a decade ago. From 2010-2016 alone, pharmaceutical companies executed more than 50 partnerships and investments to access cell and gene therapies.[1]

Larger companies have often been involved in these deals from the beginning. In 2010, Novartis established a partnership deal with GenVec worth potentially $213M (excluding royalties) for development of adenovirus-based gene therapies. That same year Novartis also formed a strategic alliance with GlaxoSmithKline and the Telethon Institute of Gene Therapy (TIGET) to pursue additional gene therapy research and development.

Unlike deals made decades ago related to mAbs, larger pharmaceutical companies are not waiting for the cell and gene therapy sector to become well established before pursuing partnerships or M&A deals.

With mAbs, financial deals were often characterised by the acquisitions of late-stage and marketed products, significantly reducing levels of risk. Conversely, acquisitions and other deals in the cell and gene therapy space often include entire product pipelines, platform technologies, and manufacturing capabilities with the potential to deliver significant clinical value and commercial potential.

Source: CRA analysis

With growing eagerness to buy into the cell and gene therapy market, the fact that companies are targeting these drugs earlier in the development cycle is also driving them to consider innovative deal structures to reduce risk.

One key difference with respect to cell and gene therapy deals is that most companies prefer to target partnerships and licensing deals rather than mergers or acquisitions, which were more commonly associated with mAbs. This shift may be based in part on the lack of long-term safety and efficacy data associated with many cell and gene therapies, but it also may be a reflection of the unique challenges in development of these drugs.

Despite the risks and unknowns, interest in the sector continues to grow dramatically. Pfizers first move into cell and gene therapy, for example, was through a collaboration with Spark Therapeutics regarding clinical development and potential commercialization of its Phase 1/2 gene therapy for treatment of hemophilia B.

Subsequently, Pfizer further expanded its cell and gene therapy portfolio by acquiring Bamboo Therapeutics in 2016, which provided a Phase 1 product and several preclinical stage assets, and by partnering with Vivet Therapeutics in early 2019 on development of a Phase 1/2 drug for treatment of a rare liver disease. The deal with Bamboo Therapeutics is a good example of a company structuring a deal to gain access to several different products or platforms rather than only one asset, which was often the case with mAbs.

Transforming the M&A and licensing landscape

While it took more than 20 years for collaborative activity around mAbs to generate significant interest from Big Pharma and lead to billion-dollar deals, the cell and gene therapy sector has reached this level of activity in less than 10 years.

This may be driven by the claims that these drugs represent innovative platforms and approaches for treatment of many conditions, including rare diseases. As research advances, industry partners recognise the potential for these drugs to represent major standard of care advances in areas where effective treatments are limited, sub-optimal, or non-existent.

As the discovery of promising new cell and gene therapies continues to expand, the emphasis on collaboration and innovative structuring in licensing, partnering, and M&A arrangements is expected to grow rapidly. It will be increasingly essential for participants in early-stage deals to have the expertise and insight necessary to conduct a thorough assessment of the risks and potential benefits of each option in structuring a deal. By working to understand and address any issues, they can better protect their interests over the long term. Companies that do not develop this capability to assess deals quickly and precisely risk being left behind.

About the authors

Lev Gerlovin is a vice president in the Life Sciences Practice at CRA. He has more than 12 years of experience in life sciences strategy consulting, focused on commercial and market access strategies.

Pascale Diesel previously served as a vice president in the Life Sciences Practice at CRA from July 2017 through December 2019. Dr Diesel has worked in global development, marketing, planning, and business development and has more than a decade of strategic consulting experience focusing on portfolio optimisation and valuation.

The views expressed herein are the authors and not those of Charles River Associates (CRA) or any of the organisations with which the authors are affiliated.

[1] Kong X., Wan J., Hu H., Su S., Hu, Y., Evolving patterns in a collaboration network of global R&D on monoclonal antibodies, mABs, 2017, 9,7, 1041-1051.

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How cell and gene therapies are transforming pharma deal-making - - pharmaphorum

It's easy to grasp how Vertex Pharmaceuticals (NASDAQ:VRTX) got to where it is today. A decade ago, the biotech's market cap hovered around $8 billion. Vertex's lead pipeline candidate was hepatitis C virus (HCV) drugtelaprevir, which went on to win FDA approval in 2011. The drug was marketed under the brand name Incivek -- but only briefly. Vertex quit selling the HCV drug in 2014 because Gilead Sciences'HCV franchise was dominating the market.

However, Vertex had another program in development targeting cystic fibrosis (CF). Its first CF drug, Kalydeco, won FDA approval in 2012. The rest is history. Vertex went on to gain FDA approvals for three other CF drugs. It's now highly profitable with annual revenue approaching $4 billion. And its stock has skyrocketed more than 500% over the last 10 years.

Trying to predict where Vertex will be 10 years from now isn't as easy. But there are some clues from the present that point to the prospects for another highly successful decade for the biotech.

Image source: Getty Images.

The safest prediction of all for Vertex is that it will remain a juggernaut in CF in 2030. Vertex won FDA approval for its most powerful CF drug yet -- Trikafta -- in October 2019. European approval for the drug is likely on the way this year.

Vertex expects that Trikafta will expand the addressable patient population for its CF therapies by more than 50%. The company also has three other CF drugs in its pipeline, including two programs that, like Trikafta, are triple-drug combos.

Currently, there are no other approved drugs that treat the underlying cause of CF. AbbVie is evaluating a triple-drug CF combo that it picked up from Galapagosin a phase 1 clinical study, but it's way behind Vertex. Even if AbbVie's drug proves to be successful, it would at best be several years before the drug could win approval. By that time, Vertex will already have further entrenched itself in the CF market.

Although the patents for Kalydeco, Orkambi, and Symdeko will expire near the end of the decade, Vertex's patents for Trikafta won't expire until 2037. The company could face generic rivals for its older CF drugs, but there's no reason to expect that Vertex's CF franchise won't still be racking up huge sales.

Vertex doesn't plan on being a one-indication company 10 years from now, though. The biotech has been busy expanding its pipeline and advancing the most promising programs.

The most likely addition to Vertex's lineup in 2030 will be a pain medication. Vertex has already completed phase 2 clinical studies for experimental pain drug VX-150. Chief Medical Officer and soon-to-be CEO ReshmaKewalramanisaid in Vertex's Q3 conference call in October that the company is "advancing multiple selective NaV1.8 inhibitors through late-stage research and early clinical development."

