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Category Archives: Gene Therapy Trials
Posted: November 4, 2015 at 12:41 pm
Challenges in Gene Therapy?
Gene therapy is not a new field; it has been evolving for decades. Despite the best efforts of researchers around the world, however, gene therapy has seen only limited success. Why?
Gene therapy poses one of the greatest technical challenges in modern medicine. It is very hard to introduce new genes into cells of the body and keep them working. And there are financial concerns: Can a company profit from developing a gene therapy to treat a rare disorder? If not, who will develop and pay for these life-saving treatments?
Let’s look at some of the main challenges in gene therapy.
For some disorders, gene therapy will work only if we can deliver a normal gene to a large number of cellssay several millionin a tissue. And they have to the correct cells, in the correct tissue. Once the gene reaches its destination, it must be activated, or turned on, to make the protein it encodes. And once it’s turned on, it must remain on; cells have a habit of shutting down genes that are too active or exhibiting other unusual behaviors.
Introducing changes into the wrong cells Targeting a gene to the correct cells is crucial to the success of any gene therapy treatment. Just as important, though, is making sure that the gene is not incorporated into the wrong cells. Delivering a gene to the wrong tissue would be inefficient, and it could cause health problems for the patient.
For example, improper targeting could incorporate the therapeutic gene into a patient’s germline, or reproductive cells, which ultimately produce sperm and eggs. Should this happen, the patient would pass the introduced gene to his or her children. The consequences would vary, depending on the gene.
Our immune systems are very good at fighting off intruders such as bacteria and viruses. Gene-delivery vectors must be able to avoid the body’s natural surveillance system. An unwelcome immune response could cause serious illness or even death.
The story of Jesse Gelsinger illustrates this challenge. Gelsinger, who had a rare liver disorder, participated in a 1999 gene therapy trial. He died of complications from an inflammatory response shortly after receiving a dose of experimental adenovirus vector. His death halted all gene therapy trials in the United States for a time, sparking a much-needed discussion on how best to regulate experimental trials and report health problems in volunteer patients.
One way researchers avoid triggering an immune response is by delivering viruses to cells outside of the patient’s body. Another is to give patients drugs to temporarily suppress the immune system during treatment. Researchers use the lowest dose of virus that is effective, and whenever possible, they use vectors that are less likely to trigger an immune response.
A good gene therapy is one that will last. Ideally, an introduced gene will continue working for the rest of the patient’s life. For this to happen, the introduced gene must become a permanent part of the target cell’s genome, usually by integrating, or “stitching” itself, into the cell’s own DNA. But what happens if the gene stitches itself into an inappropriate location, disrupting another gene?
This happened in two gene therapy trials aimed at treating children with X-linked Severe Combined Immune Deficiency (SCID). People with this disorder have virtually no immune protection against bacteria and viruses. To escape infections and illness, they must live in a completely germ-free environment.
Between 1999 and 2006, researchers tested a gene therapy treatment that would restore the function of a crucial gene, gamma c, in cells of the immune system. The treatment appeared very successful, restoring immune function to most of the children who received it.
But later, 5 of the children developed leukemia, a blood cancer. Researchers found that the newly transferred gamma c gene had stitched itself into a gene that normally helps regulate the rate at which cells divide. As a result, the cells began to divide out of control, causing leukemia. Doctors treated 4 of the patients successfully with chemotherapy, but the fifth died.
This unfortunate incident raised important safety concerns, and researchers have since developed safer ways to introduce genes. Some newer vectors have features that target DNA integration to specific “safe” places in the genome where it won’t cause problems. And genes introduced to cells outside of the patient can be tested to see where they integrated, before they are returned to the patient.
Many genetic disorders that can potentially be treated with gene therapy are extremely rare, some affecting just one person out of a million. Gene therapy could be life-saving for these patients, but the high cost of developing a treatment makes it an unappealing prospect for pharmaceutical companies.
Developing a new therapyincluding taking it through the clinical trials necessary for government approval is very expensive. With a limited number of patients to recover those expenses from, developers may never earn money from treating such rare genetic disorders. And some patients may never be able to afford them.
