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Archive for the ‘Gene Therapy Research’ Category

What is gene therapy? – Genetics Home Reference – NIH

Gene therapy is an experimental technique that uses genes to treat or prevent disease. In the future, this technique may allow doctors to treat a disorder by inserting a gene into a patients cells instead of using drugs or surgery. Researchers are testing several approaches to gene therapy, including:

Replacing a mutated gene that causes disease with a healthy copy of the gene.

Inactivating, or knocking out, a mutated gene that is functioning improperly.

Introducing a new gene into the body to help fight a disease.

Although gene therapy is a promising treatment option for a number of diseases (including inherited disorders, some types of cancer, and certain viral infections), the technique remains risky and is still under study to make sure that it will be safe and effective. Gene therapy is currently being tested only for diseases that have no other cures.

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What is gene therapy? – Genetics Home Reference – NIH

Gene Therapy Manufacturing – The Bioprocessing Summit

Cambridge Healthtech Institute s 3rd AnnualAugust 16-17, 2018

It is an exciting time for gene therapy therapies on the market, encouraging clinical data and a long list of pharma collaborations. Pricing and reimbursement takes a majority of the headlines but equally important is producing these therapies in a scalable, cost-effective and robust way, all the while developing a clear CMC and characterization profile that satisfies the regulators.

Cambridge Healthtech Institutes Gene Therapy Manufacturing meeting takes a practical, case study driven approach to the process development, scale-up and production of gene therapies, tackling key topics such as AAV, lentivirus and retrovirus process development and scale-up, CMO management from early to late-stage development.

Final Agenda

Day 1 | Day 2 | Speaker Biographies

Thursday, August 16

11:30 am Registration Open (Grand Ballroom Foyer)

12:15 pm Enjoy Lunch on Your Own

1:15 10th Anniversary Cake Break in the Exhibit Hall with Last Chance for Poster Viewing (Grand Ballroom)

1:55 Chairpersons Remarks

John Pieracci, PhD, Director, Purification, Biogen

2:00 KEYNOTE PRESENTATION: Challenges and Strategies for the Development of a Robust, Scalable, Cost-Effective Biomanufacturing Process

Sadettin Ozturk, PhD, Senior Vice President, Process and Analytical Development, MassBiologics

The use of viral vectors has increased in recent years, both as gene therapies and as vectors for ex vivo cell therapy products. Industrialization of viral vector manufacturing is maturing as companies tackle problems in process control, scale-up, facility design, characterization and quality, and regulatory considerations. This presentation will examine the current state of the art, emerging technologies and challenges.

2:45 Enabling Industrial Scale Production of Lentiviral Vectors for Gene Therapy

Kelly Kral, PhD, Associate Director, Vector Process Development and Manufacturing, bluebird bio

Lentiviral vectors are an ideal platform for indications requiring long-term, stable expression, but the production processes have historically been limited by scale. As the field has now entered commercialization, there is demand for larger quantities of vector, driving the need for more scalable processes. This presentation will review the development, scale-up, and tech transfer of our suspension-based lentiviral vector process.

3:15 Strategies to Deliver Scalable and Reliable Lentiviral Vector Biomanufacturing

Jeffrey Bartlett, PhD, CSO, Calimmune, Inc.

Large-scale clinical production of lentiviral vectors (LV) using current good manufacturing practice (cGMP) methods comes with significant challenges. We have established the Cytegrity stable cell line system for LV bioproduction and have defined key process, quality and regulatory parameters needed to achieve desired productivity and quality across multiples scales and different bioproduction systems. This approach has allowed the production of LV required for Phase I and II clinical trials, while paving the way for future commercialization.

3:45Evolving Process-Centric Facility Design

Mike Sheehan, MSc, MBA, PMP, Senior Project Manager, DPS Group

Increasingly gene therapy products transitioning from clinical phase to commercial manufacture is driving demand for companies to provide additional capacity. Bringing products to market requires exploring opportunities for leading edge facility design, implementing new & evolving technologies, responding to scalability, speed to market and financial considerations.

4:00 Refreshment Break (Foyer)

4:15 Scalable Lentiviral Vector Production Using HEK293 Suspension Cells

Parminder S Chahal, Research Officer, Human Health Therapeutics Research Centre, National Research Council Canada

We have developed expertise in the production of lentiviral vectors (LV) using packaging cell lines and stable producers. Both grow in suspension and in serum-free conditions. Using a stable producer cell line that produces LV expressing GFP, we have compared different modes of operation in bench-scale bioreactors (batch, fed-batch and perfusion). Next, a battery of filters and supplements were evaluated for clarification. A maximal recovery of 78% was obtained.

4:45 Development and Characterization of Novel Micro-RNA Attenuated Oncolytic Herpes Simplex Viruses

Jonathan Platt, PhD., Senior Research Scientist, CMC Operations, Oncorus

Oncorus is developing next generation HSV-based oncolytic virus with enhanced potency for tumor cell killing and recruitment of the immune system. Our innovative miR-attenuation strategy enables robust viral replication in tumor cells, while preventing replication in healthy tissue. The development and characterization of therapeutic oHSV requires thorough product understanding gained through process characterization. Strategies for development and characterization of manufacturing processes centered around a strong organizational infrastructure will be presented.

5:15 End of Day

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FRIDAY, AUGUST 17

8:00 am Registration Open and Morning Coffee (Grand Ballroom Foyer)

8:25 Chairpersons Remarks

Nathalie Clment, PhD, Associate Director and Associate Professor, Powell Gene Therapy Center, Pediatrics, University of Florida

8:30 FEATURED PRESENTATION: rAAV Vector Design, Capsid Directed Evolution and Scale Up Activities Using the BEVS System

Jacek Lubelski, PhD., VP, Global Pharmaceutical Development, uniQure

9:00 Towards a Pivotal Process for AAV Manufacture with HSV

David Knop, PhD, Executive Director, Process Development, AGTC

9:30 Large-Scale Manufacturing of Clinical Grade AAV in the Academic Setting

Nathalie Clment, PhD, Associate Director and Associate Professor, Powell Gene Therapy Center, Pediatrics, University of Florida

The talk will present our current methods for the production of research and clinical-grade rAAV with a special emphasis on the HSV-based suspension method capable of generating high titers of improved rAAV quality. Up-to-date in vitro, in vivo, and clinical data will be shown, and pros and cons of the method will be discussed in comparison to the two other most common methods, transfection and the baculovirus system.

10:00 Networking Coffee Break (Foyer)

10:30 Scale-Up Approach to AAV Manufacturing

Johannes C.M. van der Loo, PhD, Director, Clinical Vector Core, The Raymond G. Perelman Center for Molecular and Cellular Therapies, Childrens Hospital of Philadelphia

The Clinical Vector Core at the Childrens Hospital of Philadelphia manufactures preclinical- and clinical-grade AAV for academia and industry-sponsored clinical trials. With the field of gene therapy maturing, there is a growing need for larger scale products. We will discuss a strategy for scale-up that builds on our existing mammalian adherent cell-based manufacturing platform.

11:00 Virus-Like Particles and Other Extracellular Particles from Insect and Mammalian Cells

Alois Jungbauer, PhD, Professor, Institute of Biotechnology, University of Natural Resources and Life Sciences (BOKU)

Virus-like particles and other extra cellular particles are a next generation of biopharmaceuticals. They can be produced by a wide variety of host cells. The challenge is the production of high titers and downstream processing. The particle of interest are contaminated with other particles with similar biophysical properties and therefore difficult to separate. Examples will be given for 3 different cell types.

11:30 Considerations for the Purification Process Characterization of an AAV from Recovery to Drug Substance

Ratish Krishnan, PhD, Scientist, Bioprocessing Research & Development, Pfizer

Smart and efficient approaches for lab-scale characterization are required to ensure a robust adeno-associated manufacturing process. Specific challenges related to the uniqueness of characterizing an AAV manufacturing process will be discussed. Focus will be given to working with limited quantities of material and employing assays that are still being defined.

12:00 pm Next Generation AAV Viral Vector Manufacturing: Proven Technologies with a Modern Twist

Sandhya Buchanan, Director, Upstream Process Development, FUJIFILM Diosynth Biotechnologies

Current approaches to commercial-scale manufacture of viral vectors have been successful for many early phase trials and some late phase trials. Unique challenges/limitations arising for AAV manufacturing include quantities sufficient for patient needs and consumables for manufacturing. We discuss proven technologies blended with modern advancements to meet the needs of the advancing field of gene therapy.

12:30 Enjoy Lunch on Your Own

1:25 Chairpersons Remarks

Chia Chu, Senior Principal Scientist, Bioprocess Research & Development, Pfizer

1:30 FEATURED PRESENTATION: Separation of Full and Empty AAV Particles Using Scalable Isocratic Elution Chromatography

Meisam Bakhshayeshi, PhD, Head, Purification Development, Gene Therapy, Biogen

Robust and efficient removal of AAV empty particles is a critical part of the AAV manufacturing process. In this study, we present a scalable ion exchange chromatography process with isocratic wash and elution to separate full and empty particles. A combination of mono- and di-valent salts were used as eluents to achieve the high degree of resolution required for this separation. High product purity and recovery was achieved from this process.

2:00 Lyophilisation of AAV Gene Therapy Product

Tanvir Tabish, PhD, Head, Drug Product Development for Gene Therapy, Device and Combination Products, Shire

The gene therapy adeno-associated virus (AAV) subtype 8 containing Factor IX (FIX)(BAX335) was formulated in a new proprietary buffer and lyophilized. A stability study was established with the lyophilized material to determine its stability profile at the accelerated temperature of +5C over a 10 month period. The freeze-dried product displayed an improved stability profile when stored at a temperature of +5C. We demonstrated the feasibility of lyophilisation of the AAV viral drug product in the formulation buffer.

2:30 AAV Manufacturing at 2,000L Scale

Alex Fotopoulos, PhD., Senior Vice President, Technical Operations, Ultragenyx.

Changing the manufacturing site (tech transfer) should always include an assessment of comparability, however the ability to demonstrate this varies between early and late development. This talk will discuss common pitfalls and mistakes and highlight key aspects of the comparability exercise.

3:00 CMO Selection for Cell & Gene Therapy

Chad Green, PhD, Principal & Senior Consultant, Dark Horse

As the diversity of CMOs available for cell and gene therapies continues to grow worldwide, identifying the most suitable to engage is becoming an increasingly complex challenge. This presentation will address fundamental questions, such as whether a CMO is even the best choice for manufacturing before progressing to provide concrete guidance on the critical questions to ask prospective CMOs (and yourself), how to ask them and how to analyze the answers and make an optimal, rational choice.