I think that Vertex and its partner CRISPR Therapeutics also have a good chance of launching a few years from now a gene-editing therapy that effectively cures rare blood disorders beta-thalassemia and sickle cell disease. The two companies are currently evaluating gene-editing therapy CTX001 in phase 1/2 studies targeting both indications and have reported encouraging preliminary results.

Another indication that could be a big winner for Vertex by the end of this decade is alpha-1 antitrypsin deficiency (AATD). Like CF, AATD is a rare genetic disease caused by misfolding proteins. Vertex has two experimental AATD drugs in early stage testing. My hunch is that the company's CF expertise combined with the similarity between AATD and CF could boost the odds of success for this program.

Vertex also has an early stage program targeting APOL-1 mediated kidney diseases. The biotech hopes to advance a drug to phase 2 testing this year. If all goes well, this could be yet another new arena for Vertex to dominate by the end of the decade.

Then there's the huge potential game-changer. Vertex acquired privately held Semma Therapeutics for $950 million last year. Semma is developing a drug that could cure type 1 diabetes.

Semma's approach is to turnpluripotent stem cells into islets that produce insulin in the needed amounts to keep blood sugar levels in check. This program is in its very early innings right now. So far, Semma has conducted promising lab tests but hasn't initiated any clinical studies in humans.

Curing type 1 diabetes presents an enormous opportunity for Vertex. Over 1.5 million people have type 1 diabetes in the U.S. alone. Vertex has had its eye on several companies in recent years that have made progress in addressing issues related to islet transplantation to treat type 1 diabetes. The big biotech thinks that Semma has a solution and is confident enough about its prospects to write a really big check to acquire the small drugmaker.

Will Vertex really have successful drugs on the market that target five or more rare genetic diseases in addition to more common indications like pain and type 1 diabetes 10 years from now? There's no way to know for sure. Many promising early stage programs fail along the way.

However, there are some things we can be certain about with Vertex. It claims a commanding lead in CF. It has the expertise needed to develop therapies targeting other rare genetic diseases. It has plenty of money to continue investing in research and development and acquisitions. And it has multiple shots on goal. Not all of them have to pan out for Vertex to win.

My view is that Vertex is the best biotech stock on the market right now. I think that it's future looks really bright.

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Where Will Vertex Pharmaceuticals Be in 10 Years? - Motley Fool

Washington: A recent study has linked a variety of blood cancers to a dangerous gene mutation that triggers a chain of biological events that hinders the pathway through which DNA sends instructions to the rest of a cell.

This phenomenon has been revealed through research carried out by biologists at Cold Spring Harbor Laboratory (CSHL) in collaboration with an oncologist at Memorial Sloan Kettering Cancer Center (MSKCC).

The deadly chain of events begins with RNA splicing, a process that converts messages from DNA into instructions for making proteins in a cell. Errors in RNA splicing can result in poorly formed proteins that are unable to do their job.

The CSHL-MSKCC team found that in blood cancers, a process associated with splicing called Nonsense-mediated mRNA decay (NMD) is excessively active. After splicing converts DNA messages, the NMD process normally serves as quality control, destroying messages that contain mistakes before a broken protein is made.

The Krainer lab at CSHL determined that when the gene called SRSF2 is mutated, NMD destroys many more messages, including some that have not been likely targets of NMD before. Messages that are important for healthy blood cell production are one of these new targets.

The result of excessively active NMD is less healthy blood cells and more sickly or immature cellsa hallmark of blood cancer.

RNA splicing factor mutations are seen in virtually all forms of leukaemia, both chronic as well as acute myeloid leukaemias and also even chronic lymphocytic leukaemia, said Omar Abdel-Wahab, M.D. at MSKCC. Im a hematological oncologistI think a lot about blood cancerso this caught my attention right away.

Scientists have seen other cancers manipulate NMD into protecting solid tumours. However, the CSHL-MSKCC discovery, published in Genes and Development, is the first evidence of NMD contributing to blood cancer conditions.

To stop the mutated SRSF2 gene from affecting NMD, the researchers experimented with a technique called antisense oligonucleotide (ASO) therapy. As shown by CSHL Professor Adrian Krainer in past works, ASO therapy has been effective in combating other diseases resulting from defective RNA splicing.

The next step will be to test many ASOs in animals, perfecting the teams approach until it is ready for the clinic.

Before this collaboration, I knew very little about splicing factors or this process of NMD. Conversely, Adrians lab didnt have much disease-specific experience with blood cancers, so its been a synergistic experience, Abdel-Wahab added. By combining forces, weve really been able to address what weve learned.

Original post:
Deadly gene mutation leading to blood cancer - The Siasat Daily

OmniSpirant Limited are a leading European biotech startup company with ambitions to change the paradigm of treatment for respiratory disease. Chronic Obstructive Pulmonary Disease (COPD) is an umbrella term used to describe progressive lung diseases including emphysema, chronic bronchitis, and refractory (non-reversible) asthma. This disease is characterised by increasing breathlessness, frequent chest infections and persistent wheezing. COPD currently cannot be cured or fully reversed.

This debilitating disease today has a solution, developed by OmniSpirant, as we explain below. Until now, the current COPD therapeutics market has lacked any effective disease modifying treatments and the clinical stage pipeline is weak, given the massive disease prevalence; COPD is arguably the disease with the most severely unmet medical and patient needs.

Smoking is indeed the primary cause of this devastating disease, but 15-20% of COPD cases are due to exposures to occupational dust, chemicals, vapours or other airborne pollutants in the workplace. Air pollution is also a likely and underappreciated driver of the growth of the disease and declining lung function in COPD is strongly associated with ageing.

COPD affects up to 500 million patients globally and is the worlds fourth leading cause of death. This dire situation is projected to worsen with COPD becoming the third leading cause of death globally in 2030 and the leading cause of hospitalisations in the industrialised world. COPD is classified as a priority disease by the EU and WHO as it is the only leading cause of death that is rising in prevalence globally. The burden of this chronic respiratory disease is growing rapidly, fuelled by an ageing demographic, persistent smoking habits, and air pollution.