Some diseases that can be treated with gene therapy, such as cancer, are much more common. However, many promising gene therapy approaches are individualized to each patient. For example, a patient’s own cells may be taken out, modified with a therapeutic gene, and returned to the patient. This individualized approach may prove to be very effective, but it’s also costly. It comes at a much higher price than drugs that can be manufactured in bulk, which can quickly recover the cost of their development.
If drug companies find a gene therapy treatment too unprofitable, who will develop it? Is it right to make expensive therapies available only to the wealthy? How can we bring gene therapy to everyone who needs it?
APA format: Genetic Science Learning Center (2014, June 22) Challenges in Gene Therapy?. Learn.Genetics. Retrieved November 04, 2015, from http://learn.genetics.utah.edu/content/genetherapy/gtchallenges/ MLA format: Genetic Science Learning Center. “Challenges in Gene Therapy?.” Learn.Genetics 4 November 2015
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Challenges in Gene Therapy – Learn Genetics
Posted: August 21, 2015 at 1:45 pm
Gene therapy carries the promise of cures for many diseases and for types of medical treatment that didn’t seem possible until recently. With its potential to eliminate and prevent hereditary diseases such as cystic fibrosis and hemophilia and its use as a possible cure for heart disease, AIDS, and cancer, gene therapy is a potential medical miracle-worker.
But what about gene therapy for children? There’s a fair amount of risk involved, so thus far only seriously ill kids or those with illnesses that can’t be cured by standard medical treatments have been involved in clinical trials using gene therapy.
As those studies continue, gene therapy may soon offer hope for children with serious illnesses that don’t respond to conventional therapies.
Our genes help make us unique. Inherited from our parents, they go far in determining our physical traits like eye color and the color and texture of our hair. They also determine things like whether babies will be male or female, the amount of oxygen blood can carry, and the likelihood of getting certain diseases.
Genes are composed of strands of a molecule called DNA and are located in single file within the chromosomes. The genetic message is encoded by the building blocks of the DNA, which are called nucleotides. Approximately 3 billion pairs of nucleotides are in the chromosomes of a human cell, and each person’s genetic makeup has a unique sequence of nucleotides. This is mainly what makes us different from one another.
Scientists believe that every human has about 25,000 genes per cell. A mutation, or change, in any one of these genes can result in a disease, physical disability, or shortened life span. These mutations can be passed from one generation to another, inherited just like a mother’s curly hair or a father’s brown eyes. Mutations also can occur spontaneously in some cases, without having been passed on by a parent. With gene therapy, the treatment or elimination of inherited diseases or physical conditions due to these mutations could become a reality.
Gene therapy involves the manipulation of genes to fight or prevent diseases. Put simply, it introduces a “good” gene into a person who has a disease caused by a “bad” gene.
The two forms of gene therapy are:
Currently, gene therapy is done only through clinical trials, which often take years to complete. After new drugs or procedures are tested in laboratories, clinical trials are conducted with human patients under strictly controlled circumstances. Such trials usually last 2 to 4 years and go through several phases of research. In the United States, the U.S. Food and Drug Administration (FDA) must then approve the new therapy for the marketplace, which can take another 2 years.
The most active research being done in gene therapy for kids has been for genetic disorders (like cystic fibrosis). Other gene therapy trials involve children with severe immunodeficiencies, such as adenosine deaminase (ADA) deficiency (a rare genetic disease that makes kids prone to serious infection), sickle cell anemia, thalassemia, hemophilia, and those with familial hypercholesterolemia (extremely high levels of serum cholesterol).
Gene therapy does have risks and limitations. The viruses and other agents used to deliver the “good” genes can affect more than the cells for which they’re intended. If a gene is added to DNA, it could be put in the wrong place, which could potentially cause cancer or other damage.
Genes also can be “overexpressed,” meaning they can drive the production of so much of a protein that they can be harmful. Another risk is that a virus introduced into one person could be transmitted to others or into the environment.
