Genetherapy

Archive for the ‘Gene Therapy’ Category

Isis Enters Broad Collaboration With Ortho-McNeil, Inc. for the Discovery, Development and Commercialization of Antisense Drugs to Treat Metabolic Diseases
- Includes license of two antisense drugs in development targeting glucagon receptor and glucocorticoid receptor – Includes research collaboration to identify antisense drugs to inhibit additional targets to treat metabolic diseases.

Isis Pharmaceuticals, Inc. (Nasdaq: ISIS) today announced a broad collaboration with Ortho-McNeil, Inc., a Johnson & Johnson
company, to discover, develop and commercialize antisense drugs to treat metabolic diseases, including Type 2 diabetes. As
part of the collaboration, Isis will grant to Ortho-McNeil worldwide development and commercialization rights to two of its
diabetes development candidates, ISIS 325568 and ISIS 377131, which selectively inhibit the production of glucagon receptor
(GCGR) and glucocorticoid receptor (GCCR), respectively. Additionally, Ortho-McNeil will provide funding to Isis to support the joint discovery of novel drugs to treat metabolic diseases, including diabetes and obesity. After the initial collaboration phase,
Johnson & Johnson Pharmaceutical Research & Development, L.L.C. (J&JPRD) will continue development of these drugs.
Ortho-McNeil will pay Isis a $45 million upfront licensing fee, and will provide Isis with research and development funding over
the period of the collaboration. In addition to the licensing fee, Isis could receive over $230 million in milestone payments upon
successful development and regulatory approvals of ISIS 325568 and ISIS 377131, as well as royalties on sales. Isis could also
receive milestones and royalties on the successful development and regulatory approvals of additional drugs discovered as
part of the collaboration. The agreement is subject to clearance under the Hart-Scott-Rodino Antitrust Improvements Act. Prior
to closing of the transaction, Isis plans to purchase the equity in Symphony GenIsis, Inc. and reacquire the intellectual property
related to the GCGR and GCCR programs as well as regain full ownership of ISIS 301012, the Company’s lipid-lowering drug
targeting Apolipoprotein B-100.
“We look forward to working with Ortho-McNeil, Inc. and J&JPRD to advance our glucagon receptor and glucocorticoid receptor
drugs through the clinic and to develop additional drugs against other promising targets,” said Lynne Parshall, J.D., Executive
Vice President and Chief Financial Officer, Isis pharmaceuticals. “This collaboration represents another major step for us in capturing value from our achievements in creating a new drug discovery platform technology and discovering commercially attractive antisense drugs.”
“This collaboration has been enabled by the productivity of our metabolic drug discovery program, which has evaluated more
than 120 targets in animal models using antisense drugs,” said Jeffrey Jonas, M.D., Executive Vice President, Isis
Pharmaceuticals. “Both ISIS 325568 and ISIS 377131 have broad and exciting therapeutic profiles that include lowering of
blood lipids and body fat, in addition to significant glucose-lowering effects. These drugs have demonstrated robust effects in extremely diabetic and hyperlipidemic animals and have demonstrated a unique and preferential distribution to tissues such as liver and fat, thereby potentially minimizing the systemic side effects that would be expected with traditional approaches against the same gene targets. We are enthusiastic about our research collaboration, which should allow us to discover additional
drugs against novel targets, thereby adding to our strong pipeline in this therapeutic area.”
About glucagon receptor (GCGR), target of ISIS 325568
Glucagon is a hormone that opposes the action of insulin and stimulates the liver to produce glucose. In Type 2 diabetes,
unopposed action of glucagon can lead to increased blood glucose levels. Reducing the expression of liver GCGR using
antisense inhibitors, and thereby reducing excessive liver glucose production, is expected to lower blood glucose levels and
help control Type 2 diabetes. In preclinical studies, antisense inhibitors of GCGR led to improved glucose control and reduced
levels of blood triglycerides without producing hypoglycemia.In addition, treatment with ISIS 325568 led to an increase in
circulating glucagon-like peptide, or GLP-1, which is a hormone that helps to preserve pancreatic function, thereby enhancing
insulin secretion.