A recent study has estimated that air pollution may be a factor in as many as 47,000 COPD deaths per annum across the 28 EU Member States. Epidemiologic studies have found a measured prevalence of COPD in Europe of between 4% and 10% of adults (European COPD Coalition). However, COPD is widely undiagnosed and untreated especially in its early stages, so the actual prevalence may be higher. New therapies that can slow disease progression desperately need to be developed.

The disease costs tens of billions of euros annually to healthcare payers in reimbursement for largely ineffective pharmacological and medical interventions. In the key United States market, COPD is responsible for USD $72bn (~65bn) per year in direct healthcare expenditures. In the EU, estimated spending on inpatient, outpatient and pharmaceuticals exceeds 10bn per year and productivity losses are estimated at 28.5bn year.

The disease also causes an estimated 300,000 premature deaths in the EU annually (European Respiratory Society). These startling figures are forecast to rise dramatically as the disease prevalence is set to rise sharply.

Current COPD treatments do not include an effective disease modifying therapy which can reduce the exacerbation of symptoms and/or slow down COPD from progressing and worsening. State of the art therapies for COPD consists of combinations of oral, injected or inhaled bronchodilators, anti-muscarinics, corticosteroids, anti-inflammatories, and antibiotics, all of which are used to treat symptoms and reduce exacerbations of COPD with only modest results.

Except for a small minority of Alpha one Antitrypsin (AAT) deficient COPD patients (five in 10,000 carry the mutation responsible for AAT deficiency on both chromosomes), there are no available therapies which modulate disease progression. AAT is a protein that protects the lungs from the destructive actions of common illnesses and exposures, particularly tobacco smoke.

Furthermore, the COPD pipeline is also devoid of disease modifying treatments. The COPD pipeline is full of incremental advances on existing mainstay therapies which merely treat disease symptoms and do not target the root causes of the disease. There are a few innovative therapies in development but a small molecule or biologic agent such as a monoclonal antibody (or even combinations of several of these agents) are highly unlikely to provide a curative or even therapeutically useful intervention in a complex disease like COPD.

OmniSpirant believe that the solution to the COPD epidemic can be found in the new era of advanced therapeutics by combining several technological advances in the fields of cell culturing, genetic engineering and their innovative exosome technology platform. OmniSpirant are developing inhaled bioengineered exosome therapeutics, delivered by a tailored aerosol delivery method based on vibrating mesh nebuliser technology.

In the first instance, the presenting problem is that patients have established lung damage and an increased risk of developing lung cancer (independent of smoking history). OmniSpirant believe that microRNA/mRNA engineered stem cell exosomes can provide powerful anti-inflammatory and regenerative effects and also reduce the risk of patients developing lung malignancies.

Exosomes are naturally produced by cells and recent research highlights the vast potential of stem cell exosomes as transformative regenerative medicines. Stem cell exosomes have shown great regenerative potential in animal models of COPD by stimulation of repair mechanisms and reversing damage to the lung. Stem cells have also shown some promising results in COPD clinical trials.

Donor (Allogeneic) MSCs delivered intravenously in repeat-dose clinical trials for COPD (Prochymal Osiris Therapeutics) were found to be safe and well tolerated and reduced systemic inflammation, but no significant improvements in lung function were observed. We believe that the use of exosomes, as the therapeutic essence of stem cells, delivered by the inhaled route of administration will be capable of far greater efficacy by delivering far higher doses of exosomes directly to the affected lung tissues than intravenous delivery while typically only requiring about 1% of the overall dose. Furthermore, our exosomes will have enhanced delivery (via proprietary surface engineering) and are also bioengineered to enhance efficacy.

OmniSpirants novel technology platform is capable of delivering high doses of these exosomes across the mucus barrier and through cell membranes to deliver the therapeutic payload directly into the diseased lung cells. Such delivery has proven problematic for competing gene transfer technologies because the mucus in the lungs is a barrier that traps the carriers used to deliver gene therapies such as nanoparticles and viral vectors. These trapped gene therapy carriers are mostly cleared from the mucus layer before they can penetrate into the underlying cells and introduce their genetic cargo.

The use of exosomes overcomes other issues associated with viral and non-viral vectors which include the generation of therapy-inactivating host immune responses and poor ability to cross cell membranes. Furthermore, traditional gene transfer vectors may be immunogenic and elicit adverse inflammatory responses.

OmniSpirants solution is a proprietary method of surface engineering exosomes so they can efficiently penetrate the protective mucus barrier and enter into the underlying cells. These stem cell exosomes are therapeutic (regenerative, anti-inflammatory, antimicrobial and antifibrotic), non-immunogenic, and can be tailored via genetic modification of the parent stem cells to create ideal inhaled gene therapy vectors for any lung disease.

The surface engineered exosomes have demonstrated 100% mucus penetration and target cell uptake in the gold standard in vitro model (well-differentiated bronchial epithelial cells in air liquid interface culture), which is game changing compared with the state of the art viral vectors which can achieve only 30% of cells at best. We believe that the enhanced delivery of stem cell exosomes can translate the promising regenerative effects witnessed in various animal models of inflammatory lung diseases into the clinic.

To treat COPD, our approach is to genetically modify the stem cells so that they produce exosomes carrying carefully selected nucleic acids which are tailored for treating the underlying causes of COPD, which has been linked to gene expression and cellular senescence. The genetic element to COPD runs much deeper than just AAT deficiency.

Abnormalities in scores of genes have been clearly shown to increase or decrease the risk of developing COPD and perturbed gene expression is apparent in hundreds of disease associated genes. MicroRNAs (miRNAs) are a recently discovered class of non-coding RNAs that play key roles in the regulation of gene expression and more than 2,000 miRNAs have been identified in the human genome to date. The fact that each miRNA has the ability to target multiple genes within a pathway makes miRNAs one of the most abundant classes of regulatory genes in humans, regulating up to 30% of human protein coding genes.

MiRNAs have been widely shown to be dysregulated in the affected lung tissues of COPD patients which makes an inhaled gene therapy a highly promising approach for treating COPD. Such a gene therapy could effectively modulate the disease altered microRNAs (and their target genes) to halt or even reverse the disease. Recent advances in cell culturing techniques, isolation of exosomes and proprietary cell engineering technologies hold the promise to bring this therapy to the afflicted masses. The BOLD project estimates that there are currently 36 million patients in the EU and US alone with GOLD Stage 2 disease or higher; we need to act quickly as this figure is set to rise dramatically in the coming decade.