Gene therapy trials in children present an ethical dilemma, according to some gene therapy experts. Kids with an altered gene may have mild or severe effects and the severity often can’t be determined in infants. So just because some kids appear to have a genetic problem doesn’t mean they’ll be substantially affected by it, but they’ll have to live with the knowledge of that problem.
Kids could be tested for disorders if there is a medical treatment or a lifestyle change that could be beneficial or if knowing they don’t carry the gene reduces the medical surveillance needed. For example, finding out a child doesn’t carry the gene for a disorder that runs in the family might mean that he or she doesn’t have to undergo yearly screenings or other regular exams.
To cure genetic diseases, scientists must first determine which gene or set of genes causes each disease. The Human Genome Project and other international efforts have completed the initial work of sequencing and mapping virtually all of the 25,000 genes in the human cell. This research will provide new strategies to diagnose, treat, cure, and possibly prevent human diseases.
Although this information will help scientists determine the genetic basis of many diseases, it will be a long time before diseases actually can be treated through gene therapy.
Gene therapy’s potential to revolutionize medicine in the future is exciting, and hopes are high for its role in ;curing and preventing childhood diseases. One day it may be possible to treat an unborn child for a genetic disease even before symptoms appear.
Scientists hope that the human genome mapping will help lead to cures for many diseases and that successful clinical trials will create new opportunities. For now, however, it’s a wait-and-see situation, calling for cautious optimism.
Reviewed by: Larissa Hirsch, MD Date reviewed: April 2014 Originally reviewed by: Louis E. Bartoshesky, MD, MPH
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Gene Therapy and Children – KidsHealth
Posted: August 15, 2015 at 7:41 am
Please choose from the following list of questions for information about gene therapy, an experimental technique that uses genetic material to treat or prevent disease.
On this page:
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 only being tested for the treatment of diseases that have no other cures.
MedlinePlus from the National Library of Medicine offers a list of links to information about genes and gene therapy.
Educational resources related to gene therapy are available from GeneEd.
The Genetic Science Learning Center at the University of Utah provides an interactive introduction to gene therapy and a discussion of several diseases for which gene therapy has been successful.
The Centre for Genetics Education provides an introduction to gene therapy, including a discussion of ethical and safety considerations.
KidsHealth from Nemours offers a fact sheet called Gene Therapy and Children.
Additional information about gene therapy is available from the National Genetics and Genomics Education Centre of the National Health Service (UK)
Gene therapy is designed to introduce genetic material into cells to compensate for abnormal genes or to make a beneficial protein. If a mutated gene causes a necessary protein to be faulty or missing, gene therapy may be able to introduce a normal copy of the gene to restore the function of the protein.
A gene that is inserted directly into a cell usually does not function. Instead, a carrier called a vector is genetically engineered to deliver the gene. Certain viruses are often used as vectors because they can deliver the new gene by infecting the cell. The viruses are modified so they cant cause disease when used in people. Some types of virus, such as retroviruses, integrate their genetic material (including the new gene) into a chromosome in the human cell. Other viruses, such as adenoviruses, introduce their DNA into the nucleus of the cell, but the DNA is not integrated into a chromosome.
The vector can be injected or given intravenously (by IV) directly into a specific tissue in the body, where it is taken up by individual cells. Alternately, a sample of the patients cells can be removed and exposed to the vector in a laboratory setting. The cells containing the vector are then returned to the patient. If the treatment is successful, the new gene delivered by the vector will make a functioning protein.
Researchers must overcome many technical challenges before gene therapy will be a practical approach to treating disease. For example, scientists must find better ways to deliver genes and target them to particular cells. They must also ensure that new genes are precisely controlled by the body.
A new gene is injected into an adenovirus vector, which is used to introduce the modified DNA into a human cell. If the treatment is successful, the new gene will make a functional protein.
The Genetic Science Learning Center at the University of Utah provides information about various technical aspects of gene therapy in Gene Delivery: Tools of the Trade. They also discuss other approaches to gene therapy and offer a related learning activity called Space Doctor.
The Better Health Channel from the State Government of Victoria (Australia) provides a brief introduction to gene therapy, including the gene therapy process and delivery techniques.