About glucocorticoid receptor (GCCR), target of ISIS 377131
Glucocorticoid hormones have a variety of effects throughout the body, including promoting liver glucose production and fat
storage. Although inhibition of GCCR has long been recognized as an attractive strategy for development of therapeutics for
Type 2 diabetes, the side effects associated with systemic GCCR inhibition have challenged development of traditional drugs.
Antisense inhibitors of GCCR take advantage of the unique tissue distribution of oligonucleotides that allows the antisense
drugs to antagonize glucocortocoid action primarily in liver and fat tissue. Notably, antisense drugs do not reduce GCCR
expression in the central nervous system or adrenal glands — inhibition of GCCR expression in these two organs can lead to
systemic side effects. In preclinical studies, Isis has shown that ISIS 377131 has a broad therapeutic profile that includes
reduction of blood glucose levels, a dramatic and favorable effect on lipid levels including cholesterol and triglycerides, and a
reduction in body fat.

Dystrophin Gene Transfer safe in Duchenne muscular dystrophy
An Muscular Dystrophy Association supported trial to transfer genes for the muscle protein dystrophin, needed but missing in Duchenne muscular dystrophy (DMD), has shown that the procedure is safe and well tolerated in six boys. Researchers plan to test three additional patients at a higher dosage level.

In this trial, which began in March 2006, researchers injected a dystrophin gene compound called Biostrophin, which was developed with MDA support at Asklepios Biopharmaceutical in Chapel Hill, N.C., into the biceps muscles of boys with DMD.
Biostrophin is a combination of miniaturized dystrophin genes and adeno-associated viral shells that home to muscle fibers.

“The patients have been injected with the gene carried by an adeno-associated virus into one muscle of the arm,” said neurologist Jerry Mendell, director of the Gene Therapy Center and the clinician on the study. He also serves as co-director of the MDA clinics at Nationwide Children’s and Ohio State University Hospitals in Columbus. Mendell injected the children at Nationwide Children’s Hospital.

“The patients have been carefully followed for side effects of the treatment, and none have been encountered,” he said. “This is primarily a safety trial, and we can confidently report that safety has been achieved. An additional goal is to lay the ground work for future gene therapy trials by establishing the ideal dose for treatment. In this trial, two doses have been tested, and another will be required before completion of the study.” Mendell said the three additional trial participants will “receive a higher dose, which by all indications will be safe to administer.” {No participants are being recruited at this time.}

“Upon completion of the trial in nine subjects, we will be able to report to the scientific community and the public the results of the trial,” he said, “with recommendations for future gene therapy trials for this devastating form of muscular dystrophy.”

Researchers Identify Gene for Rare Form of Spinal Muscular Atrophy
TUCSON, Ariz. — Flaws in a gene known as UBE1 have been identified as the cause of a rare, X-chromosome-linked form of spinal muscular atrophy (SMA), a severe neurodegenerative disease, the Muscular Dystrophy Association (MDA) announced today.

Lisa Baumbach-Reardon, an associate research professor and head of the Neurogenetics Laboratory at the University of Miami (Fla.), who received MDA support for this work, led the study team with Alfons Meindl at Technical University Munich (Germany). The researchers published their findings in today’s issue of the American Journal of Human Genetics.

Having a second gene identified that causes symptoms of SMA is extremely important, not only for the development of better diagnostic tests but also for the development of new animal models and new therapeutic approaches,” said Sharon Hesterlee, MDA vice president for translational research.

The vast majority of SMA cases are caused by a mutation in the SMN1 gene on chromosome 5, which was identified in the mid-1990s. The chromosome-5 form of the disease affects both sexes and ranges in severity from the very severe and often-fatal infantile-onset form (type 1) to the somewhat less severe forms, type 2 and type 3.

The X-chromosome form of the disease, which affects male babies, occurs in a small percentage of SMA cases. Its exact incidence is unknown.

The disease closely resembles the type 1, chromosome-5 form of SMA in all respects except that it also affects the joints, which are not affected in chromosome-5 SMA.