OmniSpirant are currently seeking investors or partners to fund the preclinical development of OS002 and anticipate that clinical studies can be initiated within approximately four years an impactful investing opportunity as the rising prevalence of COPD means that by 2030 there may be over 4.5 million deaths annually worldwide and COPD is predicted to be the leading cause of hospitalisation. Lets work together to change those grim statistics.

OmniSpirant and their consortium partners were awarded a 9.3m Irish government grant award (Disruptive Technologies Innovation Fund) in December 2019 to advance the development of their novel COPD gene therapy.*

OmniSpirant have received funding from Horizon 2020, ReSpire, Grant agreement ID: 855463 and have been accelerated by EIT Health.

Gerry McCauleyCEOOmniSpirant Ltd+353 876306538gmccauley@omnispirant.comwww.omnispirant.com

Please note, this article will appear in issue 12 ofHealth Europa Quarterly, which will be available to read in February 2020.

Read more:
Innovation in the treatment of COPD - Health Europa

In a second research report published this year so far, investigators found that the U.S. Food and Drug Administration (FDA) is approving drugs faster than ever. Unfortunately, it appears that the agency is also approving those drugs on less data and weaker evidence.

The first study published in the journal SSRN was by researchers at Harvard University, the University of Texas at Dallas, and the Massachusetts Institute of Technology (MIT). It questioned if the FDA and other regulatory agencies worldwide dont rush certain approvals, particularly at the end of the year in a kind of desk-clearing activity.

The report notes, In the United States, the number of December drug approvals is roughly 80% larger than in any other month. Similar approval spikes occur at the end of each calendar month. Additionally, approvals spike before holidays, such as before Thanksgiving in the United States and the Chinese New Year in China (but not vice versa).

And more troubling is that there appears to be a correlation with more problems with these drugs. Lauren Cohen, a professor of finance and entrepreneurial management at Harvard Business School and one of the authors, told the Wall Street Journal, We see about twice as many adverse effects.

The second study appeared in the journal JAMA Network and was conducted by researchers with Harvard Medical School. The lead author, Jonathan Darrow, a lawyer with the medical schools Program on Regulation, Therapeutics and Law, told NPR, There has been a gradual erosion of the evidence thats required for FDA approval. He points out that patients and physicians should not expect that new drugs will be dramatically better than older ones.

The study notes that about half of recent drug approvals were built on a single pivotal clinical trial. Typically, two pivotal, Phase III trials were the norm. In addition, the study says that surrogate measures, which are utilized as stand-ins for presumed patient benefits, has grown. For example, in oncology drugs, what most patients would want are improvements in survival after receiving treatment. But some cancer trials use a surrogate measure of tumor shrinkage. Ideally, both would be taken into consideration.

Darrow and his research associates studied FDA approvals, changes in the law and regulations, and how the industry funds agency reviews from 1983 through 2018. They found that the average number of new drug approvals annually grew from 34 in the 1990s to 41 in the 2010s. In the 2000s, it dropped to 25 a year. But now they are increasing. For example, in 2019, the FDA approved 48 new molecular entities and new therapeutic biological products. That doesnt include vaccines, allergenic products, blood and blood products, plasma derivatives, cellular and gene therapy products, or the numerous new indications approved for existing therapies.

Darrow, with Jerry Avorn and Aaron S. Kesselheim, both with the Division of Pharmacoepidemiology & Pharmacoeconomics at Brigham & Womens Hospital, found that faster approvals were related to legislative and regulatory modifications that started in the 1980s. Although there are probably several reasons for those changes beginning in that period, much of it is likely related to the beginning of the HIV epidemic and demands from patient populations and advocates to fund more research and get therapiesany therapiesto market faster.

Just some of those regulations include: the 21st Century Cures Act (2016), which authorized funds for the Precision Medicine Initiative and Cancer Moonshot; the Biologics Price Competition and Innovation Act (BPCIA, 2010), creating an abbreviated pathway for follow-on biologic products; Breakthrough Therapy designation (2012), for drugs that showed substantial improvement over existing therapies; the Hatch-Waxman Act (1984), which created an Abbreviated New Drug Application pathway for drugs approved after 1962; and the Pediatric Research Equity Act (2003), which required results from pediatric assessments to be submitted as part of New Drug Applications (NDAs).

Congress also passed the Prescription Drug User Fee Act in 1993, and that first year, FDA collected $29 million in fees. In 2018, the agency brought in $908 million in PDUFA fees. Or, as the study notes, industry fees were responsible for about 80% of the money spent on FDA employee salaries for drug reviews.

There is some concern about the incentives that this created within the FDA, Darrow told NPR. And whether it has created a culture in the FDA where the primary client is no longer viewed as the patient, but as the industry.

Another factor that is related, is the concept of me-too drugs. These are basically drugs that are very structurally similar to approved drugs, with only minor differences. Thats not necessarily a bad thing, because they need to be at least as good as the drugs already on the market, and generally need to be betteralthough not necessarily by much. Which does mean a number of companies spend time on developing drugs that are only incrementally better than others on the market.

Joshua Sharfstein, former FDA Principal Deputy Commissioner, told NPR that there are more changes needed to ensure drugs are worthwhile for patients. Some of them are really great, and some of them [are] not so great. And a lot of them are very expensive.

Sharfstein is currently a professor at the Johns Hopkins Bloomberg School of Public Health. He wrote an editorial in JAMA that accompanied the newer study. In it, he suggests its time to reevaluate the FDAs expedited approval programs to determine which ones are working and which ones are increasing healthcare costs.

Weve kind of reached a point where it makes sense to pause and see whether we can do things better, Sharfstein said. And I think we can.

Read the original post:
The FDA Is Approving Drugs Faster, But That May Not Be A Good Thing - BioSpace

Austin was three years old and Max was a newborn when their mother, Jenn McNary, learned they had a rare genetic condition called Duchenne muscular dystrophy. The doctor painted a grim picture: Her boys would stop walking by age 12 or 13 and, shortly thereafter, they would require nighttime ventilation. They would each need a tracheotomy, a feeding tube, or both by their late teens. Death would come a few years later.