3:30 Close of Conference

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Gene Therapy Manufacturing – The Bioprocessing Summit

The Gene Therapy Plan: Taking Control of Your Genetic …

Praise for The Gene Therapy PlanA guide to harnessing the power hidden in food to subvert a genetic predisposition for disease. . . . Gaynors informative tome is worth reading. Publishers Weekly

The Gene Therapy Plan identifies how the lives we lead, and in particular, the foods and nutritional supplements we ingest, are a key determining factor in whether latent disease (which most people have to some degree) materialize or stay dormant. By identifying researched nutritional protocols that target specific conditions, and by providing a range of rich case studies from his practice as a leading oncologist and internist, Dr. Gaynor provides insight and an action plan into how the body operates that will benefit medical practitioners and patients alike. Deepak Chopra, M.D.The Human Genome Project promised to create a new era of genetic medicine, new drugs, and therapies to advance human health. But the real awakening has been the understanding of foodreal whole foods, herbs, phytonutrientsas medicine and how it can literally upgrade your biologic software by improving the expression of your genes.In The Gene Therapy Plan Dr. Gaynor makes the healthcare of the future available to you today. If you want to learn how to use food and nutrients to prevent and even reverse most chronic disease, read this book! Mark Hyman, M.D., Director of the Cleveland Clinic Center for Functional Medicine and author of the #1 New York Times bestseller The Blood Sugar SolutionThe Gene Therapy Plan is a comprehensive and practical approach to the science of epigeneticsand how to apply it to your life right now. This book is a godsend that could save your life. Christiane Northrup, M.D., author of the New York Times bestseller Womens Bodies, Womens WisdomA brilliant and important piece of work from one of our most distinguished and creative medical thinkers. Do yourself and your family a huge favor: Read this phenomenally important book and learn why and how you can live a healthier life. Devra Davis, Ph.D., M.P.H., founder and president of the Environmental Health Trust, author of The Secret History of the War on CancerDr. Gaynor is a visionary healer. This is a comprehensive, coherent, practical, and easily digestible resource for all who wish to tip the balance away from disease toward health and wellness. Sheldon Marc Feldman, M.D., Vivian L. Milstein Associate Professor of Clinical Surgery, Columbia University College of Physicians and SurgeonsDr. Gaynor presents a comprehensive strategy for readers to re-orient their diet and lifestyle using everyday activities that can help one live longer, and live better. With The Gene Therapy Plan, Dr. Gaynor brings his own integrative philosophy and practice to readers in an engaging and actionable way. William Li, M.D., president and medical director of The Angiogenesis FoundationDr. Gaynor has and always will be at the forefront of integrative medicine. The Gene Therapy Plan empowers you to take control of your health and life. Mimi Guarneri, M.D., president of the Academy of Integrative Health and Medicine

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The Gene Therapy Plan: Taking Control of Your Genetic …

GeoGene: Gene Therapy, What it is, The process and Vectors …

What is Gene Therapy?

Certain diseases are caused byfaulty genes which produce defective proteins. The symptoms of genetic disease are the result of subsequent disrupted vital cell processes caused by missing or defective proteins. In theBio Building Blockssection of this web-site, protein synthesisis outlined as the process whereby,genesultimately give rise toproteinswhich are responsible for important cell processes. If a particular gene is defective, its protein product may not be made at all, may work poorly or may behave too aggressively.

For example:Cystic Fibrosis(CF) is caused by amissing or mutated genethat results in adefective cell membrane transport protein. This ultimately results in a build-up of thick mucus in the lungs and the body’s airways.As another example,cancersare caused by cells that divide and grow uncontrollably.Particular genes can cause such cell growth to occur if they are defective. Such defective genes are calledoncogenes.

Are we treating the symptom or treating the cause? Historically, genetic disorders have been treated byaddressing the biological eventsthat result from the genetic mutation, as opposed tofixing a defective gene(or genes) the ultimate source of the problem.For example, the treatment of diabetes has historically involved the administration of insulin (a protein), instead of fixing the defective genes in pancreatic cells that actually prevent these cells from producing insulin in the proper amounts, on their own.

Gene therapy is an alternative approach whereby a genetic disorder is treated by inserting or integrating new genes into human cells. Many attempts at gene therapy aim to add a useful gene into a selected cell type to compensate for a missing or defective version. Other efforts aim to instill new properties in the target cell. This latter method is often employed in the treatment of cancer, where toxic genes are added to cancer cells in an effort to eliminate them.For an overview of how a specific gene is located and isolated from its source (so that it can be introduced into the patient) see ourGenetic Engineeringsection.

It should be noted that even the most advanced somatic cell therapy techniques are still in clinical trials, and are not yet approved for general application. Much more research is required to develop safe, reliable gene therapy techniques.

Depending on the cell types affected, gene therapy can be classified into two broad categories: germ-line gene therapy and somatic cell gene therapy.Germ-line therapyoccurs when germ cells (reproductive cells) are altered, meaning that the resultinggenetic changes will be passed on to the patient’s offspring. Alternatively,somatic cell gene therapyinvolves the alteration of somatic cells (non-reproductive body cells, like skin, brain or muscle cells). This genetic manipulation willonly affect the individualto which the changes were made. Somatic cell gene therapy is the only type presently being considered in humans.

Suppose a patient is afflicted with a genetic disorder that affected only certain cells in her or his brain. How could she or he be treated using gene therapy so that the therapeutic gene targets only those cells affected by the disorder? One solution is through the use of avector. A vector is simply a “transporter” for the genetic material that allows it to enter the target cell and, depending on the vector type, can cause new genes to be integrated into the host cell genome. Vectors must be administered totarget specific cell types.

There are three principal ways in which vectors can be administered to carry new genes into target cells. The first is calledex vivosomatic gene therapy, wherethe target cells are removed from the body, cultured in the laboratory with a vector, and re-inserted into the body. This process is usually carried out using blood cells because they are the easiest to remove and return.

The second option,in situsomatic gene therapy, occurs when thevector is placed directly into the affected tissue. This process is being developed for the treatment of cystic fibrosis (by direct infusion of the vector into the bronchi of the lungs), to destroy tumours (eg: brain cancer), and for the treatment of muscular dystrophy.

The third option isin vivosomatic gene therapy, where thevector is injected into the bloodstream, and is able to find and insert new genes only into the cells for which it was specifically designed. Although there are presently noin vivotreatments available, a breakthrough in this area will make gene therapy a very attractive option for treatment.In this case the vector designed to treat our hypothetical patient could be injected into a blood vessel in her or his arm and would find its way to the affected brain cells!

Vectors used in gene therapy can be classified as eitherviralornon-viral.

BothDNAandRNAviruses are being developed as vectors for use in gene therapy. Viruses are an excellent choice for use as vectors, because they have gained, through long periods of evolution, the ability to avoid destruction by the human immune system, and the capacity to get their own genetic material inside human cells. As discussed in theBio Building Blockssection, viruses consist of genetic material (DNA or RNA) surrounded by a protective coat made of proteins and occasionally other molecule types as well.

Normally, a virus infects a cell when its genetic material enters it. Once the viral genetic material is inside, it “hijacks” the cell’s DNA- and protein-making machinery, causing it to produce new viruses. Some viruses are even capable of integrating their own genetic material into the host cell’s genome.

It is the outer protective viral coat that allows the inner genetic material to penetrate the cell. This outer coat also determines the type of cell that a given virus will infect. Once inside, it is the harmful viral genes that actually hijack the cell and eventually cause it to die.

To trick the virus, scientists retain the outer viral coat, but modify the inner genetic material. They remove the harmful genes and replace them with therapeutic ones. Now the virus ispathogenically disabled(it is no longer harmful to the cell it infects) and incapable of reproducing itself. However, it retains its capability to transfer its genetic material to the cells for which its outer coat was designed.The transfer of genetic material by way of a viral vector is calledtransduction.

The structure and mode of infection of retroviruses is discussed in theBio Building Blockssection. Briefly, retroviruses have RNA as their genetic material. These viruses also carry a specialenzymethat, once inside a cell, makes double-stranded DNA from the virus’ RNA template. The new DNA becomes incorporated into the host cell’s genome. When the “new” chromosomal genes are transcribed, new virus particles are made, which will leave the cell to infect other cells.

Most types of retroviruses are not very harmful to the cell. Even though allviruses to be used as vectors are deactivated,’ meaning that their harmful genes are removed, the fact that the types of retroviruses presently being used as vectors are not very harmful in their natural forms means that their use poses less risk than the use of some other viruses. Even if something goes wrong and some of the original retrovirus particles are administered to the patient, they will not cause serious problems.

Themurine leukaemia virus(MuLV) is one of the more popular retroviruses used as a retroviral vector. The reproductive genes in the retrovirus are replaced with the therapeutic gene. When the virus infects the cell,the therapeutic gene gets incorporated into the cell chromosomes. The new gene causes a protein to be produced which is hoped to have some positive therapeutic effects, either providing an otherwise missing protein, or causing the destruction of harmful cells.

There are several challenges that scientists must overcome for effectivein vivotreatment of disease using retroviral vectors. For example, theviruses must be capable of targeting only those cells affected by the disorder. If this were the case, they could be injected directly into the bloodstream (in vivogene therapy) where they would become dispersed throughout the body, but would only transduce those cells for which they were designed. Presently, retroviral vectors are not terribly specific, meaning that many cells not intended for the transfer of the gene are transduced by the virus, which reduces the transfer to the targeted cell population.

To understand how viruses can be made to be more specific, we should considerhow viruses “choose” the cells they infect. A virus must bind to specific surface receptor molecules to gain entry into a cell. To this end, retroviruses have outer envelope proteins that fit perfectly into certain receptors on specific cells. The MuLV virus binds to cells containing a receptor called theamphotropic receptor. The problem is that a broad range of cell types possess the amphotropic receptor. This means that the MuLV virus, in its natural form, can infect all of these cell types, most of which are likely not the target of the therapy!

To make retroviral vectors more specific about the cells they invade, scientists are experimenting with ways ofreplacing or modifying the outer viral proteins, so that they fit into more rare receptors that appear only on specific cell types being targeted for therapy.Another approach has been toadd new proteinsto the outer viral envelope which either better recognize the target cell, or better recognize the region of the body where the target cells are located.

Another challenge is toengineer retroviral vectors to transducenon-dividingcells. Most retroviruses target actively dividing cells, which makes them ideal for the treatment of rapidly dividing tumour cells, but not in situations where a therapeutic gene is to be introduced into a non-dividing cell, like in the treatment of cystic fibrosis mentioned above. Those few retroviruses that have the ability to infect non-dividing cells are the harmful ones (HIV, the virus that results in AIDS, is one of them). HIV viruses (with their harmful genes removed) cannot be used as vectors, because even with the removal of these genes, there is still a possibility that the virus might become harmful again through a process called recombination. To virtually eliminate the possibility that harmful viruses are produced in this way, while still harnessing the capability of HIV to transduce non-dividing cells, scientists are experimenting with the development of hybrid vectors, made up mostly of other retroviruses and which contain very small and harmless parts of the HIV virus.

As of April, 1998, there was only one vector-based therapeutic technique in the final clinical trial stage(called Phase III). This technique employs a retroviral vector called G1TkSvNa for the treatment ofglioblastoma multiforma, a malignant brain tumour. The treatment is an in situ therapeutic technique, where mouse cells capable of producing and secreting the vector are injected into the tumour.The secreted vectors infect only those cells that are rapidly dividing, meaning only the tumour cells and the vessels supplying blood to the tumour are transduced. The gene transduced into the tumour cells gives rise to a protein (calledHerpes Simplex Thymidine Kinaseor HSTk).Fourteen days later, a drug called ganciclovir is injected into the patient, which is toxic to any cell that incorporates it into its DNA. Only the cells containing HSTk (the tumour cells) are capable of incorporating ganciclovir into their DNA and these cells are therefore selectively killed off.