Penn Medicines Oncolink describes how gene therapy works and how it is administered to patients.
Gene therapy is under study to determine whether it could be used to treat disease. Current research is evaluating the safety of gene therapy; future studies will test whether it is an effective treatment option. Several studies have already shown that this approach can have very serious health risks, such as toxicity, inflammation, and cancer. Because the techniques are relatively new, some of the risks may be unpredictable; however, medical researchers, institutions, and regulatory agencies are working to ensure that gene therapy research is as safe as possible.
Comprehensive federal laws, regulations, and guidelines help protect people who participate in research studies (called clinical trials). The U.S. Food and Drug Administration (FDA) regulates all gene therapy products in the United States and oversees research in this area. Researchers who wish to test an approach in a clinical trial must first obtain permission from the FDA. The FDA has the authority to reject or suspend clinical trials that are suspected of being unsafe for participants.
The National Institutes of Health (NIH) also plays an important role in ensuring the safety of gene therapy research. NIH provides guidelines for investigators and institutions (such as universities and hospitals) to follow when conducting clinical trials with gene therapy. These guidelines state that clinical trials at institutions receiving NIH funding for this type of research must be registered with the NIH Office of Biotechnology Activities. The protocol, or plan, for each clinical trial is then reviewed by the NIH Recombinant DNA Advisory Committee (RAC) to determine whether it raises medical, ethical, or safety issues that warrant further discussion at one of the RACs public meetings.
An Institutional Review Board (IRB) and an Institutional Biosafety Committee (IBC) must approve each gene therapy clinical trial before it can be carried out. An IRB is a committee of scientific and medical advisors and consumers that reviews all research within an institution. An IBC is a group that reviews and approves an institutions potentially hazardous research studies. Multiple levels of evaluation and oversight ensure that safety concerns are a top priority in the planning and carrying out of gene therapy research.
Information about the development of new gene therapies and the FDAs role in overseeing the safety of gene therapy research can be found in the fact sheet Human Gene Therapies: Novel Product Development Q&A.
The Genetic Science Learning Center at the University of Utah explains challenges related to gene therapy.
The NIHs Office of Biotechnology Activities provides NIH guidelines for biosafety.
Because gene therapy involves making changes to the bodys set of basic instructions, it raises many unique ethical concerns. The ethical questions surrounding ge
ne therapy include:
How can good and bad uses of gene therapy be distinguished?
Who decides which traits are normal and which constitute a disability or disorder?
Will the high costs of gene therapy make it available only to the wealthy?
Could the widespread use of gene therapy make society less accepting of people who are different?
Should people be allowed to use gene therapy to enhance basic human traits such as height, intelligence, or athletic ability?
Current gene therapy research has focused on treating individuals by targeting the therapy to body cells such as bone marrow or blood cells. This type of gene therapy cannot be passed on to a persons children. Gene therapy could be targeted to egg and sperm cells (germ cells), however, which would allow the inserted gene to be passed on to future generations. This approach is known as germline gene therapy.
The idea of germline gene therapy is controversial. While it could spare future generations in a family from having a particular genetic disorder, it might affect the development of a fetus in unexpected ways or have long-term side effects that are not yet known. Because people who would be affected by germline gene therapy are not yet born, they cant choose whether to have the treatment. Because of these ethical concerns, the U.S. Government does not allow federal funds to be used for research on germline gene therapy in people.
The National Human Genome Research Institute discusses scientific issues and ethical concerns surrounding germline gene therapy.
A discussion of the ethics of gene therapy and genetic enhancement is available from the University of Missouri Center for Health Ethics.
Gene therapy is currently available only in a research setting. The U.S. Food and Drug Administration (FDA) has not yet approved any gene therapy products for sale in the United States.
Hundreds of research studies (clinical trials) are under way to test gene therapy as a treatment for genetic conditions, cancer, and HIV/AIDS. If you are interested in participating in a clinical trial, talk with your doctor or a genetics professional about how to participate.