The X-linked disease, which is present at birth, results in low muscle tone, absent reflexes, and multiple contractures (frozen joints) in association with loss of muscle-controlling nerve cells (motor neurons) in the spinal cord. It leads to death within two years.

The underlying genetic cause is any of a number of abnormalities (mutations) in a gene on the X chromosome that carries instructions for “ubiquitin-activating enzyme E1” (UBE1). This enzyme’s normal job in cells is to help attach ubiquitin molecules to proteins the cell needs to destroy. The ubiquitin “tag” marks proteins for destruction. Altered function of this protein disposal system is the likely mechanism by which X-linked SMA occurs.

The investigators screened four North American, one Mexican and one Thai family in which X-linked SMA was suspected and compared their X chromosomes to X chromosomes from unaffected people.

They screened 3,550 chromosomes from unaffected people for two of the UBE1 mutations suspected of causing X-linked SMA and found no instances of either mutation. A third suspected mutation in the same gene was not found in 7,914 chromosomes from people without the disease.

“This study is the culmination of 15 years of investigation, starting with identification of the first families with X-linked SMA, through years of gene-mapping studies to finally, last year, gene discovery and mutation identification.

“It’s been a long road, but we never gave up, because we promised the families who have this devastating illness that, with their participation in our research studies, we would someday identify the causal disease gene,” Baumbach-Reardon said. “Along the way, we’ve worked with an international team of geneticists, genetic counselors and scientists. We all share in the excitement and the hope that this discovery brings.”

About MDA

MDA is a voluntary health agency working to defeat more than 40 neuromuscular diseases, including SMA, through programs of worldwide research, comprehensive services, and far-reaching professional and public health education. For more information, visit www.mda.org.

Fatal brain cancer tamed by New gene therapy
Rats with an aggressive form of human brain cancer have been successfully treated with gene therapy that “trains” the immune system to attack tumours.

The results could pave the way for human trials early next year, say researchers who developed the system at the Cedars-Sinai Medical Center in Los Angeles.

Previous attempts to treat glioblastomas with gene therapy failed because some tumour cells survived and regrew. The new treatment overcomes this problem by permanently priming the immune system to pick off any straggler tumour cells.

A harmless virus that only infects fast-dividing cancer cells is injected directly into the brain, and used to deliver the therapeutic genes into the tumour. One gene, HSV1-TK, kills the cancer cells by activating ganciclovir, an otherwise ineffective drug administered into the rat’s abdomen. Yet the key to the therapy’s long-term success is a second gene, Flt3L, which summons immune “dendritic” cells from the bloodstream into the brain.

These cells engulf the debris and transport it back to lymph nodes, where they re-prime the immune system to attack any remaining tumour cells during and after treatment. The work will appear in Molecular Therapy
For more details

http://www.newscientist.com/article/mg19726444.900-fatal-brain-cancer-tamed-by-gene-therapy.html

A New Zealand study found that a gene therapy helped obese mice reduce their body weight by 20% after three weeks of treatment. The therapy involved the injection of as many as three kinds of genetic material into their brains. Plans are under way to begin clinical trials to control obesity in humans.

Genzyme gene therapy for people with peripheral artery disease failed in a clinical trial to help them regain some mobility

Score another one in the loss column for gene therapy. Cambridge, MA-based Genzyme said yesterday at a medical meeting that its gene therapy for people with peripheral artery disease failed in a clinical trial to help them regain some mobility.

The trial—one of the largest in the field of gene therapy—enrolled 289 patients who were injected with either a placebo or a low, medium, or high dose of Genzyme’s gene therapy treatment, researchers said at the American College of Cardiology meeting in Orlando, FL. The treatment, designed to deliver a copy of a gene called HIF1a, was supposed to help stimulate the growth of new blood vessels around clogged arteries in the legs, improving circulation and allowing people with severely limited mobility to walk for longer periods of time.