Adenoviruses are DNA viruses that are able to transduce a large number of cell types, including non-dividing cells. Adenoviruses also have the capacity to carry long segments of added genetic information. In addition, it is fairly easy to produce large amounts of adenoviruses in culture. Adenoviruses, in their natural form, are not very harmful, typically causing nothing more serious than a chest cold in otherwise healthy people. This means that their use as vectors is quite safe. For all these reasons, adenoviruses are currently the most widely used DNA vectors for experiments inin situgene therapy.Research is currently under way using adenoviral vectors for the treatment of several cancers and cystic fibrosis.

The size of the adenovirus protein coat is just large enough to fit the original viral DNA inside. As a result, for every new therapeutic gene to be inserted into the viral genome, a corresponding piece of the old viral DNA must be removed.To make room for the new therapeutic DNA, a region of the old viral DNA called E3 is sometimes removed. However, removing the E3 region has drawbacks, because it codes for a protein that suppresses the human immune response against the vector. Without the E3 region, the virus is more susceptible to the immune system and is more likely to be destroyed before it has served its purpose.

Adenoviral vectors send their DNA to the nucleus, butthe DNA does not get incorporated into the host cell’s chromosomes. For this reason, the viral DNA has a finite lifetime within the cell before it is degraded, meaning that the added genes are effective only temporarily. Treatments for chronic conditions like cystic fibrosis, therefore, would need to be repeated periodically, perhaps on a monthly or yearly basis. On the other hand, the transient nature of therapeutic gene expression is useful when the added genes are needed temporarily to induce an immune response to a cancer or pathogen.

Among the other virus types being explored as vectors are theadeno-associated virus(AAV) and theherpes simplex virus(HSV). Both are DNA-based viruses. AAV integrates its genetic material into a host chromosome and cause no diseases in humans. However, because AAV are small, they cannot accommodate large genes. HSV vectors do not integrate their genes into the host genome. They tend to target neurons and thus have the potential for use in the treatment of neurological disorders.

The use of non-viral vectors can involve a direct injection ofplasmid DNAor mixing plasmid DNA with compounds that allow it to cross the cell membrane and protect the DNA from degradation. These methods are currently less efficient than the use of viral vectors. However, unlike disabled viruses which have the possibility of changing spontaneously and causing disease, non-viral vectors possess no viral genes and therefore cannot cause disease.

Liposomes are small, hollow spheres of fatty molecules that are capable of carrying DNA inside of them.A liposome can fuse with the cell membrane, releasing its contents into the cell interior.

Plasmid DNA containing the therapeutic gene is incubated with the empty liposomes under specific conditions. The negatively charged DNA binds to the positively charged (calledcationic) liposomes and the plasmids are absorbed. Liposomes containing plasmid DNA are calledlipoplexes.The lipoplexes can subsequently enter the cells of interest, and thus introduce the therapeutic DNA into the cells.

Experiments have been carried out where lipoplexes have been injected into tumours. The lipolexes contained a gene that gives rise to a protein that is recognized by the human immune system. Theoretically, thesegenes should cause the tumour cells to express the recognizable protein on their surface, which will mark the cells for destructionby the immune system.

The use of lipoplexes for the treatment of cystic fibrosis is currently being studied as well. The cause of the illness is a defective gene which causes a particular protein in the patient’s lung cells to be defective. The lipoplexes that are administered using an aerosol spray into the patient’s lungs, contain the gene for a functional version of the protein.

Lipoplexes are not as efficient as viral vectors in introducing genes into cells. To improve their efficiency, scientists are attempting to incorporate some viral proteins into the outer surfaces of lipoplexes. In particular, the viral proteins that recognize and bind to specific molecules on the host cell’s surface, are being incorporated.

Muscle cells have been shown to be capable of taking up and expressing plasmid DNA. This raises the possibility that plasmid DNA injected into muscles could stimulate the production by muscle cells of a therapeutic protein. This protein could then be secreted into the bloodstream and to the rest of the body. For example, the gene coding for erythropoietin (a protein which helps stimulate the production of red blood cells) has been experimentally injected into animal muscles with some success. Such a treatment would be useful to patients after chemotherapy or radiation therapy.

In addition,plasmid DNA shows promise for use in vaccines, stimulating protective immune responses against diseases like herpes, AIDS or malaria. When the plasmid DNA is injected into muscles, it enters muscle cells and as a result, causes the cells to produce the proteins that correspond to the genes the plasmids contain. The immune system will then learn to recognize the new proteins and will destroy them if they are encountered in the future. Experiments are currently under way where plasmids containing genes for viral coat proteins are injected, in attempt to make the immune system recognize these viruses, so that it will attack and destroy them if they are ever encountered.

As discussed in theBio Building Blockssection, viruses hijack cellular machinery to produce their own proteins and to replicate their genetic material, which results in the production of new viruses.One of the potential uses of antisense technology is to prevent viruses that infect a host cell from producing their own proteins. This would, in turn, prevent their replication.

Recall that proteins are constructed through atwo step process. In the first step,DNA is transcribed to produce messenger RNA(mRNA). The second step involves thetranslation of the mRNA to make a protein. Antisense drugs interact with mRNA, preventing them from being translated into their corresponding protein.

An mRNA molecule is a chain of nucleotides, that gets “read” by a ribosome in the synthesis of a protein. An antisense drug is anoligonucleotide(a relatively small, single stranded chain of nucleotides) that iscomplementaryto a small segment of a target mRNA molecule. When the drug comes into contact with its complementary mRNA, it binds to the mRNA in the same way as the two strands of a DNA molecule bind together.This makes the mRNA “unreadable” by the ribosome, and so no protein is produced.

Because an antisense drug is designed to be complementary to a particular mRNA sequence that is specific to a particular virus’ mRNA, it will not interfere with any of the host cell’s naturally produced mRNA, meaning that the side effects of the drug are minimal.

At the end of August, 1998, the US Food and Drug Administration (FDA) approved a drug calledformivirsenfor the treatment of cytomegalovirus (CMV) retinitis in patients with AIDS.This makes formivirsen the first antisense drug on the market.Formivirsen blocks the replication ofcytomegalovirus(CMV) which causesretinitis, an eye infection leading to blindness that mainly affects AIDS patients. The drug is periodically injected into the patient’s eye, and is claimed to cause only mild side-effects as compared to some other antiviral drugs.

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GeoGene: Gene Therapy, What it is, The process and Vectors …

Antiviral Gene Therapy Research Unit – Wits University

Welcome to the Antiviral Gene Therapy Research Unit (AGTRU) of the University of the Witwatersrand and South African Medical Research Council (SAMRC)

Investigation by the AGTRU team is focused on countering viral infections that cause serious health problems in South Africa. The long term objectives of AGTRU are to

Discovery of the RNA interference (RNAi) pathway and advances in the engineering of sequence-specific nucleases have provided the means for powerful and specific disabling of genes. These advances led to considerable enthusiasm for use of gene therapy to counter viral infections, such as are caused by persistence of hepatitis B virus (HBV) and human immunodeficiency virus type 1 (HIV-1). The focus of the AGTRU has been on optimising use of RNAi activators and transcription activator-like effector nucleases (TALENs) to inhibit viral proliferation. Development of suitable vectors for delivery of antiviral sequences to infected cells is also an active field of investigation within the unit.

Research activities are generously supported by South African and International funding agencies. South African and international partnerships have been established, and these are an important contributor to the groups resource base.

The unit currently has approximately 20 members and these include molecular biologists, clinicians and postgraduate students. There are four tenured university appointees in the unit and the director is Professor Patrick Arbuthnot. AGTRU is equipped as a modern molecular biology research laboratory and has expertise in a range of techniques. These are advanced methods of nucleic acid manipulation, gene transfer to mammalian cells, use of lipoplex and recombinant viral vectors. AGTRU is set up to investigate efficacy of antiviral compounds in vivo in murine (e.g. HBV transgenic mice) and cell culture models of viral replication.

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Antiviral Gene Therapy Research Unit – Wits University

Gene Therapy Research | Ophthotech

Gene Therapy Research Programs

Ophthotech initiated an innovative gene therapy program focused on applying novel gene therapy technology to discover and develop new therapies for ocular diseases. We intend to investigate promising gene therapy product candidates and other technologies through collaborations with leading companies and academic institutions in the United States and internationally.

As we evaluate the unmet medical need for the treatment of orphan ophthalmic diseases, we have considered that many of these diseases are caused by one or more genetic mutations and currently have no approved treatment options available. Further, the potential to achieve an extended treatment effect and possibly a cure through a single gene therapy administration is particularly appealing to patients who do not have any treatment options, as well as for patients with age-related retinal diseases who currently require chronic therapy over years, if not decades.

Gene therapy consists of delivering DNA encoding for a functional protein to a target tissue to facilitate protein synthesis using a recipients existing cellular machinery. Gene therapy can be used to replace a non-functional protein produced innately by the subject as a result of a genetic mutation or simply as a means of producing and delivering a therapeutic protein that would not otherwise be produced within the body. The DNA, which is generally delivered by a viral vector, is governed by a promoter sequence which controls transcription of the gene of interest, or transgene, into RNA to initiate protein synthesis. Some of the challenges that gene therapy faces are producing vectors that transfect, or deposit the transgene, in only specific cell types, producing the desired protein at the therapeutic dose levels, and avoiding inducing an inflammatory response that leads to tissue damage. We are particularly interested in adeno-associated virus, or AAV, gene therapy delivery vehicles, as AAV vectors are relatively specific to retinal cells and their safety profile in humans is relatively well-documented as compared to other delivery vehicles and gene therapy technologies currently in development.

University of Massachusetts Medical School and its Horae Gene Therapy Center

For our first gene therapy collaboration, we entered into a series of sponsored research agreements with the University of Massachusetts Medical School (UMMS) and its Horae Gene Therapy Center to utilize their minigene therapy approach and other novel gene delivery technologies to target retinal diseases. As a condition of each research agreement, UMMS has granted the Company an option to obtain an exclusive license to any patent or patent applications that result from this research.

The use of minigenes as a novel therapeutic strategy seeks to deliver a shortened but still functional form of a large gene packaged into a standard-size AAV delivery vector commonly used in gene therapy. The minigene strategy may offer an innovative solution for diseases that would otherwise be difficult to address through conventional AAV gene replacement therapy where the size of the gene of interest exceeds the transgene packaging capacity of conventional AAV vectors. Research in this newly evolving area of gene therapy is led by Prof. Hemant Khanna and colleagues in the Horae Gene Therapy Center and was described in a recent journal article in Human Gene Therapy, Gene Therapy Using a miniCEP290 Fragment Delays Photoreceptor Degeneration in a Mouse Model of Leber Congenital Amaurosis by Wei Zhang, Linjing Li, Qin Su, Guangping Gao, and Hemant Khanna, all at the University of Massachusetts Medical School.

The collaboration with UMass Medical School will also focus on developing the next generation of gene therapy vectors to allow novel delivery approaches for treatment of retinal diseases.

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Gene Therapy Research | Ophthotech

Gene Therapy – Genetics Generation

What is Gene Therapy?