You can also search for clinical trials online. ClinicalTrials.gov, a service of the National Institutes of Health, provides easy access to information on clinical trials. You can search for specific trials or browse by condition or trial sponsor. You may wish to refer to a list of gene therapy trials that are accepting (or will accept) participants.
Next: The Human Genome Project
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Gene Therapy – Genetics Home Reference
Posted: December 27, 2014 at 5:42 pm
Prof Krystof Bankiewicz. Overview of AADC Deficiency – AAV2-hAADC Gene Therapy Trials.
Prof Krystof Bankiewicz of University of California, San Francisco, USA presents an overview of AADC Deficiency and AAV2-hAADC Gene Therapy Trials. He describes the technique and background…
Posted: December 10, 2014 at 1:46 pm
Ethical questions are crucial, but they shouldnt stall the progress of this promising branch of medicine
In late November, Reuters reported a milestone in medical history: a gene therapy drug could go on sale in Germany next year, after winning the approval of European regulators two years ago. The drug, Glybera, by a Dutch firm called UniQure currently being scrutinised by Germanys federal joint committee would be the first commercial use of gene therapy in the Western world (China has had a gene therapy drug for a specific form of cancer in the market since 2004). This marks a potential turning point in an area of medicine that has been the subject of highs and lows over more than two decades of clinical trials.
Gene therapy which can involve a number of things, including replacing a malfunctioning gene or introducing a new gene with the ability to fight a disease has been in conceptual development for far longer. Its origins could be said to go back as early as the 1920s, well before the discovery of the structure of DNA, when a British scientist, Frederick Griffith, put forward what he described as the transforming principle; he successfully converted a non-virulent strain of bacteria into a virulent one, after injecting mice with both.
From the late 1960s, when the concept of gene therapy began to involve, it took several decades for the first clinical trial to take place in 1990. A young girl in the US with a genetic defect that had left her with a severely weakened immune system was successfully injected with her own white blood cells containing a corrected form of the malfunctioning gene.
However, the boost gene therapy got following that first successful trial was soon tarnished, in the view of the public, by a tragedy in 1999; an 18-year-old American boy, who had a mild version of a liver condition, which meant his body couldnt process ammonia, died during a gene therapy treatment. This was after a massive response by his immune system to the vector or carrier used to introduce the corrected gene.
The episode raised a number of issues including that of informed consent of those participating in clinical trials as well as the fact that identifying and correcting a defective gene was far from the only challenge facing gene therapy. Selecting the appropriate vector was also vital and not without risks.
Despite predictions that gene therapy would be lastingly damaged by the tragedy, research and trials continued with many promising results for a range of conditions ranging from immune system conditions to cancer, cystic fibrosis, Parkinsons disease and hemophilia.
The renewed confidence in gene therapy is highlighted by the fact that the worlds largest pharmaceutical companies have also entered the market (earlier this week, Pfizer announced collaboration with Spark Therapeutics, a Philadelphia based company on the development of a hemophilia B treatment).
Over 1,700 approved gene therapy trials have taken place in the past two decades, estimated an article on the history of gene therapy in Gene magazine last year with many successes and a few hits. Among the latter were trials conducted in France in 2001 on Severe Combined Immunodeficiency, a condition where the immune system is so crippled that in one case it required a boy to live in a germ-free bubble. Several infants involved in the trial subsequently developed leukemia, though other clinical trials for gene therapy since have been successful.
There have been some understandable public concerns about gene therapy and its impact on the one hand it offers that tantalising potential of curing some of the most lethal conditions while on the other, tampering with genetic makeup is something that has long conjured up fears in the public imagination of genetic engineering and exacerbating discrimination against those with disabilities and disease.
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Gene therapy makes a slow comeback
Posted: October 21, 2014 at 1:45 am
A new variation of gene therapy raises hopes for a safe and effective long-term treatment for X-linked severe combined immunodeficiency syndrome (SCID-X1), a life-threatening heritable disorder.
The research was produced by a collaborative research team from Dana-Farber/Boston Children’s Cancer and Blood Disorders Center, along with other institutions participating in an international clinical trial that involved boys from the United States and France.
