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Other Therapies

Mouse Study Raises Hope for Muscular Dystrophy Patients
By Linda Carroll
[Medical Tribune: Family Physician Edition 39(7): 1998. 1998 Jobson Healthcare Group]
Courtesy of

Italian researchers have discovered that certain bone-marrow cells can differentiate into muscle cells, according to a new study. After injecting bone-marrow cells into mice with muscle damage, researchers found that some of the nuclei from the bone-marrow cells were incorporated into the mouse muscle tissue, according to the report in Science (1998;279:1528-1530).

Until recently, scientists had assumed that new muscle tissue could only be formed by specialized cells called satellite cells. But the new research shows that certain bone-marrow cells may be more flexible than previously thought, according to lead study author Giuliana Ferrari, Ph.D., a molecular biologist at the San Raffaele-Telethon Institute for Gene Therapy in Milan. And this finding may ultimately give hope to patients suffering from muscular dystrophy, experts said.

"This is extremely exciting," said Leon Charash, M.D., a pediatric neurologist at Cornell University Medical College in New York.

Attempts to cure muscular dystrophy have been hampered by a number of factors, including the patient's own immune system, Dr. Charash said.

"But this [new discovery] means we may be able to harvest bone marrow from the sick child himself," he noted. "And thus, he won't have antibodies to kill it."

In the study, the researchers collected bone marrow from mice that had been altered to express blue-colored cell nuclei.

The researchers injected the bone marrow from the blue-nuclei mice into other mice with a suppressed immune system and muscle damage.

Three weeks later, the blue-colored nuclei had been bound into the mouse muscle tissue.

"Our experiments suggest that the bone marrow could serve as a reservoir of progenitors for muscle tissue," Dr. Ferrari suggested.

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An approach that has the potential to reduce the severity of a Duchenne mutation to the milder Becker phenotype.

Antisense oligonucleotides as a therapy for Duchenne muscular dystrophy.
Steve Wilton1, Tina Ly1, Sue Fletcher1, Frances Lloyd1, Ryszard Kole2.

1: Australian Neuromuscular Research Institute, 4th Floor "A" Block, QE II Medical Centre, Nedlands, WA (
2: Lineberger Comprehensive Cancer Centre, University of North Carolina, Chapel Hill, NC 27599.

Nonsense or frame-shift mutations in the dystrophin gene are responsible for the severe X-linked recessive Duchenne muscular dystrophy (DMD). Unable to synthesize a full length and functional dystrophin protein, affected boys show signs of muscle weakness between the ages of 3 to 5 years and will be restricted to a wheel chair by the age of 12 years of age. Becker muscular dystrophy (BMD) also arises from mutations in the dystrophin gene but in these cases, the mutations are generally in-frame deletions so that a shorter but semi-functional dystrophin protein can be produced. There is a spectrum of BMD phenotypes ranging from almost asymptomatic to borderline DMD, highlighting the general tendency that some dystrophin, albeit of reduced quantity and or quality, can significantly reduce the severity of dystrophin mutations.

Rare dystrophin-positive fibres have been immunohistochemically detected in dystrophic muscle tissue from most DMD patients. These fibres (so called "revertant fibres" as they have "reverted" back to the normal phenotype) have also been observed in both animal models (mdx mouse and GRMD dog) that have been used to study DMD. These dystrophin-positive fibres have somehow managed to synthesize a functional dystrophin protein despite the presence of a DMD mutation (nonsense or frame-shift in the dystrophin mRNA). An exon skipping mechanism, arising from either a somatic mutation or alternative splicing, has been proposed to by-pass the primary disease-causing mutation so that a shorter but functional protein can be made.

The mdx mouse has a nonsense mutation in exon 23 of the dystrophin gene resulting in a truncated protein that cannot be correctly localized at the sarcolemma of the muscle fibres. Rather than replacing the defective mdx gene with a functional dystrophin cDNA, we wished to evaluate intervention at the stage of dystrophin gene transcript processing (splicing). In this manner, exon 23 carrying the nonsense mutation could be deleted from the mature mdx mRNA which could then be translated into a slightly shorter but presumably functional dystrophin.

The splice sites flanking exon 23 were characterized by direct DNA sequencing of long range PCR products. We used antisense 2'-O-methylribo oligonucleotides directed to the 3' and 5' splice site of introns 22 and 23 respectively to induce specific skipping of only exon 23 in primary cultured mdx myotubes. Approximately 50% of the dystrophin transcripts had skipped exon 23 within 6 hours of the addition of the antisense oligonucleotide : lipofectin complex with complete skipping observed after 24 hours.

The deletion of exon 23 does not disrupt the reading frame of the dystrophin transcript and should allow the synthesis of a shorter but presumably functional protein. This antisense oligonucleotide approach could be used to by-pass nonsense mutations or even remove one or more exons flanking gross genomic deletions within the dystrophin gene to maintain/restore the reading frame. Such an approach has the potential to reduce the severity of a Duchenne mutation to the milder Becker phenotype.

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