Gene therapy is a technique used to correct defective genes genes that are responsible for disease development. Specifically, according to the American Society of Gene and Cell Therapy-

Gene therapy is defined as a set of strategies that modify the expressionof an individuals genes or that correct abnormal genes. Each strategyinvolves the administration of a specific DNA (or RNA).

Gene therapy is the manipulation of the expression of specific genes in a persons body, in hopes of treating a disease or disorder. Gene therapy is still considered experimental and only available via clinical trial. Although many successful trials have been documented (see Interesting Links below), gene therapy has a checkered history. In some gene therapy trials, there were cases of leukemia as an unintended side-effect, and even cases of death (see link on Jesse Gelsinger below).

Image courtesy of Wikimedia Commons

How Does Gene Therapy Work?

Although there are several strategies for gene therapy, the most commonly used method involves inserting a therapeutic gene into the genome to replace the abnormal or disease-causing gene. The gene that is inserted is delivered into a target cell via a vector. Usually, this vector is a virus, although non-viral vectors are in development. Viruses are a good choice for introducing genes into a cell because they typically operate by transferring their own genetic material while replicating themselves. Once target cells are infected with the viral vector, the vector releases its therapeutic gene which then incorporates into the cells DNA. The goal is that the cell will start using the new gene to make functional, healthy proteins.

There are three main strategies for using gene therapy to restore the target cells or target tissues to a normal, healthy state.

1. Insert the functional version of a gene in hopes of replacing the abnormal form. This is used to treat single-gene disorders like hemophilia A and B and cystic fibrosis.

2. Insert a gene that encodes for a therapeutic protein that treats a disease. This is used to treat acquired diseases likeinfection or ischemic heart disease.

3. Use gene transfer to down-regulate gene expression in hopes of decreasing the activity of a harmful gene.

Current Areas of Research

Although gene therapy is still experimental, many diseases have been targets for gene therapy in clinical trials. Some of these trials have produced promising results. Diseases that may be treated successfully in the future with gene therapy include (but are not limited to):* Anemias* Cardiovascular diseases* Cystic Fibrosis* Diabetes* Diseases of the bones and joints* Eye disease and Blindness* Gauschers Disease* Hemophilia* Huntingtons Disease* Lysosomal storage diseases* Muscular Dystrophy* Sickle cell disorder

The main challenges facing gene therapy are the identification of disease causing genes, the targeted delivery of the therapeutic gene specifically to the affected tissues, and the prevention of side effects (such as an immune response) in the patient.

Gene Therapy for Enhancement Purposes

If gene therapy becomes routine medical practice, then it is reasonable to believe that some will seek it out for enhancement purposes. For example, a gene therapy designed to help patients with Alzheimers disease may be appealing to a normal individual hoping to boost memory. One potential area of enhancement that has been discussed is gene doping in sports. Gene doping is defined by the World Anti-Doping Agency (WADA) as the non-therapeutic use of genes, genetic elements and/or cells that have the capacity to enhance athletic performance. The purpose of gene doping is toenhancea given gene rather thancorrecta faulty one. Potential targets of gene doping include:

* Erythropoietin (EPO) for increased production of red blood cells* Insulin-like Growth Factor-1 gene for increased muscle mass* Myostatin for increased muscle mass* Vascular Endothelial Growth Factor (VEGF) for an increase in blood flow

This form of doping would be hard to detect because the doping substances are produced directly in an individuals own cells after these genes with performance-enhancing effects have been expressed. Whether or not to use gene therapy in the future for enhancement purposes, and how to regulate it, will require a complex discussion of ethics in which there will likely be many differing opinions.

Interesting Links*The American Society of Gene and Cell Therapy* National Geographic articleon gene doping* Science Daily article onrecent gene therapy news* New York Times article on the death of Jesse Gelsinger* Scientific American article on treating blindness with gene therapy

CLICK HERE to read our case study involving ethical issues associated with gene therapy

REFERENCES

Gene Therapy and Cell Therapy Defined. American Society of Gene and Cell Therapy, n.d. Web. 04 Nov. 2012. .

Gene Therapy..Human Genome Project Information, n.d. We. 04 Nov. 2012.

Pawliuk R et al. Correction of sickle cell disease in transgenic mouse models by gene therapy. Science. 2001; 294:2368-2371.

Unal M, Unal DO. Gene doping in sports. Sports Medicine. 2004; 34:357-362.

Wells DJ. Gene doping: the hype and the reality. British Journal of Pharmacology. 2008 January; 154: 623-631.

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Gene Therapy – Genetics Generation

Gene Therapy Clinical Research – nationwidechildrens.org

Purpose of Study

The Newcastle University and the University of Rochester, in collaboration with the United States National Institutes of Health, and the National Institute of Neurological Disorders and Stroke, are conducting a phase III study with corticosteroids in boys with Duchenne Muscular Dystrophy (FOR DMD study).

Corticosteroids are currently the only medicine that has been shown to increase muscle strength in boys with DMD. Doctors have tried different ways of prescribing corticosteroids in order to decrease undesirable side effects. Currently, different doctors in different countries prescribe the drugs in different ways, and some do not prescribe corticosteroids at all.

The FOR DMD study aims to compare three ways of giving corticosteroids to boys with DMD to determine which increases muscle strength the most, and which causes the fewest side effects.

Using the results of this study, we aim to provide patients and families with clearer information about the best way to take these drugs.

This study will look at three ways of taking corticosteroids by the mouth:

All three dosages are commonly used in boys with DMD and have shown to be beneficial.

In this study there is no placebo group, which means that all participants will receive active drugs (Prednisone or Deflazacort). However, neither the boys nor the clinicians will know which treatment or regime the boy is taking.

The study will recruit 300 boys around Europe, United States and Canada.

In North America, 16 centers will take part in the study:

Patients who do not attend one of these hospitals for their routine follow-up can also participate, but will have to travel to their closest participating site to receive the study drug and for the check-ups.

Participants will receive study medication for a minimum of three years and a maximum of five years (depending on how early the boy was recruited into the study) and participation involves visits to the study hospital every three months for the first 6 months and every six months thereafter. At these visits we will be repeating many of the tests your child usually has in clinic for his routine DMD follow up.

Who can participate:

In order to take part in the study boys need to fulfil a number of criteria. These can only be checked when you come into the clinic. However, at this stage if your child may be eligible if he:

Who to contact:

If you feel that your child might be able to participate in this trial, please feel free to discuss it with your doctor locally. Alternatively, if you would like further information, please contact the University of Rochester Medical Center: Kim Hart | Phone: 1 (585) 275-3767.

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Gene Therapy Clinical Research – nationwidechildrens.org

The Cancer Gene Therapy Research Team | Kids Research

> Dr Geoffrey McCowage, Cancer Gene Therapy Group Leader

Geoffisa Paediatric Oncologist at The Children’s Hospital at Westmead and a member of Sydney Cell and Gene Therapy (SCGT). He is a Principal Investigator for clinical trialswithin the Children’s Oncology Group. He has a particular clinical interest in neuro-oncology and sarcomas of bone and soft tissue. Dr McCowage leads the clinicaland translational researchof the Cancer Gene Therapy group.

> Dr Belinda Kramer,Cancer Gene Therapy Group Co-Leader, email: belinda.kramer@health.nsw.gov.au

Belinda is a senior research scientist and leadslaboratory research within the Cancer Gene Therapy Group. She is also a member of Sydney Cell and Gene Therapy (SCGT) and highly experienced in genetransfer techniquesand cell therapies.

> Dr Kenneth Hsu, Senior Post-doctoral Research Officer, Cancer Gene Therapy Group Co-Leader, email: kenneth.hsu@health.nsw.gov.au

Ken is an experienced post-doctoral scientist working on the development of novel vectors for gene modification of T cells to target tumours and the development of clinically applicable T cell manufacturing methodology for the project.

> Other Research Team Members

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The Cancer Gene Therapy Research Team | Kids Research

World Gene Therapy Research Report 2018: Technologies …

DUBLIN–(BUSINESS WIRE)–The “Gene Therapy – Technologies, Markets and Companies” report from Jain PharmaBiotech has been added to ResearchAndMarkets.com’s offering

Gene therapy technologies are described in detail including viral vectors, nonviral vectors and cell therapy with genetically modified vectors. Gene therapy is an excellent method of drug delivery and various routes of administration as well as targeted gene therapy are described. There is an introduction to technologies for gene suppression as well as molecular diagnostics to detect and monitor gene expression. Gene editing technologies such as CRISPR-Cas9 and CAR-T cell therapies are also included

Clinical applications of gene therapy are extensive and cover most systems and their disorders. Full chapters are devoted to genetic syndromes, cancer, cardiovascular diseases, neurological disorders and viral infections with emphasis on AIDS. Applications of gene therapy in veterinary medicine, particularly for treating cats and dogs, are included.

Research and development is in progress in both the academic and the industrial sectors. The National Institutes of Health (NIH) of the US is playing an important part. As of 2016, over 2050 clinical trials were completed, were ongoing or had been approved worldwide. A breakdown of these trials is shown according to the geographical areas and applications.

The markets for gene therapy have been difficult to estimate as there only a few approved gene therapy products. Gene therapy markets are estimated for the years 2017-2027. The estimates are based on epidemiology of diseases to be treated with gene therapy, the portion of those who will be eligible for these treatments, competing technologies and the technical developments anticipated in the next decades. In spite of some setbacks, the future for gene therapy is bright. The markets for DNA vaccines are calculated separately as only genetically modified vaccines and those using viral vectors are included in the gene therapy markets.

The voluminous literature on gene therapy was reviewed and selected 750 references are appended in the bibliography. The references are constantly updated. The text is supplemented with 78 tables and 25 figures.

Profiles of 183 companies involved in developing gene therapy are presented along with 250 collaborations. There were only 44 companies involved in this area in 1995. In spite of some failures and mergers, the number of companies has increased more than 4-fold in 2 decades. These companies have been followed up since they were the topic of a book on gene therapy companies by the author of this report.

Key Topics Covered:

Part I: Technologies & Markets

Executive Summary

1. Introduction

2. Gene Therapy Technologies

3. Clinical Applications of Gene Therapy

4. Gene Therapy of Genetic Disorders

5. Gene Therapy of Cancer

6. Gene Therapy of Neurological Disorders

7. Gene Therapy of Cardiovascular Disorders

8. Gene therapy of viral infections

9. Research, Development and Future of Gene Therapy

10. Regulatory, Safety, Ethical Patent Issues of Gene Therapy

11. Markets for Gene Therapy

12. References

Part II: Companies

13. Companies involved in Gene Therapy

For more information about this report visit https://www.researchandmarkets.com/research/ck3cjd/world_gene?w=4

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World Gene Therapy Research Report 2018: Technologies …

Operationalizing Gene Therapy Trials – Premier Research

Even measured against the vast scientific mystery that defines the biotech industry, gene therapy poses extraordinary challenges. Its still a young field, the science is stunningly complex, and the regulatory terrain is still evolving.

Sponsors and CROs have an understandably challenging time operationalizing clinical trials for new gene therapy treatments. In this webcast, well examine the history and current state of gene therapy research and investigate the obstacles in both patient recruitment and retention, study start-up regulations, and types of gene therapy vectors and vector delivery strategies.

