A late summer meeting of some 20 MDA-supported gene therapy experts, MDA staff members and representatives of the Food and Drug Administration (FDA) led to an expansion of the proposed gene therapy trial in Duchenne muscular dystrophy (DMD) to include two other forms of muscular dystrophy. The rapid scientific advances of the last year or so are responsible for the increased scope of the gene therapy effort.

TRIALS SLATED IN THREE DISEASES

The expanded plans now include gene therapy safety tests in Becker muscular dystrophy (BMD) and some forms of limb-girdle muscular dystrophy (LGMD). The LGMD trial will have an extended preliminary phase in which prospective trial participants will undergo testing to see which LGMD gene is responsible for their disorder.

Three representatives of the Center for Biologics Evaluation and Research (CBER) of the FDA attended the August meeting. The CBER reviews gene therapy proposals through a multistep process, and among its mandates are ensuring the safety and rights of participants and the public during all phases of gene therapy clinical trials.

The initial proposal for the DMD trial (see story in Quest, vol. 5, no. 1) must be reviewed by the FDA, which will recommend revisions to the trial proposal. One likely modification will be with regard to immunosuppressive drugs, since concerns about this aspect were discussed at the meeting.

A number of institutions will collaborate in the trials. The DMD trial will draw on the resources of researchers and clinicians at Ohio State University in Columbus, the University of Michigan in Ann Arbor and the University of Pennsylvania in Philadelphia.

The BMD and LGMD trials will draw on these same resources, as well as on a collaborative network involving the University of Iowa in Iowa City, Washington University in St. Louis and possibly other institutions.

IMMUNOLOGIC HURDLES HIGHEST IN DMD

The scientific advances of the last few years, which were summarized at the meeting, suggest that the immunologic problems likely to be encountered when transferring a gene are more formidable in DMD than in BMD or LGMD.

To treat DMD or BMD, it will be necessary to insert the gene for dystrophin, a muscle membrane protein missing or deficient in these disorders. But inserting this very large gene requires the use of the outer shell of the large adenovirus.

The researchers and the FDA suggest that inserting this viral shell and the dystrophin protein (which will be made from the gene) into boys who have previously produced very little or no dystrophin may pose an immunologic hurdle, which could threaten the success or even the safety of the gene transfer. Details about how much immunosuppression will be needed and the timing of such immunosuppression are still being worked out.

Immunologic hurdles in BMD are likely to be less severe, although no one can say for sure. The reason for the optimistic prediction is that boys and men with BMD already make some dystrophin, so their immune systems are less likely to regard the intruding protein as "foreign." The viral shell used to carry the gene may still cause some difficulties, however.

LGMD TESTS TO USE AAV

Animal experiments using the delta-sarcoglycan gene, which would theoretically correct the muscle abnormality in one form of LGMD, have been highly promising with regard to acceptance by the immune system.

There are four sarcoglycan genes -- alpha, beta, gamma and delta -- each of which, when absent, leads to a form of LGMD. (Sarcoglycans lie near dystrophin in the muscle fiber membrane.) Each of the sarcoglycans could theoretically correct a form of LGMD if inserted by gene transfer.

The sarcoglycan genes are very small, so they can be carried by a small virus known as AAV (for adeno-associated virus). This virus has been well tolerated by the immune system in animal experiments, suggesting that it would be an excellent choice for gene delivery.

Prospective trial participants who have LGMD will need to undergo genetic testing prior to any gene transfer to see precisely which gene is involved in their disorder. Those with BMD or DMD are likely to need genetic testing as well.

The researchers aren't certain how many of the sarcoglycan-related forms of LGMD they can include in these first trials.

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MDA is now taking calls from families interested in placing the name of an adult or child with BMD or LGMD, or a child between ages 5 and 7 with DMD, on a waiting list to be considered for a gene therapy safety trial. No therapeutic benefit is expected from any of these early trials. To be put on the list, call (800) 572-1717, and MDA will forward your name to the researchers; or visit the Clinical Trials listing in the Research area of MDA's Web site, www.mda.org.