It hasn't worked out that way, thanks to two new drugs that became available after the boys' 2002 diagnosis. Exondys 51, a medicine that targets their genetic mutation, slows the disease's progression, and Emflaza, a corticosteroid, mitigates some of its symptoms. Thanks to these treatments, Austin now attends college and interns at a biotech company. Max attends his local high school in Newton, Massachusetts. Both are able to get around in wheelchairs, and neither needs ventilation. McNary just rented an apartment for her boys because they can function on their own with the help of an aide.

By all accounts, the drugs have been transformative, McNary said. But, she added, her boys "aren't going to be cured," and extending and improving their life for an unknown period of time comes at a high price. Emflaza came onto the market in 2017 at an annual cost of $65,000. Exondys 51 appeared in 2016 at $748,500. Neither of the drugs will help the young men walk again and, in the eyes of some U.S. health economists, the drugs are not worth the price.

That's why McNary hates the quality-adjusted life year (QALY, pronounced "qua-lee"), an economic calculation that attempts to quantify the value of a medical intervention, based in part on the quality of life it bestows on recipients.

First developed by U.S. economists in the late 1960s and early 1970s, variations of the QALY have been used for years by governments around the world to help determine what treatments citizens can obtain under public health care. In America's free-market health care system, however, QALY calculations have largely been avoided. As McNary and others like her are finding out, that's starting to change.

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As policymakers and insurance companies scramble to get a handle on skyrocketing health care costs, they are promoting the idea of paying for value. In this view, drugs designated as higher-value should be prioritized over lower-value treatments. But this raises a thorny question: Who gets to define "value"? Health economists and insurance companies who seek to use limited health care dollars judiciously? Or patients, parents, and doctors who want to receive the best health care for their situation?

Because the quality-adjusted life year threatens her sons' ability to get the medicine they need, McNary is clear about her answer. "To me, the QALY is a measurement that says that keeping my sons alive by providing incremental benefit but not totally curing them is never going to be valuable," McNary said. "Just mull that around in your head if you are less than perfect, you are worth less money."

* * *

In QALY math, a year of perfect health is equal to 1; death equates to 0. The value of other health states is derived from surveys of patients, caregivers, or the general public. Paralysis might be valued at .35, for example, and mild Alzheimer's disease at .52, depending on the survey. Those numbers can then be plugged into a formula that allows the relative cost-effectiveness of treatments to be compared to identify the best buys.

Economists developed the QALY concept more than 40 years ago to address a fundamental question: "Where should we spend whose money to undertake what programs to save which lives with what probability?' Richard J. Zeckhauser and Donald Shepard asked in a 1976 article describing the basic QALY formula. The next year, as U.S. health care spending topped $120 billion, Harvard health policy professor Milton C. Weinstein and his colleague, cardiologist William B. Stason, sounded an alarm bell. "It is now almost universally believed that the resources available to meet the demands for health care are limited," they wrote in the New England Journal of Medicine. "We, as a nation, will have to think very carefully about how to allocate the resources we are willing to make available for health care."

Their article cited by other authors more than a thousand times in the past four decades pointed out that resources were already being allocated by millions of individual decisions: hospitals rationing beds where they didn't have room for all patients, for example, and insurers agreeing to pay for some tests and treatments but not for others. Such decisions, they argued, were often inconsistent with the "societal objective of deriving the maximum health benefits from the dollars spent," an objective that could be achieved by putting the QALY to work.

In the intervening decades, some countries the United Kingdom, the Netherlands, and Sweden, for example have embraced QALY-based evaluations. In the U.K., cost-effectiveness studies are used, in part, to determine which therapies the National Health Service will provide for residents. The publicly-funded health system does not cover Orkambi, the first cystic fibrosis treatment that targets the cause of the disease, for example, because its cost-per-QALY far exceeds the U.K. cost-effectiveness threshold.

In the United States, however, QALY-based assessments have not gained traction until recently. "Perhaps the general reason is that we as patients and our providers don't want to be limited in the treatment options available," said Louis P. Garrison Jr., an economist in the Pharmaceutical Outcomes Research and Policy Program at the University of Washington.

In fact, QALY-based cost-effectiveness reviews are so controversial that the federal government has repeatedly quashed their use. In 1992, the Department of Health and Human Services rejected Oregon's attempt to use QALY-based cost-effectiveness assessments to determine what services its Medicaid program would cover. In 2010, as part of the Patient Protection and Affordable Care Act, Congress prohibited the use of QALYs by the Medicare program. It also banned the federal Patient-Centered Outcomes Research Institute from using QALY thresholds in its assessments of comparative treatments.

* * *

A QALY Primer

A QALY reflects quality of life and length of life. A year in "perfect health" is worth 1 QALY, death is worth 0 QALYs, and other health states fall between 0 and 1. The amount that a drug lengthens or improves the quality of life is calculated as "QALYs gained." The cost of getting a certain level of health improvement is the "cost per QALY gained," shown here for several interventions targeting asthma.

But more than half of U.S. residents are covered by private insurance companies, which are not prohibited from using QALY-based assessments to decide which medicines they will cover for their members. Traditionally, however, private insurers have generally not used QALYs explicitly in their decisions about what tests and treatments they will pay for, according to a recent report by the National Council on Disability. Instead, when major U.S. insurers decide to limit access to a given medication, they usually cite insufficient data to justify its use in a given situation.

Indeed, until recently, U.S. insurers did not have a source for QALY-based cost-effectiveness reports. That began to change in 2014, when the Institute for Clinical and Economic Review, a nonprofit research organization based in Boston, turned its attention to high-cost drugs. Founded in 2006 as a research project based at Harvard Medical School, ICER initially issued reports on broad topics such as obesity management and palliative care. But when Sovaldi, a drug for deadly hepatitis C, came on the market at the then-shocking price of $84,000 for a 12-week course of treatment, ICER kicked into action. Despite the high price, its assessment found that Sovaldi is cost-effective for some patients. Insurers took notice.

Since then, the organization has been churning out several drug-assessment reports each year. Each report includes its opinion of how much the drug is worth; drugs priced higher than that are deemed not cost-effective. ICER has no authority over anyone, but its reports have become popular reading for U.S. insurers. "If there is a drug of note being approved by the FDA, there's also likely going to be an ICER assessment of that drug that can factor into their decision-making," said David Whitrap, the research organization's vice president of communications and outreach.