Lisa Dilworth, Executive Director Program Strategy Rare Disease and Pediatrics, regularly consults with clients on key factors such as study design, eligibility criteria, appropriate patient populations, end point selection and program strategy in order to develop global therapeutic product strategies for rare and pediatric trials. Ms. Dilworths expertise and experience includes multiple gene therapy trials in subjects ranging from neonates to adults around the globe.

Ms. Dilworth holds a masters degree in Clinical Research from the University of California, San Diego and a Bachelors in Biology from the University of California, Berkeley. Her prior work as a study coordinator and various clinical operations roles enable her to work closely with clients, physicians and patients with a variety of disorders.

Nadia Zeini is currently working as Sr. Regulatory Study Start Up Manager at Premier Research since December 2016. She is responsible for all regulatory and start up activities in EU and non-EU countries, as applicable. Nadia Zeini has a solid regulatory background where she grew from local start up associate to Global Regulatory lead for ten years

Ms. Zeini holds a Chemistry-Major in Biochemistry from Complutense University in Spain as well as a Masters degree in Clinical Trials from Universidad of Seville in Spain.

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Operationalizing Gene Therapy Trials – Premier Research

Gene therapy – Mayo Clinic

Overview

Gene therapy involves altering the genes inside your body’s cells in an effort to treat or stop disease.

Genes contain your DNA the code that controls much of your body’s form and function, from making you grow taller to regulating your body systems. Genes that don’t work properly can cause disease.

Gene therapy replaces a faulty gene or adds a new gene in an attempt to cure disease or improve your body’s ability to fight disease. Gene therapy holds promise for treating a wide range of diseases, such as cancer, cystic fibrosis, heart disease, diabetes, hemophilia and AIDS.

Researchers are still studying how and when to use gene therapy. Currently, in the United States, gene therapy is available only as part of a clinical trial.

Gene therapy is used to correct defective genes in order to cure a disease or help your body better fight disease.

Researchers are investigating several ways to do this, including:

Gene therapy has some potential risks. A gene can’t easily be inserted directly into your cells. Rather, it usually has to be delivered using a carrier, called a vector.

The most common gene therapy vectors are viruses because they can recognize certain cells and carry genetic material into the cells’ genes. Researchers remove the original disease-causing genes from the viruses, replacing them with the genes needed to stop disease.

This technique presents the following risks:

The gene therapy clinical trials underway in the U.S. are closely monitored by the Food and Drug Administration and the National Institutes of Health to ensure that patient safety issues are a top priority during research.

Currently, the only way for you to receive gene therapy is to participate in a clinical trial. Clinical trials are research studies that help doctors determine whether a gene therapy approach is safe for people. They also help doctors understand the effects of gene therapy on the body.

Your specific procedure will depend on the disease you have and the type of gene therapy being used.

For example, in one type of gene therapy:

Viruses aren’t the only vectors that can be used to carry altered genes into your body’s cells. Other vectors being studied in clinical trials include:

The possibilities of gene therapy hold much promise. Clinical trials of gene therapy in people have shown some success in treating certain diseases, such as:

But several significant barriers stand in the way of gene therapy becoming a reliable form of treatment, including:

Gene therapy continues to be a very important and active area of research aimed at developing new, effective treatments for a variety of diseases.

Explore Mayo Clinic studies testing new treatments, interventions and tests as a means to prevent, detect, treat or manage this disease.

Dec. 29, 2017

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Gene therapy – Mayo Clinic

Center for Gene Therapy :: The Research Institute at Nationwide …

The mission of the Center for Gene Therapy is to investigate and employ the use of gene and cell based therapeutics for prevention and treatment of human diseases including: neuromuscular and neurodegenerative diseases, lysosomal storage disorders, ischemia and re-perfusion injury, neonatal hypertension, cancer and infectious diseases.

Learn about our areas of focus and featured research projects.

The Center for Gene Therapy and the Viral Vector Core are home to a Good Manufacturing Practice (GMP) production facility for manufacture of clinical-grade rAAV vectors.

View the Viral Vector Core & Clinical Manufacturing Facility site.

TheOSU and Nationwide Children’s Muscle Groupbrings together investigators with diverse research interests in skeletal muscle, cardiac muscle, and neuromuscular biology.

Hosted by Kevin Flanigan, MD,”This Month in Muscular Dystrophy” podcastshighlight the latest in muscular dystrophy and other inherited neuromuscular disease research.During each podcast, authors of recent publications discuss how their work improves our understanding of inherited neuromuscular diseases, and what their work might mean for treatment of these diseases.

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Center for Gene Therapy :: The Research Institute at Nationwide …

Human Gene Therapy | Mary Ann Liebert, Inc. publishers

Human Gene Therapy is the premier, multidisciplinary journal covering all aspects of gene therapy. The Journal publishes in-depth coverage of DNA, RNA, and cell therapies by delivering the latest breakthroughs in research and technologies. Human Gene Therapy provides a central forum for scientific and clinical information, including ethical, legal, regulatory, social, and commercial issues, which enables the advancement and progress of therapeutic procedures leading to improved patient outcomes, and ultimately, to curing diseases.

The Journal is divided into three parts. Human Gene Therapy, the flagship, is published 12 times per year. HGT Methods, a bimonthly journal, focuses on the applications of gene therapy to product testing and development. HGT Clinical Development, a quarterly journal, serves as a venue for publishing data relevant to the regulatory review and commercial development of cell and gene therapy products.

Human Gene Therapy was voted one of the most influential journals in Biology and Medicine over the last 100 years by the Biomedical & Life Sciences Division of the Special Libraries Association.

Human Gene Therapy, HGT Methods, and HGT Clinical Development are under the editorial leadership of Editor-in-Chief Terence R. Flotte, MD, University of Massachusetts Medical School; Deput Editors Europe Nathalie Cartier, MD, INSERM, andThierry VandenDriessche, PhD, Free University of Brussels (VUB); Deputy Editors U.S. Barry J. Byrne, MD, PhD,Powell Gene Therapy Center, University of Florida, College of Medicine and Mark A. Kay, MD, PhD, Stanford University School of Medicine; Human Gene Therapy Editor Guangping Gao, PhD, University of Massachusetts Medical School; Methods Editor Hildegard Bning, PhD, Hannover Medical School; Clinical Development Editor James M. Wilson, MD, PhD,University of Pennsylvania School of Medicine, Gene Therapy Program; and other leading investigators. View the entire editorial board.

Audience: Geneticists, medical geneticists, molecular biologists, virologists, experimental researchers, and experimental medicine specialists, among others.

Human Gene Therapy and HGT Methods provide Instant Online publication 72 hours after acceptance

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Human Gene Therapy | Mary Ann Liebert, Inc. publishers

Foundation Fighting Blindness Celebrates Historic FDA …

Foundations early investment in LUXTURNA boosts vision-restoring treatment for people with RPE65 mutations and will help advance other gene therapies currently in development.

(Columbia, MD) Todays U.S. Food and Drug Administration (FDA) approval of voretigene neparvovec, to be marketed as LUXTURNA, will be life-changing for patients with vision loss due to mutations in the RPE65 gene and a watershed moment for the inherited retinal disease field, says the Foundation Fighting Blindness. The Foundation was an important early investor in LUXTURNA, providing $10 million in critical seed funding for the therapy.

The groundbreaking treatment is the first gene therapy for the eye and for any inherited disease to be approved by the FDA. The treatment restores vision by delivering working copies of the RPE65 gene directly into the retina, thereby compensating for the nonfunctional, mutated genes.

We are thrilled for the patients whose lives will change dramatically because of this treatment, says David Brint, Foundation Fighting Blindness chairman. We are also pleased to have this concrete example of the strength of the Foundations strategy of identifying and investing early in promising treatments. Doing so helps attract industry investment that can usher promising treatments through clinical trials and ultimately FDA approval.

LUXTURNA is the result of more than two decades of research and development at the University of Florida, the University of Pennsylvania, Childrens Hospital of Philadelphia, and Spark Therapeutics. The Foundation Fighting Blindness seed investment allowed researchers to take the therapy through the early investigational stages critical to any treatment development.

LUXTURNA will be life-changing for people with an inherited retinal disease caused by RPE65 mutations. For them, the treatment means a life of independence. Also important is the momentum this approval provides to other gene-based therapies for the eye and other diseases now in the clinic, says Benjamin Yerxa, PhD, Foundation CEO.

Twenty-four-year-old Katelyn Corey participated in the clinical trial that led to LUXTURNAs FDA approval. Before the trial, failing vision was causing her to consider giving up her lifelong dream of completing college and working in science. But, in December 2013, she received the RPE65 gene therapy in Sparks Phase 3 clinical trial, and her education and science career got quickly back on track.

Within days, I could see vibrant colors. I could even see the Philadelphia City Hall clock tower at night, she says. Also, now, I can go to a restaurant and see everything by candlelight, and I can see stars in the night sky. Corey recently earned a masters degree in epidemiology and now works as a research analyst for the U.S. Department of Veterans Affairs.

An additional noteworthy milestone is the demonstrated value of a new clinical endpoint devised by the Spark Therapeutics team to measure LUXTURNAs impact. The new measure, a multi-luminance mobility test (informally called the maze), measured the impact of the treatment beyond the traditional visual acuity measure the eye chart. This new clinical endpoint moves vision measures beyond the eye chart, which is particularly significant for people with low or no vision.

Spark Therapeutics, which holds the biologics license for LUXTURNA and conducted the clinical trials that showed its safety and efficacy, will also manage the treatment rollout. Spark has announced that in order to ensure the treatment is safely administered, it will only be available through a small number of centers of clinical excellence across the country. Spark has also expressed its commitment to educating third-party payers about the value of LUXTURNA and to working to help ensure treatment access to all eligible patients.

Anyone in need of more information about LUXTURNA should contact Spark Therapeutics at 1-833-SPARK-PS (833-772-7577). Another resource for information is Sparks website: http://www.Sparktx.com.

# # #

The Foundation Fighting Blindness is the worlds leading private funder of research on potential treatments and cures for inherited retinal degenerative diseases and currently funds 77 research projects overseen by 65 investigators at 67 universities, hospitals, and affiliated eye institutes worldwide. The Foundation was established in 1971 and has since raised more than $725 million toward its mission to prevent, treat, and cure blindness caused by inherited retinal diseases. In excess of 10 million Americans, and millions more worldwide, experience vision loss due to retinal degenerations. Through its support of focused and innovative science, the Foundation drives the research that has and will continue to provide treatments and cures for people affected by retinitis pigmentosa, LCA, macular degeneration, Usher syndrome, and other retinal diseases.

