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An Article from Quest Magazine


TUCSON, Ariz., January 16, 1998 -- An important milestone in the battle against neuromuscular diseases was reached today, as Muscular Dystrophy Association-funded researchers at the University of Pennsylvania, Ohio State University and the University of Michigan began initiatives that will lead to human trials of gene therapy for muscular dystrophy in as little as nine months.

"We're starting to screen patients for a limited trial using a gene delivery system that's worked well in the laboratory and is capable of carrying the incredibly large gene that produces the dystrophin protein, which when absent or defective causes Duchenne and Becker muscular dystrophies," said Dr. Jerry Mendell, director of the MDA Clinic at The Ohio State University Medical Center in Columbus. "I feel especially privileged to be collaborating on this exciting project with Jeffrey Chamberlain of the University of Michigan, one of the pioneers of gene therapy for muscular dystrophy."

Dystrophin plays a critical role in maintaining the structure of muscle cell membranes. Absence of the protein leads to increased cell injury, and eventual destruction of the muscle. Boys affected by Duchenne muscular dystrophy usually lose the ability to walk in late childhood, and die from respiratory insufficiency in their twenties. Those with Becker muscular dystrophy are less severely affected.

"By March we'll begin following 36 youngsters with Duchenne, analyzing their biochemistry and regularly assessing their muscle function and overall health," Mendell added. "Then, with this detailed 'before' picture complete, 12 boys, ages five, six, and seven, will receive gene therapy injections in the fall (pending FDA authorization). If they respond well to receiving the dystrophin gene, then additional boys will be added to the trial in two phases."

Dr. Chamberlain underscored that the initial trials are designed to assess the safety of the procedure and to provide data that will allow larger scale trials to be undertaken. He said the initial trials do not represent a treatment for the disease but are designed to provide answers to questions that hopefully will lead to a treatment or cure.

Dr. James M. Wilson, director of the Institute for Human Gene Therapy (IHGT) at the University of Pennsylvania in Philadelphia, agrees now is the time to focus on the discovery of promising gene therapies for humans with inherited muscular dystrophies and their rapid evaluation in humans. IHGT is already testing several novel gene delivery systems in monkeys and mice. Human pilot trials of the most promising systems could begin as early as September.

"As a result of a series of positive developments, it's become clear that muscle is a very receptive host for gene therapy, and that there's every reason to be optimistic about our aggressive program to make this therapy a reality," said Wilson.

Recognized worldwide for his pioneering gene therapy research, Dr. Wilson now leads a multidisciplinary team of MDA-supported investigators capable of discovery research, vector manufacturing, pharmacology/toxicology, quality assurance and clinical trials. A new $3.2 million commitment to IHGT is the largest single grant in MDA's history.

IHGT's unique infrastructure has supported a number of gene therapy initiatives which rapidly have led to successful applications in humans. Under Dr. Wilson's stewardship, IHGT has tested or is testing seven investigational new drugs in unique human applications and has pioneered important advances toward gene therapies for cystic fibrosis, cancer, cardiovascular disease, as well as genetic, immunology and infectious disorders.

"Thanks to the elegant work of hundreds of MDA-supported investigators worldwide, muscular dystrophy tops the list of diseases showing promise as targets for gene therapy," said Jerry Lewis, MDA National Chairman. "It's now time to move from bench to bedside. We've done our homework, and the Food and Drug Administration, as it has for all gene therapy efforts, has committed to work closely with the MDA and its investigators to assure that studies proceed with patient safety as the primary consideration while helping to reduce redundant laboratory and clinical studies.

Mendell is experienced with clinical trials for muscular dystrophy. He led a three-year clinical trial (1992-1995) in which healthy immature muscle cells, or myoblasts, were injected into the muscles of youngsters with Duchenne muscular dystrophy.

His collaborator, MDA grantee Jeffrey Chamberlain, led a team of researchers that in 1996 created one of the first gene delivery systems to improve prospects for reducing or eliminating host immune response. Chamberlain's team removed all viral genes from the adenovirus. This opens up a lot of space for the therapeutic gene, dystrophin, which is some 200 times larger than most other genes. It also prevents the virus from expressing its own genes once it gets into muscle, an action that otherwise would trigger an immune response. Chamberlain also led a team that in 1993 proved gene therapy can halt Duchenne-like muscular dystrophy in mice.

"We have, for the first time, a real opportunity to move forward now," said Donald S. Wood, MDA Director of Science Technology.