SCID-X1, dubbed bubble boy disease after a patient who lived for 12 years in a sterile bubble, is a rare genetic disorder that hinders the ability of individuals to combat infections. Because the disease is carried in an X-chromosome recessive pattern, the disorder occurs almost only in males. The resulting mutations inactivate a gene called IL-2 receptor gamma (IL2RG), severely weakening immune system functions. Left untreated, individuals who inherit the disorder usually die within a year.
Previous gene therapy trials conducted in Europe over a decade ago promised dramatic progress, until a quarter of patients developed leukemia about two to five years following treatment. Scientists found that the previously used vectorthe device for transporting the correct gene in therapyinadvertently activated oncogenes, which can cause cancer.
In this new study, the vector in use is a self-inactivating gammaretrovirus, which has a specific sequence deleted that basic research had implicated in the process of inappropriate activation of oncogenes, David A. Williams, chief of the hematology/oncology department at Boston Children’s Hospital, wrote in an email.
Of the nine patients who underwent the treatment, eight had survived between 12 and 38 months after treatment. One boy died from a severe infection he was fighting at the time he enrolled in the study.
A single round of therapy restored normal disease-fighting T cell count300 cells or more per microliter of bloodin six of the eight patients. One patient underwent a second round of treatment and remains healthy despite a low cell count. The eighth patient received a hematopoietic stem cell transplant after the therapy led to less than optimal uptake of the virus and failed to stimulate T-cell production, according to Williams.
We feel the surrogate assays for safety look excellent and are very encouraged, Williams said. However, because leukemia can take years to develop (and although some of our patients are now approaching 4 years of [follow-up]) we must be cautious and continue to follow these children closely.
Williams noted that the research was the result of positive collaboration between institutions.
Work by Sung-Yun Pai and Gigi Notarangelo, funding from [Boston Childrens Hospital] (and other childrens hospitals) and [the National Institute of Health] were essential for success, he said. This is the first international collaborative trial in stem cell gene therapy, which was critical for success due [to the] rarity of [this] disease.
Posted: May 29, 2014 at 6:46 am
Researchers used an emerging technique to correct the gene behind a fatal immune system disorder in an infant.
A new kind of gene therapy which involves editing, rather than replacing, faulty genes in sick people, is being used experimentally in patients. The latest report shows how scientists can correct a broken gene as it sits in the patients genome. How the health of the patient, a 4-month old infant, will change is yet to be reported.
Genome editing technology is considered a promising new tool for curing disease. For decades, gene therapy has meant that a virus delivers a functional copy of a gene that is dysfunctional in a patient. The dysfunctional copy remains and the therapeutic version typically remains separate from the rest of the genome.
The technology has drawbacks. First, by sitting outside of the genome, the activity of therapeutic gene isnt regulated properly. In some cases, the therapeutic copy is delivered by a retrovirus the plunks the new gene down near randomly in the patients genome, which risks disrupting another gene, potentially causing cells to turn cancerous. Second, some diseases, such as Huntingtons, cant be treated this way because the broken copy of the gene causes harm. To treat these kinds of conditions, the original copy of the gene must be corrected. Using genome editing to repair genes could circumvent these issues (see Genome Surgery).
In the new study, published today in the journal Nature, researchers in Milan treated a condition known as Severe Combined Immunodeficiency Syndrome, or SCID (this condition is sometimes referred to as bubble boy disease because children afflicted may live in protected environments because the risk of death from infectious disease is extremely likely). Children with this genetic condition have been treated with the additive gene therapy method in the past, and some suffered leukemia-like diseases as a side effect (see The Glimmering Promise of Gene Therapy). In the new report, researchers describe treating a single infant with zinc-finger nucleases designed to repair a defective copy of an important immune system gene.
The report does not look at the long term health effects for the infant. But the team shows that the genome editing did reconstitute a functional copy of the immune system gene in a small fraction of bone marrow cells (which give rise to immune cells). This work is undoubtedly a step towards using gene repair for gene therapy, writes immunologist Alain Fischer in an accompany article also published in Nature. Fischer led the first successful gene therapy trials for SCID patients.