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Foundation Fighting Blindness Celebrates Historic FDA …

Gene Therapy Clinical Trials Databases

Wiley database on Gene Therapy Trials WorldwideThe Journal of Gene Medicine clinical trial site presenting charts and tables showing the number of approved, ongoing or completed clinical trials worldwide. Data is available for: Continents and countries where trials are being performed; Indications addressed; Vectors used; Gene types transferred; Phases of clinical trials; Number of trial approved/initiated 1989-2007.A searchable database is also present with detailed information on individual trials. The data are compiled and are regularly updated from official agency sources (RAC, GTAC etc..), the published literature, presentations at conferences and from information kindly provided by investigators or trial sponsors themselves. Beware that information on some trials is incomplete as some countries regulatory agencies simply do not disclose any information.See also: Gene therapy clinical trials worldwide to 2012 – an update. J. Gene Med. 2013 Feb;15(2):65-77.ClinicalTrials.gov database on clinical trials performed in the US and worldwideThe U.S. National Institutes of Health, through its National Library of Medicine, has developed ClinicalTrials.gov to provide patients, family members and members of the public current information about clinical research studies. The database is a registry of federally and privately supported clinical trials conducted in the United States and around the world. ClinicalTrials.gov gives you information about a trial’s purpose, who may participate, locations, and phone numbers for more details.>> Overview of gene therapy trials recently received in the last 30 days. International Standard Randomised Controlled Trial Number RegisterThe ISRCTN Register is a register containing a basic set of data items on clinical trials that have been assigned an ISRCTN. Records are never removed from the ISRCTN Register (except in cases of duplications), which ensures that basic information about trials registered with an ISRCTN will always be available. The ISRCTN Register complies with requirements set out by the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) and the International Committee of Medical Journal Editors (ICMJE) guidelines, and complies with the WHO 20-item Trial Registration Data Set. Selected Gene Transfer and Therapy References databaseThe database is managed by Clinigene. The aim of this webpage is to provide database of selected references in the field of Gene Transfer and Therapy, addressing technological issues, applications, ethics and regulation from four main databases: Quality/Efficacy; Safety (pre-clinical); Adverse events (clinical); Important clinical trials. The database is open to the public and it is by no means intended to be either complete or comprehensive. Published Human Gene Therapy Clinical Trials database The database is maintained by Clinigene. The aim of this website is to provide a complete database of all published clinical gene therapy trials carried out worldwide. At this point in time the database is nearing completion and is open to the public.

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Gene Therapy Clinical Trials Databases

Gene therapy | medicine | Britannica.com

Gene therapy, also called gene transfer therapy, introduction of a normal gene into an individuals genome in order to repair a mutation that causes a genetic disease. When a normal gene is inserted into the nucleus of a mutant cell, the gene most likely will integrate into a chromosomal site different from the defective allele; although that may repair the mutation, a new mutation may result if the normal gene integrates into another functional gene. If the normal gene replaces the mutant allele, there is a chance that the transformed cells will proliferate and produce enough normal gene product for the entire body to be restored to the undiseased phenotype.

Human gene therapy has been attempted on somatic (body) cells for diseases such as cystic fibrosis, adenosine deaminase deficiency, familial hypercholesterolemia, cancer, and severe combined immunodeficiency (SCID) syndrome. Somatic cells cured by gene therapy may reverse the symptoms of disease in the treated individual, but the modification is not passed on to the next generation. Germline gene therapy aims to place corrected cells inside the germ line (e.g., cells of the ovary or testis). If that is achieved, those cells will undergo meiosis and provide a normal gametic contribution to the next generation. Germline gene therapy has been achieved experimentally in animals but not in humans.

Scientists have also explored the possibility of combining gene therapy with stem cell therapy. In a preliminary test of that approach, scientists collected skin cells from a patient with alpha-1 antitrypsin deficiency (an inherited disorder associated with certain types of lung and liver disease), reprogrammed the cells into stem cells, corrected the causative gene mutation, and then stimulated the cells to mature into liver cells. The reprogrammed, genetically corrected cells functioned normally.

Prerequisites for gene therapy include finding the best delivery system (often a virus, typically referred to as a viral vector) for the gene, demonstrating that the transferred gene can express itself in the host cell, and establishing that the procedure is safe. Few clinical trials of gene therapy in humans have satisfied all those conditions, often because the delivery system fails to reach cells or the genes are not expressed by cells. Improved gene therapy systems are being developed by using nanotechnology. A promising application of that research involves packaging genes into nanoparticles that are targeted to cancer cells, thereby killing cancer cells specifically and leaving healthy cells unharmed.

Some aspects of gene therapy, including genetic manipulation and selection, research on embryonic tissue, and experimentation on human subjects, have aroused ethical controversy and safety concerns. Some objections to gene therapy are based on the view that humans should not play God and interfere in the natural order. On the other hand, others have argued that genetic engineering may be justified where it is consistent with the purposes of God as creator. Some critics are particularly concerned about the safety of germline gene therapy, because any harm caused by such treatment could be passed to successive generations. Benefits, however, would also be passed on indefinitely. There also has been concern that the use of somatic gene therapy may affect germ cells.

Although the successful use of somatic gene therapy has been reported, clinical trials have revealed risks. In 1999 American teenager Jesse Gelsinger died after having taken part in a gene therapy trial. In 2000 researchers in France announced that they had successfully used gene therapy to treat infants who suffered from X-linked SCID (XSCID; an inherited disorder that affects males). The researchers treated 11 patients, two of whom later developed a leukemia-like illness. Those outcomes highlight the difficulties foreseen in the use of viral vectors in somatic gene therapy. Although the viruses that are used as vectors are disabled so that they cannot replicate, patients may suffer an immune response.

Another concern associated with gene therapy is that it represents a form of eugenics, which aims to improve future generations through the selection of desired traits. Some have argued that gene therapy is eugenic but that it is a treatment that can be adopted to avoid disability. To others, such a view of gene therapy legitimates the so-called medical model of disability (in which disability is seen as an individual problem to be fixed with medicine) and raises peoples hopes for new treatments that may never materialize.

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Gene therapy | medicine | Britannica.com

The coming of age of gene therapy: A review of the past …

Media Advisory

Friday, January 12, 2018

No longer the future of medicine, gene therapy is part of present-day clinical treatment.

After three decades of hopes tempered by setbacks, gene therapythe process of treating a disease by modifying a persons DNAis no longer the future of medicine, but is part of the present-day clinical treatment toolkit. The Jan. 12 issue of the journal Science provides an in-depth and timely review of the key developments that have led to several successful gene therapy treatments for patients with serious medical conditions.

Co-authored by Cynthia E. Dunbar, M.D., senior investigator at the Hematology Branch of the National Heart, Lung and Blood Institute (NHLBI), part of the National Institutes of Health, the article also discusses emerging genome editing technologies. According to Dunbar and her colleagues, these methods, including the CRISPR/Cas9 approach, would provide ways to correct or alter an individual’s genome with precision, which should translate into broader and more effective gene therapy approaches.

Gene therapy is designed to introduce genetic material into cells to compensate for or correct abnormal genes. If a mutated gene causes damage to or spurs the disappearance of a necessary protein, for example, gene therapy may be able to introduce a normal copy of the gene to restore the function of that protein.

The authors focused on the approaches that have delivered the best outcomes in gene therapy so far: 1) direct in vivo administration of viral vectors, or the use of viruses to deliver the therapeutic genes into human cells; and 2) the transfer of genetically engineered blood or bone marrow stem cells from a patient, modified in a lab, then injected back into the same patient.

Originally envisioned as a treatment solely for inherited disorders, gene therapy is now being applied to acquired conditions such as cancer. For example, the engineering of lymphocytes, white blood cells, that can be used in the targeted killing of cancer cells.

In 2017, a steady stream of encouraging clinical results showed progress in gene therapies for hemophilia, sickle-cell disease, blindness, several serious inherited neurodegenerative disorders, an array of other genetic diseases, and multiple cancers of the bone marrow and lymph nodes.

Three gene therapies have been approved by the U.S. Food and Drug Administration in the past year, and many more are under active clinical investigation. The authors looked to the future of gene therapies, and the challenges of delivering these complex treatments to patients.

Much of this research has been funded by NIH, and key advances took place in the NIH Clinical Center.

Cynthia E. Dunbar, M.D., senior investigator, Hematology Branch, NHLBI, NIH, is available for comments.

Dunbar et al., Gene therapy comes of age. Science 359, eaan4672 (2018)

For more information or to schedule an interview, please contact the NHLBI Office of Science Policy, Engagement, Education, and Communications at 301-496-5449 or nhlbi_news@nhlbi.nih.gov.

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The coming of age of gene therapy: A review of the past …

Gene therapy comes of age | Science

Gene therapy: The power of persistence

Nearly 50 years after the concept was first proposed, gene therapy is now considered a promising treatment option for several human diseases. The path to success has been long and tortuous. Serious adverse effects were encountered in early clinical studies, but this fueled basic research that led to safer and more efficient gene transfer vectors. Gene therapy in various forms has produced clinical benefits in patients with blindness, neuromuscular disease, hemophilia, immunodeficiencies, and cancer. Dunbar et al. review the pioneering work that led the gene therapy field to its current state, describe gene-editing technologies that are expected to play a major role in the field’s future, and discuss practical challenges in getting these therapies to patients who need them.

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Nearly five decades ago, visionary scientists hypothesized that genetic modification by exogenous DNA might be an effective treatment for inherited human diseases. This gene therapy strategy offered the theoretical advantage that a durable and possibly curative clinical benefit would be achieved by a single treatment. Although the journey from concept to clinical application has been long and tortuous, gene therapy is now bringing new treatment options to multiple fields of medicine. We review critical discoveries leading to the development of successful gene therapies, focusing on direct in vivo administration of viral vectors, adoptive transfer of genetically engineered T cells or hematopoietic stem cells, and emerging genome editing technologies.

The development of gene delivery vectors such as replication-defective retro viruses and adeno-associated virus (AAV), coupled with encouraging results in preclinical disease models, led to the initiation of clinical trials in the early 1990s. Unfortunately, these early trials exposed serious therapy-related toxicities, including inflammatory responses to the vectors and malignancies caused by vector-mediated insertional activation of proto-oncogenes. These setbacks fueled more basic research in virology, immunology, cell biology, model development, and target disease, which ultimately led to successful clinical translation of gene therapies in the 2000s. Lentiviral vectors improved efficiency of gene transfer to nondividing cells. In early-phase clinical trials, these safer and more efficient vectors were used for transduction of autologous hematopoietic stem cells, leading to clinical benefit in patients with immunodeficiencies, hemoglobinopathies, and metabolic and storage disorders. T cells engineered to express CD19-specific chimeric antigen receptors were shown to have potent antitumor activity in patients with lymphoid malignancies. In vivo delivery of therapeutic AAV vectors to the retina, liver, and nervous system resulted in clinical improvement in patients with congenital blindness, hemophilia B, and spinal muscular atrophy, respectively. In the United States, Food and Drug Administration (FDA) approvals of the first gene therapy products occurred in 2017, including chimeric antigen receptor (CAR)T cells to treat B cell malignancies and AAV vectors for in vivo treatment of congenital blindness. Promising clinical trial results in neuromuscular diseases and hemophilia will likely result in additional approvals in the near future.

In recent years, genome editing technologies have been developed that are based on engineered or bacterial nucleases. In contrast to viral vectors, which can mediate only gene addition, genome editing approaches offer a precise scalpel for gene addition, gene ablation, and gene correction. Genome editing can be performed on cells ex vivo or the editing machinery can be delivered in vivo to effect in situ genome editing. Translation of these technologies to patient care is in its infancy in comparison to viral gene addition therapies, but multiple clinical genome editing trials are expected to open over the next decade.