"We've shown gene therapy is safe in diseases other than muscular dystrophy," Wood added. "Patients have been enrolled in trials, and investigators report that there hasn't been a single adverse event related to the inserted gene. These studies demonstrate that it is possible to make vectors that can deliver genes into cells of patients. We've seen these vectors deliver their genes, express their genes and evoke the biologic and physiologic responses we would predict.

"We also have learned the limitations of the first generation of gene therapy technology. The efficiencies were not what we needed to achieve effective cures. Frequently we achieved expression for weeks or months. But, for treating chronic diseases, the vector must be stable for the life of a patient or at least for a very long time."

First generation vectors were recognized as foreign invaders, he added. To prevent immune response, the challenge has been to make the viral vector more stealth-like, and a second generation of delivery vehicles is currently being tested in clinical trials for cystic fibrosis.

Initial concerns about using neuromuscular diseases as a gene therapy model have been replaced by enthusiasm. During the past few years, a few discoveries in the laboratory have created new paradigms and skeletal and cardiac muscle, as well as neurons, almost overnight have become the gene therapy targets of choice.

In clinical trials using the adenovirus in liver and lung, investigators found immunologic responses to the first generation vectors. However, when IHGT used the same vector in muscle, the immunologic problems were not as dominant, and the adenovirus gene delivery system worked extremely well.

Other vectors are being tried. The adeno-associated virus (AAV) is a relatively new gene therapy vehicle. It's a small virus not associated with any disease. As a result, if it gets into a cell, it should have a greater chance of avoiding the body's immune response. Yet, in early non-muscle trials of gene therapy the AAV didn't work.

Recent research, however, has shown a dramatically different story when AAV is injected into the central nervous system or muscle. The AAV vector spreads out throughout the muscle fibers. It inserts the gene with stability. It doesn't elicit immunity, and persists in expressing the inserted gene for a long period of time. Similar results with AAV have been documented in neurons, thereby broadening the spectrum of neuromuscular diseases that could be treatment candidates for the AAV vector.

Since the discovery of the dystrophin gene in 1986, MDA-funded scientists have pioneered gene therapy research in their efforts to develop cures for the host of genetic neuromuscular diseases included in the Association's program.

Efforts have been hampered by three major obstacles: the size of the dystrophin gene prevents its administration by the common viral gene vectors; large numbers of cells must contain the gene in order to improve muscle strength; and apparent immune rejection of cells infected by the vector probably limits the duration of the gene correction.

MDA is a voluntary health agency working to defeat 40 neuromuscular diseases through programs of worldwide research, comprehensive patient and community services, and far-reaching professional and public health education.

Recognized by the American Medical Association with a Lifetime Achievement Award "for significant and lasting contributions to the health and welfare of humanity," MDA maintains 230 hospital-affiliated clinics that offer families the best in care for progressive neuromuscular diseases.

MDA annually funds some 400 scientific teams worldwide. These investigators have made significant advances toward cures for several muscle-wasting diseases. They've pioneered breakthroughs that may lead to therapies for heart disease, cancer, AIDS, Alzheimer's, Parkinson's, Huntington's, and cystic fibrosis. For information about these gene therapy projects, MDA, and/or referrals to MDA clinics, call 1-800-572-1717, or visit its Web Site at MDA programs are funded almost entirely by individual private contributors.

Email from the trial.

January 16, 1998
TO:Families of Those Inquiring about Participation in Duchenne Muscular Dystrophy Gene Therapy Trials
RE:Gene Therapy Research Projects
FROM:Ronald J. Schenkenberger
Director of Research and Patient Services Administration
Thank you for your recent inquiry about the ground-breaking gene therapy research being conducted by MDA-supported investigators at Ohio State University in collaboration with researchers at the University of Michigan. We welcome your submission of an application form*. In doing so, please keep in mind that the initial trials are designed to assess the safety of the procedure and to provide data that will allow larger scale trials to be undertaken. The initial trials do not represent a treatment for the disease but are designed to provide answers to questions that hopefully will lead to an expanded trial.

Researchers are targeting March of this year to begin screening youngsters ages 5, 6, and 7 and, pending FDA authorization, 12 will be selected in the initial trial to begin receiving injections by Fall of this year. While MDA is funding the project, the final decision regarding participation rests with the researchers conducting the study.

The budget for the project does not allow for reimbursement for travel and lodging related to participation in these initial trials. Participants will be expected to make at least monthly visits to Ohio State University in Columbus for at least the first year of the program.

Your completed application should be sent to researchers at Ohio State University, at the address shown on the application form. They will be responding to you directly.


To receive an application, please call the MDA national office at (800) 572-1717.

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