In March, researchers reported an even more dramatic example of gene repair. Scientists used zinc fingers to engineer the immune cells of patients with HIV to resist the virus (see Can Gene Therapy Cure HIV?). In a few patients, the amount of virus in the blood decreased and in one patient, the virus could no longer be found.
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Genome Editing to Reverse Bubble Boy Syndrome
Posted: May 8, 2014 at 7:46 am
FOR IMMEDIATE RELEASE Tuesday, March 7, 2000 Contact: FDA Press Office (301) 827-6250 NIH Press Office (301) 496-5787
New Initiatives to Protect Participants in Gene Therapy Trials
FDA’s clinical trials monitoring plan addresses emerging evidence that the monitoring by study sponsors of several recent gene therapy trials has been less than adequate. To buttress the rigor of the oversight, FDA will require that sponsors of gene therapy trials routinely submit their monitoring plans to the FDA.
FDA will review these monitoring plans and seek modifications as warranted to improve the quality of monitoring. FDA will also perform surveillance and “for cause” inspections of clinical trials to assess whether the plans are being followed and whether monitoring has been adequate to identify and correct critical problems. The sponsors will also have to address such issues as the experience and training of the monitors and the adequacy of the monitoring in their plans. In addition, NIH and FDA will seek to enhance the conduct of gene therapy trials by convening a conference of investigators at which the appropriate monitoring practices will be discussed by the most experienced professionals in the field.
Clinical trial monitoring is a powerful tool in enhancing the safety and protection of research subjects during a trial. Monitors are selected by and report to the sponsor or the sponsor’s designee (e.g., a contract research organization). These monitors verify that the rights and well-being of human subjects are protected; that the conduct of the trial is in accordance with the protocol, regulatory requirements, and good clinical practices; and that data reporting (including safety reporting to IRB, FDA, and NIH) is accurate and complete.
In addition, in those instances where the gene therapy trial has an independent data and safety monitoring board (or equivalent) associated with it, the board’s findings and recommendations regarding patient safety are shared with the IRB, FDA, and NIH. In some gene therapy trials, one or more of the investigators is also the sponsor or a member or employee of the sponsoring organization. NIH will work to develop procedures to further assure appropriately independent oversight of the conduct of such trials.
“Clinical trial monitoring and responsible reporting must be taken seriously by all parties involved in gene therapy trials,” said Commissioner of Food and Drugs Jane E. Henney, M.D. “Our plan will help restore the confidence in the trials’ integrity that is essential if gene therapy studies are to be able to fulfill their potential.”
In a second new initiative, a series of Gene Transfer Safety Symposia, NIH and FDA will enhance patient safety by providing critical forums for the sharing and analysis of medical and scientific data from gene transfer research.
The symposia, which are expected to take place about four times a year, will bring together leading experts in gene transfer research and give them an opportunity to publicly discuss medical and scientific data germane to their specialties.
The first symposium will take place during this week’s meeting of the Recombinant DNA Advisory Committee (RAC). Scientists and physicians will discuss the safety and future clinical applications of a new class of adenoviral vectors that have been extensively altered with the aim of improved safety.
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New Initiatives to Protect Participants in Gene Therapy Trials
Posted: December 26, 2013 at 11:48 pm
Patient Receives First-Ever Gene Therapy for Parkinson’s at NewYork-Presbyterian Hospital/Weill Cornell Medical Center Historic Procedure Also Marks First In Vivo Gene Therapy in Adult Brain
NEW YORK (Aug 20, 2003)
Surgeons at NewYork-Presbyterian/Weill Cornell performed the world’s first gene therapy for Parkinson’s disease on a 55-year-old New York man on Monday, August 18. The historic surgery, which also marked the first-ever in vivo gene therapy in the brain for an adult neurological disease, was part of a Phase I clinical trial approved by the Food and Drug Administration in October 2002.
The five-hour procedure was performed by Dr. Michael G. Kaplitt, Director of Stereotactic and Functional Neurosurgery at NewYork-Presbyterian Hospital and Assistant Professor of Neurological Surgery at Weill Cornell Medical College. The patient is recovering normally and is expected to return home today, just two days after the surgery was performed.
