MD Briefs: Gene Therapy, Exon Skipping, Stem Cells

A follistatin gene therapy compound gains orphan drug status; potential improvements are reported for utrophin-based therapies, exon skipping and stem cell transplantation

Article Highlights:
  • The U.S. Food and Drug Administration has given orphan drug status to a follistatin gene therapy compound for development as a treatment for Duchenne or Becker muscular dystrophy. (The compound also is being tested in inclusion-body myositis.)
  • Tweaking the utrophin gene allows it to perform more of dystrophin's functions and improves the likelihood that utrophin-based therapies can be effective in Duchenne or Becker MD.
  • The prescription drug dantrolene unexpectedly enhanced exon skipping in a mouse model of Duchenne MD and in human DMD-affected cells.
  • Embedding muscle stem cells in a gel improved their survival and maturation in a mouse model of limb-girdle MD.
by Margaret Wahl on December 27, 2012 - 5:00am

Update (Jan. 23, 2013): The "Building better utrophin" section was updated to reflect the availability of a Jan. 22, 2013, press release from the University of Missouri.

Below is a wrap-up of recent research news about the development of therapies for Duchenne, Becker and limb-girdle muscular dystrophies.

Follistatin compound gains orphan drug status

A potentially therapeutic construct that combines the gene for the follistatin protein with the shell of an AAV1 virus as a delivery vehicle has been granted orphan drug designation by the U.S. Food and Drug Administration (FDA) for the treatment of Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD).

Orphan drug designation is a mechanism the FDA uses to encourage development of treatment for rare disorders. It qualifies the developer of the experimental drug for a tax credit and other financial incentives. However, it does not alter the requirements for safety and efficacy that a compound must meet for approval. Milo Biotechnology, a Cleveland-based company, announced the designation Dec. 12.

Follistatin gene transfer, which may help build muscle size and strength, is now being tested in a clinical trial in people with BMD and sporadic inclusion-body myositis (IBM).

To learn more, see:

Building better utrophin

Scientists funded in part by MDA have modified the gene for the utrophin protein, potentially making utrophin supplementation a more effective therapy for DMD or BMD, two disorders that result from a deficiency of the dystrophin protein.

Dongsheng Duan, an MDA grantee at the University of Missouri, Columbia, and colleagues, changed the utrophin gene so that a protein that helps regulate blood flow to exercising muscles can stick to it the same way it does to the dystrophin protein. When mice missing both utrophin and dystrophin were given gene therapy using the new, modified utrophin genes, the blood-flow protein known as nNOS was properly located in muscle fibers.

To learn more, see:

Dantrolene enhances exon skipping

The prescription drug dantrolene has been found to have an unexpected benefit — it appears to enhance the effectiveness of the experimental, gene-altering therapy known as exon skipping in a mouse model of DMD and in cells taken from patients with the disorder.

Dantrolene is used to treat chronic spasticity and an adverse anesthesia reaction known as malignant hyperthermia. When given along with an exon-skipping therapy to DMD mice, it improved exon skipping, resulting in additional production of the needed dystrophin protein and allowing the dantrolene-treated mice to hang on a wire for 50 percent longer than those treated with exon skipping alone.

To learn more, see:

Improving muscle stem cell transplantation

Muscle stem cells embedded in a jelly-like material called a hydrogel showed better survival and maturation into muscle cells than did muscle stem cells injected in a standard salt solution, in experiments conducted in mice with a disease resembling limb-girdle muscular dystrophy (LGMD). The type of stem cell used, a mesoangioblast, is a muscle precursor cell associated with blood vessels. The LGMD mice were missing the alpha-sarcoglycan protein and showed a disorder resembling human LGMD2D.

To learn more, see:

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