* * *

U.S. health care spending has risen dramatically since Weinstein and Stason expressed concern in the mid-1970s. In 2016, the U.S. spent nearly 18 percent of its gross domestic product on health care, far outstripping the average of 11 percent for 10 other high-income nations. High prices for prescription drugs is one reason. "We're seeing price tags now of $1 million, $2 million," said Seema Verma, administrator for the federal Centers for Medicare and Medicaid Services, at a conference recently. "That's completely unsustainable for the system."

That's why Peter Neumann, director of the Center for the Evaluation of Value and Risk in Health at Tufts Medical Center, said cost-effectiveness analyses are needed more than ever. But there are many reasons for the resistance, Neumann and his co-authors wrote in the Journal of the American Medical Association, including "an inclination on the part of many individuals in the United States to minimize the underlying problem of resource scarcity and the consequent need to explicitly ration care."

Further, Ari Ne'eman, a disability rights activist and consultant to Partnership to Improve Patient Care, a coalition of advocacy groups, said the idea that two health conditions can be numerically compared to one another is simply wrong. "Proponents of the QALY will say it is this mathematically perfect measure that gives us a superpower ability to compare depression drugs to cystic fibrosis drugs to cancer drugs even though all of those drugs do different things because it lets you translate them back to this common measure," he said. "Our concern is that when you engage in that process of translation, you lose some significant nuance in terms of the amount of benefit that's being delivered."

The Partnership argues the QALY calculation is flawed because it assumes quality of life can be captured by a certain number, despite the fact that different surveys arrive at different numbers. For example, a 2006 quality-of-life survey in the U.S. assigns blindness/low vision as .69 on the 0-to-1 scale, while a 2011 survey in the U.K. gives blindness/low vision a score of .78.

Beyond the methodological issues, Ne'eman said, "there are all kinds of ethical problems with it." People with disabilities and chronic medical conditions may value a treatment that offers an incremental improvement in the quality or length of their lives, even though the "QALYs gained" are less than those for a treatment that prevents the loss of perfect health.

Former U.S. Representative Tony Coelho, a Democrat from California and a primary author of the Americans with Disabilities Act, is the Partnership's chairman. "I worry that more focus is being given to what is most cost-effective for the 'average patient' than creating a system that works for each individual patient," he wrote in 2018. "The medication I take for epilepsy isn't 'high value' for every patient. But it's the only one that works for me."

That's why, Ne'eman said, cost-effectiveness analyses must consider the fact that not all patients respond the same way to a drug. Some patients need drugs that aren't deemed cost-effective for the general population. It's important to account for that, he said. "Otherwise we're giving insurers a tool to deny care to people who need it."

When an insurer decides to cover a specific drug, that decision affects everybody who pays into the insurance pool. Michael Sherman, chief medical officer for the insurer Harvard Pilgrim Health Care, uses the example of a gene therapy that costs $1 million to treat a child who will die without it. Under the ACA, families will hit their out-of-pocket maximum at about $16,000, and many health plans have out-of-pocket maximums far below that. "The rest of that million dollars is going to be paid by everyone else that's the way it works in insurance," he said. When insurers see that kind of unanticipated budget impact, they raise premiums or out-of-pocket cost-sharing for everyone.

Like other proponents of the QALY, Neumann sees it as an imperfect but useful tool. "Any single number is never going to capture everything," he said.

"The problem is, if you're not going to use QALYs, what are you going to use?"

* * *

That's an urgent question, particularly now when there is a huge pipeline for rare-disease therapies, often called orphan drugs. By 2024, orphan drug sales are expected to reach $242 billion.

In the U.S., a rare disease is defined as one that affects fewer than 200,000 people. While these conditions are individually rare, in the aggregate, an estimated 25 to 30 million Americans that's about one in 10 live with a rare disease. Most rare diseases affect children, and many are fatal or disabling.

Historically, drugmakers spent little effort developing treatments for rare diseases, but that changed with the passage of the Orphan Drug Act of 1983, which provides tax credits and a seven-year marketing exclusivity to companies that develop rare-disease treatments. Hundreds of such treatments have won FDA approval in recent years, with more than 560 medicines in the works.

Those treatments are generally expensive. On average, the per-patient cost for orphan drugs in the U.S. is almost 4.5 times more than for non-orphan drugs.

In the two decades ending in 2017, the average annual cost for orphan drugs was $123,543, based on the price at the time the drug launched, compared to $4,961 for traditional drugs. For Duchenne alone, more than 30 orphan therapies are in development. None of them are going to cure patients, McNary said. But she hopes new treatments, generally used in combination, will help her sons live longer, healthier lives and completely change the disease trajectory for younger patients whose disease has not yet progressed as far.

The barrier she worries about is cost-effectiveness analysis. In August, the Institute for Clinical and Economic Review published its assessment of treatments for Duchenne, which affects about 400 to 600 boys born in the U.S. each year. Emflaza, the corticosteroid, appears to be as good as or better than prednisone, another corticosteroid approved to treat the disease, but it would need a price cut of at least 73 percent to be considered cost-effective.

Exondys 51 approved by the FDA for about 13 percent of the Duchenne population got a worse review. In the clinical trials used to seek FDA approval, no clinical benefit, including motor function improvement, was demonstrated. (The FDA approved the drug because some of the patients treated with Exondys 51 had a slight increase in dystrophin levels in skeletal muscle.) In light of that, Exondys 51 was not deemed cost-effective at any price.

But Jenn McNary said the drug works for her sons. Austin, who was not eligible for the Exondys 51 clinical trial, stopped walking at age 10. Max got in the trial and started taking the drug at age 9."They have the same mutation, they have been raised by the same mother, so one would expect they would progress similarly," she said. "But Max walked until he was 17."

Austin was already in a wheelchair when, at age 15, he started taking Exondys 51. He regained some upper-body strength that changed his life, according to his mother. "He's able to use a urinal on his own, which makes is possible for him to have a job and to go to college without an aide," she said.

The Medicaid program in Massachusetts, where the McNarys live, won't pay for Max's Duchenne therapies. For the time-being, the drugmakers are giving him the drugs free through a patient-assistance program. Austin, because he's enrolled in college, is eligible for student coverage through Blue Cross Blue Shield of Massachusetts. The insurer, by policy, does not cover Exondys 51 for patients who can no longer walk. His mother appeals the insurance denial. Every six months, she sends a video of Austin in action, along with a letter from his doctor and so far, his medicines have been covered.