Building on decades of scientific, clinical, and manufacturing advances, gene therapies have begun to improve the lives of patients with cancer and a variety of inherited genetic diseases. Partnerships with biotechnology and pharmaceutical companies with expertise in manufacturing and scale-up will be required for these therapies to have a broad impact on human disease. Many challenges remain, including understanding and preventing genotoxicity from integrating vectors or off-target genome editing, improving gene transfer or editing efficiency to levels necessary for treatment of many target diseases, preventing immune responses that limit in vivo administration of vectors or genome editing complexes, and overcoming manufacturing and regulatory hurdles. Importantly, a societal consensus must be reached on the ethics of germline genome editing in light of rapid scientific advances that have made this a real, rather than hypothetical, issue. Finally, payers and gene therapy clinicians and companies will need to work together to design and test new payment models to facilitate delivery of expensive but potentially curative therapies to patients in need. The ability of gene therapies to provide durable benefits to human health, exemplified by the scientific advances and clinical successes over the past several years, justifies continued optimism and increasing efforts toward making these therapies part of our standard treatment armamentarium for human disease.

AAV and lentiviral vectors are the basis of several recently approved gene therapies. Gene editing technologies are in their translational and clinical infancy but are expected to play an increasing role in the field.

After almost 30 years of promise tempered by setbacks, gene therapies are rapidly becoming a critical component of the therapeutic armamentarium for a variety of inherited and acquired human diseases. Gene therapies for inherited immune disorders, hemophilia, eye and neurodegenerative disorders, and lymphoid cancers recently progressed to approved drug status in the United States and Europe, or are anticipated to receive approval in the near future. In this Review, we discuss milestones in the development of gene therapies, focusing on direct in vivo administration of viral vectors and adoptive transfer of genetically engineered T cells or hematopoietic stem cells. We also discuss emerging genome editing technologies that should further advance the scope and efficacy of gene therapy approaches.

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Gene therapy comes of age | Science

Gene therapy – About – Mayo Clinic

Overview

Gene therapy involves altering the genes inside your body’s cells in an effort to treat or stop disease.

Genes contain your DNA the code that controls much of your body’s form and function, from making you grow taller to regulating your body systems. Genes that don’t work properly can cause disease.

Gene therapy replaces a faulty gene or adds a new gene in an attempt to cure disease or improve your body’s ability to fight disease. Gene therapy holds promise for treating a wide range of diseases, such as cancer, cystic fibrosis, heart disease, diabetes, hemophilia and AIDS.

Researchers are still studying how and when to use gene therapy. Currently, in the United States, gene therapy is available only as part of a clinical trial.

Gene therapy is used to correct defective genes in order to cure a disease or help your body better fight disease.

Researchers are investigating several ways to do this, including:

Gene therapy has some potential risks. A gene can’t easily be inserted directly into your cells. Rather, it usually has to be delivered using a carrier, called a vector.

The most common gene therapy vectors are viruses because they can recognize certain cells and carry genetic material into the cells’ genes. Researchers remove the original disease-causing genes from the viruses, replacing them with the genes needed to stop disease.

This technique presents the following risks:

The gene therapy clinical trials underway in the U.S. are closely monitored by the Food and Drug Administration and the National Institutes of Health to ensure that patient safety issues are a top priority during research.

Currently, the only way for you to receive gene therapy is to participate in a clinical trial. Clinical trials are research studies that help doctors determine whether a gene therapy approach is safe for people. They also help doctors understand the effects of gene therapy on the body.

Your specific procedure will depend on the disease you have and the type of gene therapy being used.

For example, in one type of gene therapy:

Viruses aren’t the only vectors that can be used to carry altered genes into your body’s cells. Other vectors being studied in clinical trials include:

The possibilities of gene therapy hold much promise. Clinical trials of gene therapy in people have shown some success in treating certain diseases, such as:

But several significant barriers stand in the way of gene therapy becoming a reliable form of treatment, including:

Gene therapy continues to be a very important and active area of research aimed at developing new, effective treatments for a variety of diseases.

Explore Mayo Clinic studies testing new treatments, interventions and tests as a means to prevent, detect, treat or manage this disease.

Sept. 13, 2016

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Gene therapy – About – Mayo Clinic

Gene Therapy Consortium – Rett Syndrome Research Trust

$3,595,265 AWARDED

Rett Syndrome, as awful as the symptoms may be, provides us with several enormous advantages. First we know the cause: mutations in a single gene: MECP2. Second, Rett is not degenerative brain cells dont die. Third, work from RSRT trustee, Adrian Bird, suggests that the symptoms of Rett need not be permanent. These three facts make gene therapy an attractive therapeutic strategy.

In 2014 we launched a bold international collaboration of two gene therapy labs, Brian Kaspar and Steven Gray, and two MECP2 labs, Gail Mandel and Stuart Cobb. Together these labs brought together all the necessary skills and experience to determine if gene therapy is a viable therapeutic.

The Consortium worked through numerous challenges involving vector optimization (the Trojan horse that delivers the gene into a cell), gene construct optimization (what you package into the vector that regulates MeCP2 protein production), gene therapy dosage, and the best route to deliver it.

The data generated by the Consortium exceeded our expectations. They were able to develop a gene therapy product candidate with impressive efficacy, safety and delivery characteristics. Importantly, the magnitude of improvement in the mouse models of Rett is much greater than that of any drug tested and suggests that significant benefit may be achieved in people. We expect improvements, at least to some degree, regardless of age.

Based on the Consortium data the biotech company, AveXis, has now committed to advancing a gene therapy candidate into clinical trials. The company will announce before the end of 2017 what their timeline for trials will be.

Technological advances in gene therapy are happening quickly with more effective vectors being discovered that can carry larger DNA cargos and target a greater percentage of brain cells. While we anticipate encouraging results with our first clinical trial there will undoubtedly be room to improve. We have therefore recently awarded continued funding to the Gene Therapy Consortium to support second-generation gene therapy programs to leverage all technological advances.

Targeting the root problem in Rett, MECP2, can be done either at the DNA level (gene therapy or MECP2 Reactivation), the mRNA level or protein level.

Both the DNA and protein approaches carry a risk of potential dosage problems (too much MeCP2 may be harmful). An alternative approach is to use a technology called Spliceosome-Mediated RNA Trans-Splicing (SMaRT). This technology allows a mutation to be spliced out and repaired in RNA. The advantage is that this approach avoids any potential over-expression issues. Consortium member, Stuart Cobb, is working on this approach.

Gail Mandel of the Consortium is working on yet another approach, RNA editing. The possibility of correcting mutations in RNA has profound therapeutic potential, but had remained largely theoretical. Our focused investments have already demonstrated the potential for correcting MECP2 mutations in RNA in cells. We are currently increasing our investment to improve the editing efficiency and to identify optimal delivery methods.

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Gene Therapy Consortium – Rett Syndrome Research Trust

Germline Gene Transfer – National Human Genome Research …

Germline Gene Transfer

Gene transfer represents a relatively new possibility for the treatment of rare genetic disorders and common multifactorial diseases by changing the expression of a person’s genes. Typically gene transfer involves using a vector such as a virus to deliver a therapeutic gene to the appropriate target cells. The technique, which is still in its infancy and is not yet available outside clinical trials, was originally envisaged as a treatment of monogenic disorders, but the majority of trials now involve the treatment of cancer, infectious diseases and vascular disease. Human gene transfer raises several important ethical issues, in particular the potential use of genetic therapies for genetic enhancement and the potential impact of germline gene transfer on future generations.

Gene transfer can be targeted to somatic (body) or germ (egg and sperm) cells. In somatic gene transfer the recipient’s genome is changed, but the change is not passed on to the next generation. In germline gene transfer, the parents’ egg and sperm cells are changed with the goal of passing on the changes to their offspring. Germline gene transfer is not being actively investigated, at least in larger animals and humans, although a great deal of discussion is being conducted about its value and desirability.

Many people falsely assume that germline gene transfer is already routine. For example, news reports of parents selecting a genetically tested egg for implantation or choosing the sex of their unborn child may lead the public to think that gene transfer is occurring, when actually, in these cases, genetic information is being used for selection, with no cells being altered or changed. In addition, in 2001 scientists confirmed the birth of 30 genetically altered children whose mothers had undergone a procedure called ooplasmic transfer. In this process, doctors injected some of the contents of a healthy donor egg into an egg from a woman with infertility problems. The result was an egg with two types of mitochondria, cellular structures that contain a minuscule amount of DNA and that provide energy for the cell. The children born following this procedure thus have three genetic parents, since they carry DNA from the donor as well as the mother and father. Although the researchers announced this as the “first case of human germline genetic modification,” the gene transfer was an inadvertent side effect of the infertility procedure.

Many factors have prevented researchers from developing successful gene transfer techniques in both somatic and germline attempts (the latter in animals). The first hurdle is the gene delivery tool. The new gene is inserted into the body through vehicles called vectors (gene carriers), which deliver therapeutic genes to the patients’ cells. Currently, the most common vectors are viruses, which have evolved a mechanism to encapsulate and deliver their genes to human cells in a pathogenic manner. Scientists have tried to take advantage of the virus’s biology and manipulate its genome to remove human disease-causing genes and insert therapeutic genes. However, viruses, while effective, introduce other problems to the body, such as toxicity, immune and inflammatory responses, and gene control and targeting issues. Complexes of DNA with lipids and proteins provide an alternative to viruses, and researchers are also experimenting with introducing a 47th (artificial human) chromosome to the body that would exist autonomously along side the standard 46 chromosomes, presumably not affecting their functioning or causing any mutations. An additional chromosome would be a large vector capable of carrying substantial amounts of genetic code, and it is anticipated that, because of its construction and autonomy, the body’s immune systems would not attack it.

Some of the concerns raised about somatic gene transfer are related to the possibility that it could inadvertently lead to germline gene transfer. The possibility of germline modification through these techniques is the result of the hit-or-miss nature of the current technologies. It is always possible that a vector will introduce the gene into a cell other than that for which it is supposed to be targeted (e.g., a spermatocytic cell) or that through a secondary mechanism target cells that have taken up the new gene will through some independent natural process (such as transfection) transfer the gene to a germline cell. Moreover, if somatic gene transfer were to be conducted in utero, especially before the second trimester, it would increase the likelihood that some of the cells into which the gene is taken up will become part of the germline. It is possible that to effectively treat certain diseases using gene transfer, it might be necessary to apply somatic techniques early in development so that germline transfer is inevitable.

In contrast to inadvertent germline transfer following somatic gene transfer, intentional germline gene transfer would involve the deliberate introduction of new genetic material into either germ cells (sperm or oocytes) or into zygotes in vitro prior to fertilization or implantation. Currently, this technology has not been applied to humans; however, it has been successfully applied to some plants and animals. The aim of this process is to produce a developing embryo in which each cell (including those that will develop into gametes in the future) carries the newly inserted gene as part of its genetic make-up.

Current efforts in animals have demonstrated the difficulty of this approach. Some cells do not acquire the gene or acquire multiple or partial copies of the gene. In addition, it is not yet possible to specify with any accuracy where in the genome the new gene will be introduced, and some insertion locations may interfere with other important genes. If these kinds of errors are detected, then theoretically embryos with these defects could be “selected out.” However, should germline gene transfer be attempted in humans, it is likely that not all errors introduced as a result of the gene transfer will be detected.

