Scientists Share Gene Therapy Advances

by Quest Staff on September 1, 2006 - 10:36am

QUEST Vol. 13, No. 5

Researchers, including MDA grantees, working on gene therapy for muscle and nerve diseases presented findings and exchanged ideas at the ninth annual meeting of the American Society of Gene Therapy, held in Baltimore in June.

Improved cell therapy has promise, drawbacks

Transplantation of cells committed to forming muscle (termed myogenic precursor cells in this study) from donors to patients, using updated techniques, may result in considerable production of a needed protein in Duchenne muscular dystrophy (DMD), said molecular biologist Jacques Tremblay, of the Human Genetics Unit of Laval University in Quebec, and colleagues, at the meeting.

Jacques Tremblay
Jacques Tremblay

Tremblay, who’s had intermittent MDA funding since 1996, has improved upon myoblast transfer, a technique tested in the 1990s that transplanted cells located around the periphery of muscle fibers and capable of repairing muscle. The trials failed to keep the transplanted cells alive for long and didn’t help boys with DMD get stronger.

Tremblay and colleagues have changed the way in which the satellite cells are processed after being retrieved from donors’ muscles. They also administered the powerful immunosuppressant tacrolimus to the cell recipients, and spaced the cell injections every 1 to 2 millimeters in recipients’ muscles.

They say eight out of nine DMD-affected boys, all of whom received myogenic precursor cells from their parents, showed some benefit from the transplant, with dystrophin-producing fibers ranging from 4 percent to 26 percent four weeks after injec-tions into a very small area in a leg muscle.

Tremblay’s group plans to conduct a new trial of cell transplantation in 10 men with DMD or its milder variant, Becker MD, who are at least 18 years old. (The study is accepting only Canadians.)

Concerns remain about the safety and effectiveness of long-term immunosuppression and the practicality of administering intramuscular injections hundredths of an inch apart throughout the body.

However, Tremblay said, he thinks that “transplantation of cells derived from satellite cells will one day be a treatment for most skeletal muscles.”

Cells with SMA coaxed to make needed protein

Conference attendees saw some exciting data from MDA grantee Christian Lorson at the University of Missouri-Columbia, and colleagues, who presented a new molecular strategy to coax cells affected by spinal muscular atrophy (SMA) to make needed SMN protein molecules. (A paper from this group is in the July issue of Molecular Therapy.)

In people with SMA, cells usually make a shortened, nonfunctional version of the SMN protein when guided by SMN2 RNA instructions.

University of Missouri investigators have created a bifunctional RNA that sticks to the SMN2 instructions (A) and attracts compounds (B) that lead to production of full-length SMN.

People with SMA have either mutated or no SMN1 genes, which normally produce the full-length SMN. But they have SMN2 genes, which produce some full-length SMN protein molecules but mostly short, nonfunctional SMN molecules.

Fortuitously, instructions for making full-length SMN are embedded in the SMN2 genetic recipe, at the RNA stage (made from the DNA genetic code), but these instructions are for the most part ignored by SMA-affected nerve cells. Now, Lorson’s group has figured out an elegant way to coax the cell into following them.

The Missouri investigators designed bifunctional RNA molecules that stick to the SMN2 RNA instructions at a specific place (one function). They then recruit so-called splicing factors, proteins that lead to the production of full-length SMN (a second function).

They delivered the molecules to SMA-affected cells in a lab dish, in some cases using altered adeno-associated viruses to continuously make the desired RNA pieces from DNA.

If the approach were used in people with SMA, Lorson said, “the idea would be that a single administration would last for many months or years. Therefore, it would not require frequent boosts, but it’s very likely that multiple muscle groups would need to be targeted at the time of initial treatment.”

Duan receives award

Dongsheng Duan
Dongsheng Duan

MDA research grantee Dongsheng Duan, at the University of Missouri-Columbia, received a prestigious Outstanding New Investigator Award from the society.

The $1,000 award is given to a scientist who’s held a full-time faculty position for no more than seven years. Duan is an as-sociate professor in the Department of Molecular Microbiology & Immunology.

Duan’s current MDA grant is for the development of gene therapy for heart disease in a mouse model of Duchenne muscular dystrophy (DMD).

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