Biomedical researchers suspect graphene, a novel nanomaterial made of sheets of single carbon atoms, would be useful in a variety of applications. But no one had studied the interaction between graphene and DNA, the building block of all living things. To learn more, PNNL’s Zhiwen Tang, Yuehe Lin and colleagues from both PNNL and Princeton University built nanostructures of graphene and DNA.

read more

Scientists have used gene therapy to make insulin-producing cells in a mouse’s pancreas
Insulin producing cells (like the ones shown in green) have
been made in a mouse’s pancreas. Photo credit by Masur.
A new study out in Nature shows how to turn one kind of pancreas cell into an insulin-producing islet cell. This research is an important step in finding a cure for Type 1 diabetes.

People get Type 1 diabetes when their bodies attack and destroy their own islet cells. These people can’t make insulin anymore and so have to inject it. The best cure would be if scientists could replace the old islet cells with new ones. This is what the researchers in this study set out to do in mice.

The researchers made islet cells directly in a mouse’s pancreas. They did this by using gene therapy to reprogram one type of pancreas cell (an exocrine cell) into islet cells.

All cells share the same DNA. What makes each cell type different is which genes are on (or have been on in the past). Proteins called transcription factors are a big part of this programming.

The authors reasoned that they might be able to directly reprogram one kind of adult cell into another by adding the right mix of transcription factors. They couldn’t just add transcription factors though. Instead, they added transcription factor genes*.

Finding the right transcription factors was not simple. There are thousands of these things scattered throughout our DNA.

The researchers narrowed the list of possible candidates down by looking at those that were found in the pancreas. And then they further narrowed down the candidates by mutating these transcription factor genes and looking for effects on pancreas development. Nine transcription factors made it through these tests.

By testing different combinations of these genes, the authors were able to find a cocktail of three that turned an exocrine cell into an islet cell. These new cells looked and acted like islet cells. And what is also important, the new cells stayed islet cells even after the transcription factors were gone.

One of the big problems with gene therapy is that eventually the body recognizes the viral DNA as other and shuts it down. So the best gene therapies are the ones like this–the hit and run kind.

This is all very promising but the procedure is nowhere near ready for prime time yet. One problem, of course, is that mice aren’t people. What worked in a mouse might not work in a person.

An even bigger problem is that the created islet cells are scattered here and there throughout the pancreas. Islet cells work best in clumps (as they exist naturally). So scientists will need to figure out how to get them to clump together.

* Transcription factors are proteins and like all proteins, their instructions are found in genes.

Tags: exocrine, gene therapy, genes, genetics, islet cells, KQED, pancreas, pbs, QUEST, Science, transcription, transcription factor, Type 1 diabetes

Last blog I talked about how scientists turned skin cells into embryonic stem (ES) cells. This was big news because scientists can now make an ES-like cell without destroying an embryo.

This blog I thought I’d talk about how scientists have used these cells to cure a mouse’s sickle cell anemia. If the mouse stays cured, this is a hugely important finding.

First some terminology so I don’t have to keep saying, “skin cell turned ES cell.” Scientists are now starting to call these cells iPS for induced pluripotent stem cells and I figured I’d jump on the bandwagon too. (Pluripotent is just a way to say that a cell can turn into lots of other kinds of cells).

Now as you probably know, sickle cell anemia is a genetic disease that is more common in people whose ancestors came from areas where there was lots of malaria. In sickle cell anemia, the red blood cells “sickle up,” forming crescent shapes. These shapes can’t fit in the smallest blood vessels causing the problems associated with the disease. Right now there are treatments but no cure.

The way to cure the disease is to fix the broken hemoglobin gene in the cells that make red blood cells. Since red blood cells are all replaced within a few months, this would lead to a cure pretty quickly.

Unfortunately, fixing a gene is not like falling off a log–it is really hard to do. The scientists in this study decided to try it with iPS cells. Basically they replaced the mouse’s blood stem cells with newly repaired ones so that the new blood stem cells made healthy new red blood cells. The mouse has not shown signs of sickle cell anemia for 12 weeks so far.