The payers made their coverage policies before the quality-adjusted life year analysis was published. Now, insurers who have been covering the Duchenne treatments have an independent analysis with which to rethink that decision.

For now, there is one thing that QALY supporters and critics agree on. "Very promising drugs are coming, and they're going to be very expensive," said Neumann, the health economist at Tufts. Increasingly, the QALY appears poised to influence how American health care money is spent.

* * *

Lola Butcher is a health care business and policy writer based in Missouri.

This article was originally published on Undark. Read the original article.

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Is the medication you're taking worth its price? - Salon

For Immediate Release: January 28, 2020

This is a pivotal time in the field of gene therapy as the FDA continues its efforts to support innovators developing new medical products for Americans and others around the world. To date, the FDA has approved four gene therapy products, which insert new genetic material into a patients cells. The agency anticipates many more approvals in the coming years, as evidenced by the more than 900 investigational new drug (IND) applications for ongoing clinical studies in this area. The FDA believes this will provide patients and providers with increased therapeutic choices.

In that spirit, today, the FDA is announcing the release of a number of important policies: six final guidances on gene therapy manufacturing and clinical development of products and a draft guidance, Interpreting Sameness of Gene Therapy Products Under the Orphan Drug Regulations.

The growth of innovative research and product development in the field of gene therapy is exciting to us as physicians, scientists and regulators, said FDA Commissioner Stephen M. Hahn, M.D. We understand and appreciate the tremendous impact that gene therapies can have on patients by potentially reversing the debilitating trajectory of diseases. These therapies, once only conceptual, are rapidly becoming a therapeutic reality for an increasing number of patients with a wide range of diseases, including rare genetic disorders and autoimmune diseases.

As the regulators of these novel therapies, we know that the framework we construct for product development and review will set the stage for continued advancement of this cutting-edge field and further enable innovators to safely develop effective therapies for many diseases with unmet medical needs, said Peter Marks, M.D., Ph.D., director of the FDAs Center for Biologics Evaluation and Research. Scientific development in this area is fast-paced, complex, and poses many unique questions during a product review; including how these products work, how to administer them safely, and whether they will continue to achieve a therapeutic effect in the body without causing adverse side effects over a long period of time.

One of the most important steps the FDA can take to support safe innovation in this field is to create policies that provide product developers with meaningful guidance to answer critical questions as they research and design their gene therapy products.

The six final guidances issued today provide the agencys recommendations for product developers on manufacturing issues and recommendations for those focusing on gene therapy products to address specific disease areas. The six guidance documents incorporate input from many stakeholders and take a significant step toward helping to shape the modern structure for the development and manufacture of gene therapies. The agency is issuing this suite of documents to help advance the field of gene therapy while providing recommendations to help ensure that these innovative products meet the FDAs standards for safety and effectiveness.

The scientific review of gene therapies includes the need to evaluate highly complex information on product manufacturing and quality. In addition, the clinical review of these products frequently poses more challenging questions to regulators than reviews of more conventional drugs, such as questions about the durability of response, and these questions often cant be fully answered in pre-market trials of reasonable size and duration. For some gene therapy products, therefore, although they have met the FDAs standards for approval, we may need to accept some level of uncertainty around questions of the duration of the response at the time of marketing authorization. Effective tools for reliable post-market follow up, such as post-market clinical trials, are going to be key to advancing this field and helping to ensure that our approach fosters safe and innovative treatments.

The draft guidance on interpreting sameness of gene therapy products under the orphan drug regulations provides the FDAs proposed current thinking on an interpretation of sameness between gene therapy products for the purposes of obtaining orphan-drug designation and eligibility for orphan-drug exclusivity. The draft guidance focuses on how the FDA will evaluate differences between gene therapy products when they are intended to treat the same disease. As laid out in the draft guidance and our regulations, the agencys determination will consider the principal molecular structural features of the gene therapy products, which includes transgenes (the transferred gene) and vectors (the vehicle for delivering the transgene to a cell).

With the large volume of products currently being studied, gene therapy product developers have asked the agency important questions about orphan-drug designation incentives to develop products for rare diseases with very small patient populations. The draft guidance has potential positive implications both for product developers and patients by providing insight into the agencys most current thinking on the sameness of products, and thus, not discourage the development of multiple gene therapy products to treat the same disease or condition. For patients, this policy could help lead to the development and approval of multiple treatments, creating a more competitive market with choices. We encourage stakeholders to provide their comments.

In sum, these policy documents are representative of efforts to help advance product development in the field of gene therapy. We will continue to work with product innovators, sponsors, researchers, patients, and other stakeholders to help make the development and review of these products more efficient, while putting in place the regulatory controls needed to ensure that the resulting therapies are both safe and effective. We also encourage developers of new gene therapy products to make full use of our expedited programs available for products intended to address unmet medical needs in the treatment of serious or life-threatening conditions. These programs include breakthrough therapy designation, regenerative medicine advanced therapy designation, and fast track designation, as well as priority review and accelerated approval. Developers should pursue these programs whenever possible to help bring the benefits of important advances to patients as soon as possible. We believe our work will help advance innovations in a way that assures their safety and effectiveness, provides new therapeutic choices to patients and providers and continues to build confidence in this novel and emerging area of medicine.

The FDA is an agency within the U.S. Department of Health and Human Services, protects the public health by assuring the safety, effectiveness, and security of human and veterinary drugs, vaccines and other biological products for human use, and medical devices. The agency also is responsible for the safety and security of our nations food supply, cosmetics, dietary supplements, products that give off electronic radiation, and for regulating tobacco products.

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FDA Continues Strong Support of Innovation in Development of Gene Therapy Products - FDA.gov

Aperio Clinical Outcomes, a leading clinical research organization (CRO), announced today that Jonathan Yusi, an expert in the coordination and management of cell and gene therapy clinical trials, has joined the company as Senior Clinical Trials Manager to support their biotechnology clients in the immuno-oncology space.

Yusi has been managing immune-based therapy trials for over seven years. Prior to joining Aperio, he was a program manager for CAR-T studies and oversaw the first CAR-T program at a large CRO. He has provided independent trial management consulting for CAR-T trials, and his expertise has resulted in lasting KOL relationships within the immuno-oncology space. In addition to his adoptive cell therapy knowledge, Yusi brings over 20 years of clinical research experience to Aperio, with a focus on trial logistics, management, and monitoring of targeted and immune therapies in oncology trials.