Currently, however, animal studies have shown that gene transfer approaches that involve the early embryo can be far more effective than somatic cell gene therapy methodologies used later in development, depending on the complexity of the trait that is being improved or eliminated. Embryo gene transfer affords the opportunity to transform most or all cells of the organism and thus overcome the inefficient transformation that plagues somatic cell gene transfer protocols. Gene transfer selects one relevant locus for a trait (when in fact there might be many interactive loci) and then attempts to improve the trait in isolation. This approach, while potentially more powerful and efficient than conventional breeding techniques, involves more uncertainty risks.

Thus, both kinds of studies – germline gene transfer at the gamete and zygote stages – have significant risks. In cases in which the gene has failed to be introduced or fails to be activated, the resulting child would likely be no worse off than he or she would have been without the attempted gene transfer. However, those with partial or multiple copies of a gene could be in significantly worse condition. The problems resulting from errors caused by the gene insertion could be severe – even lethal – or they might not be evident until well after the child has been born, perhaps even well into adulthood, when the errors could be passed on to future generations. For these reasons, given the limits of current technology, germline gene transfer has been considered ethically impermissible.

Beyond the medical risks to the potential child, a number of long-standing ethical concerns exist regarding the possible practice of germline gene transfer in both human and nonhuman cases. Such modifications in human beings raise the possibility that we are changing not merely a single individual but a host of future individuals as well, with potential for harm to occur to those individuals and perhaps to humanity as a whole. Concerns involve issues ranging from the autonomy of future individuals to distributive justice, fairness, and the application of these technologies to “enhancement” rather than treating disease. In germline gene transfer, the persons being affected by the procedure – those for whom the procedure is undertaken – do not yet exist. Thus, the potential beneficiaries are not in a position to consent to or refuse such a procedure.

Gene transfer clinical trials have a unique oversight process that is conducted by the National Institutes of Health (NIH) through the Recombinant DNA Advisory Committee (RAC) and the NIH Guidelines for Research Involving Recombinant DNA Molecules, and by the Food and Drug Administration (FDA) through regulation (including scientific review, regulatory research, testing, and compliance activities, including inspection and education). Of note, FDA regulations apply to all clinical gene transfer research, while NIH governs gene transfer research that is supported with NIH funds or that is conducted at or sponsored by institutions that receive funding for recombinant DNA research. Currently, the majority of somatic cell gene transfer research is subject to the NIH Guidelines; however RAC will not currently consider protocols using germline gene transfer.

In addition, NIH has added to its guidelines the following statement:

The RAC continues to explore the issues raised by the potential of in utero gene transfer clinical research. However, the RAC concludes that, at present, it is premature to undertake any in utero gene transfer clinical trial. Significant additional preclinical and clinical studies addressing vector transduction efficacy, biodistribution, and toxicity are required before a human in utero gene transfer protocol can proceed. In addition, a more thorough understanding of the development of human organ systems, such as the immune and nervous systems, is needed to better define the potential efficacy and risks of human in utero gene transfer. Prerequisites for considering any specific human in utero gene transfer procedure include an understanding of the pathophysiology of the candidate disease and a demonstrable advantage to the in utero approach. Once the above criteria are met, the RAC would be willing to consider well rationalized human in utero gene transfer clinical trials.

Prepared by Kathi E. Hanna, M.S., Ph.D., Science and Health Policy Consultant

Last Reviewed: March 2006

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Germline Gene Transfer – National Human Genome Research …

Small viruses could accelerate cell and gene therapy research

Interest in the field of genome editing continues to heat up, fueled by technological advances and the first approval of a gene therapy in the United States. The latest development in this exciting frontier of science involves small viruses called AAVs (short for adeno-associated viruses) that have the power to overwrite DNA in human cells.

AAV biology is one of the most febrile areas of basic research, and were planning to explore its therapeutic potential through a new collaboration, says Craig Mickanin, who focuses on new tools and technologies as a director at the Novartis Institutes for BioMedical Research (NIBR).

Novartis will work with Homology Medicines, a biotech company with a proprietary AAV platform, to adapt and refine the technology for the treatment of a blood disorder and certain eye diseases. Novartis biologists with expertise in these conditions will work side-by-side with Homology scientists over the course of the collaboration announced November 13 to move projects toward clinical testing.

The collaboration is designed to accelerate an initiative at NIBR that engages researchers across the company who are involved in projects with a common denominator: the genetic reprogramming of cells. Homologys AAV technology may aid their work.

It is our hope that this collaboration will help advance our Cell and Gene Therapy initiative, says Susan Stevenson, an executive director at NIBR who leads the initiative.

AAV biology is one of the most febrile areas of basic research, and were planning to explore its therapeutic potential through a new collaboration.

Craig Mickanin, a director at NIBR who focuses on new tools and technologies

AAVs are unusual in one key respect. In contrast to larger viruses, they dont seem to cause illness. This built-in safety feature makes AAVs attractive tools for genome editing.

The benign viruses can be engineered to carry a specific genetic sequence, and they can be programmed to home in on a target site in the genome. When they arrive, AAVs trigger a process called homologous recombination, which overwrites a particular portion of a gene or even replaces an entire gene. In this way, AAVs can be used to correct genetic defects.

Homologous recombination may give AAVs an edge over other genome editing tools such as CRISPR in certain contexts.

Unlike AAVs, CRISPR employs molecular scissors to generate double-stranded breaks in DNA. The breaks can be repaired one of two ways. The repair mechanism that tends to dominate called non-homologous end joining results in the insertion or deletion of short DNA sequences, which typically break the original gene. As a result, its relatively easy for researchers to disrupt a gene with CRISPR, but its harder for them to fix an error in a gene.

We aim to select the right tool for the right project, says Mickanin, the technology specialist. In some cases, that will mean using AAVs to correct a genetic defect rather than disabling a gene.

The collaboration with Homology includes three work streams. The first focuses on a blood disorder. The Novartis-Homology team hopes to design a single AAV reagent that can be injected directly into the bloodstream of any patient with a defective gene to cure the disease. We want to figure out if these AAVs are safe enough to inject directly into the bloodstream and if we can use them to fix a defective gene once and for all, says Stevenson, the cell and gene therapy expert.

The second work stream involves diseases of the eye, a testing ground for gene editing therapies because such therapies can be delivered locally. Gene editing agents can be injected directly under the retina, for example, where researchers hope they will work without affecting the rest of the body. The fact that we can directly observe the treatment and its effects in the eye gives us an important opportunity for assessing gene editing efficacy and helping patients with eye disease, explains Cynthia Grosskreutz, Global Head of Ophthalmology at NIBR.

The final work stream is exploratory. Researchers from across NIBR will be able to nominate projects that could benefit from Homologys AAV technology. Homologys viruses will be tested on a variety of cell types and model systems, potentially exposing new opportunities for therapeutic applications.

This technology could be applied to many different diseases, Mickanin says. Were excited to work with the Homology team to explore the possibilities.

In addition to collaborating with Homology Medicines, Novartis has made an equity investment in the company.

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Small viruses could accelerate cell and gene therapy research

Gene therapy at OHSU Casey Eye Institute | Casey Eye …

Ongoing gene therapy trials open to enrollment

These studies are actively seeking new participants.

The purpose of this study is to learn about a new gene therapy that may help patients with Achromatopsia. This is the first study that aims to treat Achromatopsia disease by gene therapy. The study investigators want to find out whether it is safe for use in humans. The gene therapy is given by a surgical injection into the retina (the lining of the back of the eye that detects light) of one eye. The eye with worse vision will receive the gene therapy.

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The purpose of this study is to learn about a new gene therapy that may help patients with Achromatopsia. The study investigators want to find out whether it is safe for use in humans. The gene therapy is given by a surgical injection into the retina (the lining of the back of the eye that detects light) of one eye. The eye with worse vision will receive the gene therapy.

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The purpose of this study is to learn about a new gene therapy that may help patients with X-Linked Retinoschisis (XLRS).This is the first study that aims to treat XLRS disease by gene therapy. The study investigators want to find out whether it is safe for use in humans. The gene therapy is given by a surgical injection into the vitreous (a thick, gel-like transparent substance that fills the center of the eye) of one eye. The eye with worse vision will receive the gene therapy.

Contact 503 494-0020 or email the ORDC.

The purpose of this study is to learn about a new gene therapy being studied in patients with Retinitis Pigmentosa (RP) as a result of Usher Syndrome.This is the first study that aims to treat RP due to Usher Syndrome by gene therapy.The study investigators want to find out if UshStat is safe for use in humans.The gene therapy is given by surgical injection underneath the retina of one eye.The eye with worse vision will receive the gene therapy

Contact 503 494-0020 or email the ORDC.

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The purpose of this study is to learn about a new gene therapy that may help patients with Stargardt’s Macular Degeneration (SMD). This is the first study that aims to treat Stargardt’s disease by gene therapy. The study investigators want to find out whether it is safe for use in humans. The gene therapy is given by a surgical injection underneath the retina of one eye. The eye with worse vision will receive the gene therapy.

Contact 503 494-0020 or email the ORDC.

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Purpose: To evaluate the safety and dosing levels of a gene-based treatment, RetinoStat, for wet AMD. In this study, two helpful genes are delivered directly to the retina, where they “turn on” proteins that block abnormal blood vessel growth in a sustained fashion. Enrollment is completed and study patients are being followed.

Contact: Ann Lundquist, 503 494-6364.

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Gene therapy at OHSU Casey Eye Institute | Casey Eye …

Gene Therapy Advisory Committee – Health Research Authority

If your application is for ethical approval of a gene therapy clinical trial you must apply to the Gene Therapy Advisory Committee (GTAC).

GTAC is the UK national REC for gene therapy clinical research according to regulation 14(5) of The Medicines for Human Use (Clinical Trials) Regulations 2004.

You may book applications to the following RECs:

Once a booking is accepted, you must electronically submit your application and supporting documentation on the same day. If your application is valid, you will be sent an acknowledgement within five days of receipt and arrangements subsequently made for you to attend the REC meeting.

Historically, GTAC would send applications for external peer review. In future, as with all other RECs, the responsibility for providing peer review will rest with the sponsor.

We will seek to work in partnership with other organisations to determine whether it is possible to develop some agreed standards. More information can be found here.

You are no longer required to seek pre-application regulatory advice from GTAC. The MHRA will continue to provide this service to commercial companies, and will consider requests for advice from academic researchers.

Members of the research community have requested clarity on the type of application that needs to be submitted to GTAC.

Legally, all gene therapy applications must be submitted to a GTAC that is able to transfer to other designated RECs.

To make it easier for researchers and sponsors to identify other studies needing review, other applications that involve cell therapy and/or that are submitted to the MHRA Clinical Trials Expert Advisory Group must also be submitted to GTAC.

All gene therapy and cell therapy applications for Clinical Trials Authorisation will be assessed by the MHRA and, where appropriate will now be submitted to the MHRA Clinical Trials Expert Advisory Group for review. This review will assure the RECs that appropriate scrutiny of the safety of the application has been carried out.

The REC will raise any concerns directly with the MHRA.

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Gene Therapy Advisory Committee – Health Research Authority

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