I don’t want you to come away thinking that it was an easy thing to do. It wasn’t (see below). But it does show that it is possible to treat and possibly cure sickle cell anemia in mice using iPS cells.

To move it to humans, we need to make sure that the treatment sticks. When these kinds of things have been tried with gene therapy, the cure almost always wears off over time. It shouldn’t happen at the DNA level with the way they did their experiment, but we need to wait and see.

The scientists also need to find genes that can turn a skin cell into an iPS with less risk of causing cancer. And to find better ways to get these genes into the skin cell so that, again, the treatment doesn’t cause cancer.

Even taking all of this into account, this is a very promising first step. Curing a genetic disease with stem cells that do not get rejected by the recipient’s body is one of the big goals of stem cell research. And these researchers may have accomplished this in mice.

More details on how to cure a mouse’s sickle cell anemia:

1. Add four genes to turn the skin cell into an iPS cell.

See the previous blogto see how to do this. To decrease the risk of the mouse developing cancer from these cells, the researchers chopped out one of the genes they used, the myc gene.

2. Use the ES cell to fix the gene using a process called homologous recombination.

Homologous recombination is a way to swap out one DNA for another. It is incredibly inefficient and we can really only get it to work at all in ES cells. Out of 72 cells, they managed to get one where one copy of the gene was repaired.* This result showed that homologous recombination would work in iPS cells which was an open question.

3. Turn the ES cell into a blood-like stem cell by adding the HoxB4 gene.

4.Destroy the mouse’s bone marrow and replace the cells with the new blood stem cells.

This is really just a bone marrow transplant using the newly created cells as the blood stem cells.

*In the end they had a mouse with one of its copies of the hemoglobin gene repaired in its blood cells. (All the rest of the cells including its sperm cells still carried the disease version of the hemoglobin gene.) The mouse exhibited no sickle cell anemia symptoms similar to most human carriers of the disease who have a single broken copy.

Dr. Barry Starr is a Geneticist-in-Residence at The Tech Museum of Innovation in San Jose, CA.

latitude 37.3316, longitude -121.89

Tags: gene therapy, genetics, HoxB4, induced pluripotent stem cells, KQED, kqedquest, myc, pbs, QUEST, Science, sickle cell anemia

Scientists can now turn skin cells into embryonic
stem cells like these.(Image: Nissim Benvenisty)It is amazing how fast stem cell research is accelerating. Six months ago, we had to destroy embryos to get at their precious embryonic stem (ES) cells. Or we had to at least steal them.

Now, as 2008 begins, we can turn skin cells into ES cells in mice and humans. This is huge and here’s why:

1) No embryos need to be destroyed
2) No one needs to be cloned
3) ES cells derived from skin cells won’t be rejected by the body

So how’d the researchers do it? As with any important new finding, this one started out as basic research. And like many other findings, this one also started out not in humans but in an animal model system.

A Japanese group had been studying how a mouse ES cell eventually gets turned into a skin cell. In the end, they identified around 20 genes that were turned on to reprogram a skin cell into an ES cell.

The 20 genes the Japanese group identified are really master control genes. They are responsible for affecting how lots of other genes work. So, all a scientist would have to do is turn on these 20 genes in a skin cell and you’d get back to an ES cell. Sounds simple, right?

Unfortunately, scientists aren’t very good at all at turning on a specific gene in a cell let alone 20. To get around this limitation, the scientists decided to add the genes to a skin cell using gene therapy.

Unfortunately, scientists can’t easily add 20 genes to a cell with gene therapy either. This meant they had to find the bare minimum that might work. After much research, the group settled on four genes that could turn a skin cell into an ES cell.

Remember, this was all in mice. Now this same group (and another from the U.S.) has accomplished the same thing with a human cell. Both groups have taken a human skin cell, added four genes, and changed it into an ES cell.

We aren’t going to be curing diseases with these cells quite yet though. When the Japanese group put the mouse cells back into a mouse, 20% of them developed cancer. This is probably due to one of the genes they used (myc), as well as the way they did their gene therapy (viral mediated).