Says Suzanne Kincaid, Aperios COO and an oncology industry veteran herself, "FDA expects to see over 200 INDs for cell and gene therapies in 2020, so it is imperative that our biotech clients have expertise like Jonathans to manage their trials. He has a strong understanding of the complexities of cell and gene therapy studies and can break down the components for ideal study set-up. We are so excited to have Jonathan help our immuno-oncology clients as they explore these groundbreaking treatments."

"Cell and gene therapy trials are a logistical maze, and one missed endpoint can be catastrophic to the study," says Yusi. "These programs allow me to utilize everything Ive learned about clinical research and oncology, and my medical and scientific background brings an understanding to the science behind the treatments. The bulk of my career has involved oncology trials, so as the treatments have evolved and become more personalized, my experience has evolved as well. These are life-saving breakthroughs, and Im happy to bring this experience to Aperio and our immune-based therapy clients."

About Aperio Clinical Outcomes

In a data driven industry, Aperio remains dedicated to transparency with clients and focused on the most important part of the process: people. Aperio provides full, customizable clinical research services across multiple therapeutic areas, as well as consulting services in Quality Assurance, Strategic Resourcing and Clinical Trial Technology. For more information: http://www.aperioclinical.com.

View source version on businesswire.com: https://www.businesswire.com/news/home/20200131005540/en/

Contacts

Heather Newbold: +1 919-604-5704heather.newbold@aperioclinical.com

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Aperio Hires CAR-T Trials Expert Jonathan Yusi to Support Cell and Gene Therapy Studies - Yahoo Finance

Gene therapy developers targeting the US market have a clearer idea of what it will take to win approval thanks to new guidance documents issued by the FDA.

The US regulator set out its expectations for developers in six documents published last week. There are final guidance documents on gene therapies for hemophilia, retinal disorders and rare diseases.

In addition, there are final guidance documents on chemistry, manufacturing and controls (CMC), observational studies and on the assessment of gene therapies that use retroviral vectors.

Image: iStock/Piotrekswat

There is also draft guidance explaining how the FDA will interpret sameness when deciding whether to award orphan drug status.

The agency said that when assessing two gene therapies targeting the same disease it will consider both the gene itself and the viral vector.

To date only four gene therapies that introduce new genetic material into a patients cell have been approved by the FDA.

However, many more gene therapies are on the way according to the agency which said it anticipates more approvals in the coming years based on the 900 investigational new drug (IND) it has received.

FDA Commissioner Stephen Hahn said, The growth of innovative research and product development in the field of gene therapy is exciting to us as physicians, scientists and regulators.

These therapies, once only conceptual, are rapidly becoming a therapeutic reality for an increasing number of patients with a wide range of diseases, including rare genetic disorders and autoimmune diseases.

This was echoed by Peter Marks, director of the FDAs Center for Biologics Evaluation and Research, who stressed the importance of effective gene therapy regulations.

As the regulators of these novel therapies, we know that the framework we construct for product development and review will set the stage for continued advancement of this cutting-edge field and further enable innovators to safely develop effective therapies for many diseases with unmet medical needs.

Marks cited the rapid pace of scientific development as a challenge for the agency, explaining that assessing the safety, efficacy and long-term impact of gene therapies is highly complex.

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US FDA predicts gene therapy surge - Bioprocess Insider - BioProcess Insider

With more than 900 investigational new drug (IND) applications for ongoing clinical studies related to gene therapies, and with the number of advanced therapy medicinal products at clinical stage worldwide exceeding 1,000, the US Food and Drug Administration (FDA) this week released a number of policies.

The policies, addressed to developers and manufacturers, include six final guidance documents on gene therapy manufacturing and clinical development of products, following up to respective draft guidance documents released in 2018, and a draft guidance related to orphan drug designations for therapeutic candidates.

Scientific development in this area is fast-paced, complex, and poses many unique questions during a product review, commented Peter Marks, director of the FDAs Center for Biologics Evaluation and Research, adding The framework we construct for product development and review will set the stage for continued advancement of this cutting-edge field.

Regarding the draft guidanceInterpreting Sameness of Gene Therapy Products Under the Orphan Drug Regulations, the agency explained that it focuses on how the FDA will evaluate differences between gene therapy products when they are intended to treat the same disease.

The final guidance titled Chemistry, Manufacturing, and Control (CMC) Information for Human Gene Therapy Investigational New Drug Applications (INDs) aims to inform sponsors on how to provide sufficient CMC information, in order to assure product safety, identity, quality, purity, and strength (including potency) of the investigational product and to be able to claim market authorization from the regulatory body.

Addressed to developers and manufacturers of retroviral vector-based human gene therapy products, the second document titled Testing of Retroviral Vector-Based Gene Therapy Products for Replication Competent Retrovirus (RCR) during Product Manufacture and Patient Follow-up determines testing for RCR during manufacture, as well as the regulations for follow-up monitoring of patients who have received such treatments.

Titled Long-Term Follow-Up After Administration of Human Gene Therapy Products, the third document includes recommendations by the FDA regarding the design of long-term follow-up studies for the collection of data on delayed adverse events.

Specifically, the FDA suggests that, as a result of long-term exposure to an investigational gene therapy, patients may be at increased risk of undesirable and unpredictable outcomes, and therefore they may be monitored for an extended period of time past the active follow-up period. The document outlines several factors based on which a risk assessment should be performed to determine the necessity of long-term monitoring for each product.

Another guidance of the FDA is focused on Human Gene Therapy for Hemophilia, and it provides recommendations regarding the clinical trial design for such therapies, as well as addressing discrepancies between Hemophilia A and B coagulation factors activity assays.

Focusing on Human Gene Therapy for Retinal Disorders, the fourth FDA guidance includes recommendations related to product development, preclinical testing, and clinical trial design for such gene therapy products.

Finally, the guidance on Human Gene Therapy for Rare Diseases, with suggestions on the clinical design for such products, is needed, according to the FDA, due to the limited study population size and potential feasibility and safety issues. Moreover, the FDA cites issues related to the interpretability of bioactivity/efficacy outcomes that may be unique to rare diseases or to the nature of the product.

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FDA guidance on gene therapies development and manufacturing - BioPharma-Reporter.com