“Monday’s surgery represents the realization of nearly 15 years of research in this area,” said Dr. Kaplitt. “The goal of our gene therapy approach is to ‘re-set’ a specific group of cells that have become overactive in an affected part of the brain, causing the impaired movements associated with Parkinson’s disease. We hope that this trial, which is the first of its kind, will prove to be a safe treatment to allow gene therapy to move forward for Parkinson’s disease and other brain disorders.”
Dr. Antonio M. Gotto, Jr., Dean of Weill Cornell Medical College, said: “This research represents a new approach to treating one of the most devastating diseases known to man.”
Dr. Herbert Pardes, President and CEO of NewYork-Presbyterian Hospital, said, “This major breakthrough can only be realized in an academic medical center, such as ours, where a unique synergy between bench and bedside, between research and patient care, can meet and flourish.”
In the procedure, Dr. Kaplitt pinpoints the optimal location in the patient’s brain using information from an advanced 3T MRI image, which is subsequently merged with a CT scan, using the latest computer imaging technology. Then, the final target is confirmed using fine electrical probes that identify the signature pattern of electrical activity of individual cells within the brain. During this process, the patient is awake and not medicated because medication and anesthesia can confuse the electrical information obtained. With the target obtained, the gene therapy agent (adeno-associated virus or AAV) is slowly delivered through a very fine catheter. After a 90-minute infusion, the catheter is removed, the skin closed, and the patient sent to the recovery room.
AAV is the means by which the GAD (glutamic acid decarboxylase) gene enters the appropriate brain cells and begins production of a protein that produces GABAa molecule that is released by nerve cells to inhibit, or dampen, activity. “Our intent, ultimately, is to normalize the chemical signaling of key affected brain areas in order to reduce the devastating effects of Parkinson’s,” says Dr. Kaplitt.
In 1994, Dr. Kaplitt was the lead author of a paper published in Nature Genetics, along with senior author Dr. Matthew During, Professor of Molecular Medicine at the University of Auckland, which demonstrated, for the first time, that AAV could be a safe and effective vehicle for gene therapy in the brain. Last October, Dr. During was the lead author and Dr. Kaplitt the co-author of a paper in Science demonstrating the feasibility of the gene therapy approach used in today’s operation. Since 1994, AAV has been used safely in several clinical gene therapy trials, and the virus has never been associated with any human disease.
Posted: November 28, 2013 at 5:45 pm
Wiley database on Gene Therapy Trials Worldwide The 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 2007 – an update. J. Gene Med. 2007 Oct;9(10):833-842. ClinicalTrials.gov database on clinical trials performed in the US and worldwide The 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 Register The 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 database The 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. GeMCRIS – NIH Genetic Modification Clinical Research Information GeMCRIS allows users to access an array of information about human gene transfer trials registered with the NIH, including medical conditions under study, institutions where trials are being conducted, investigators carrying out these trials, gene products being used, route of gene product delivery, and summaries of study protocols. US National Cancer Institute – Cancer Trials The database includes most clinical trials sponsored by NCI. The registry contains more than 5,000 abstracts of clinical trial protocols that are open/active and approved for patient accrual (accepting patients), including trials for cancer treatment, genetics, diagnosis, supportive care, screening, and prevention. In addition, the registry contains more than 16,000 abstracts of clinical trial protocols that have been completed or are closed to patient accrual. Australia New Zealand Clinical Trials Registry (ANZCTR) The ANZCTR is an online register of clinical trials being undertaken in Australia and New Zealand. The ANZCTR
includes trials from the full spectrum of therapeutic areas trials of pharmaceuticals, surgical procedures, preventive measures, lifestyle, devices, treatment and rehabilitation strategies and complementary therapies. It has coverage all clinical trials involving Australian/New Zealand researchers or participants. Trials that do not involve Australian/New Zealand researchers or participants will be accepted if there is not a more appropriate national registry with which they should be lodged.
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Gene Therapy Clinical Trials Databases