The U.S. researchers who converted the human skin cell were able to do it without the myc gene. This tells us there are different sets of genes that can work in this process. Hopefully scientists can discover a set of genes and a way to get them into cells that won’t cause cancer.

All this work got me to thinking. I wonder if scientists would have worked this hard to make ES cells from skin cells without George Bush’s ban on ES cell research. They certainly would have got there eventually but would they have gotten there so quickly?

Dr. Barry Starr is a Geneticist-in-Residence at The Tech Museum of Innovation in San Jose, CA.

latitude 37.3316, longitude -121.89

Tags: gene therapy, genetics, KQED, kqedquest, myc, pbs stem cells, QUEST, Science

A research report featured on the cover of the September 2009 print issue of The FASEB Journal (http://www.fasebj.org) describes how Australian scientists developed a new gene therapy vector that uses the same machinery that viruses use to transport their cargo into our cells.

read more

GAINESVILLE — A common antibiotic can function as an “off switch” for a gene therapy being developed for Parkinson’s disease, according to University of Florida researchers writing online in advance of September’s Molecular Therapy.

read more

COLUMBIA, Mo. — A new study from the University of Missouri may shed light on how to increase the level and quality of activity in the elderly. In the study, published in this week’s edition of Public Library of Science — ONE, MU researchers found that gene therapy with a proven “longevity” gene energized mice during exercise, and might be applicable to humans in the future.

read more

A study from the Center for Molecular Genetics at the University of California, San Diego School of Medicine shows that a gene called HPRT plays an important role in setting the program by which primitive or precursor cells decide to become normal nerve cells in the human brain.

read more

Gene therapy holds promise in the treatment of a myriad of diseases, including cancer, heart disease and diabetes, among many others. However, developing a scalable system for delivering genes to cells both efficiently and safely has been challenging.

read more

PORTLAND, Ore — Researchers at Oregon Health & Science University’s Oregon National Primate Research Center (ONPRC) believe they have developed one of the first forms of genetic therapy — a therapy aimed at preventing serious diseases in unborn children.

read more

OKLAHOMA CITY — Researchers at the University of Oklahoma Health Sciences Center have shown the first link between a newly discovered anti-aging gene and high blood pressure. The results, which appear this month in the journal Hypertension, offer new clues on how we age and how we might live longer.

read more

NEW YORK (September 20, 2009) — Genes previously known to be essential to the coordinated, rhythmic electrical activity of cardiac muscle — a healthy heartbeat — have now also been found to play a key role in thyroid hormone (TH) biosynthesis, according to Weill Cornell Medical College researchers.

read more

GAINESVILLE, Fla. — Researchers from the University of Washington and the University of Florida used gene therapy to cure two squirrel monkeys of color blindness — the most common genetic disorder in people.

read more

PHILADELPHIA — One year after a trio of young adults received gene therapy for an inherited form of blindness, researchers have documented that the patients are still experiencing the same level of remarkable vision improvements previously measured within weeks.

read more

GAINESVILLE, Fla. — Scientists have discovered that even in adults born with extremely impaired sight, the brain can rewire itself to recognize sections of the retina that have been restored by gene therapy.

read more

Three young adults who received gene therapy for a blinding eye condition remained healthy and maintained previous visual gains one year later, according to an August online report in Human Gene Therapy. One patient also noticed a visual improvement that helped her perform daily tasks, which scientists describe in an Aug.

read more

Washington, DC — Researchers in the Memory Disorders Program at Georgetown University Medical Center are now recruiting volunteers for a national gene therapy trial — the first study of its kind for the treatment of patients with dementia due to Alzheimer’s disease.

read more

Researchers have identified a mechanism that may keep a well known signaling molecule from eroding bone and inflaming joints, according to an early study published online today in the Journal of Clinical Investigation.

read more

The blood brain barrier is generally considered an obstacle to delivering therapies from the bloodstream to the brain. However, University of Iowa researchers have discovered a way to turn the blood vessels surrounding brain cells into a production and delivery system for getting therapeutic molecules directly into brain cells.

read more