Research Updates May-June 2007

Article Highlights:

The latest research news as of April 2007

by Margaret Wahl on May 1, 2007 - 4:04pm

QUEST Vol. 14, No. 3

New muscle-generating stem cells isolated from human tissue

Researchers at several U.S. and Italian institutions say they’ve isolated from human skeletal muscle a new type of stem cell that they believe could be “ideal” for the treatment of muscular dystrophy.

MDA-supported Giulio Cossu at the San Raffaele Scientific Institute in Milan, Italy, and Paolo Bianco of the San Raffaele Biomedical Science Park in Rome, led the team, which published results online Feb. 11 in Nature Cell Biology.

The researchers have dubbed the newfound cells, which are located around small blood vessels in muscles, pericyte-derived.

In November, Cossu and colleagues announced they had isolated another blood-vessel-associated stem cell, in dogs, that can also give rise to muscle. They used these cells (mesoangioblasts) to successfully treat canine muscular dystrophy. They say the cells in this new set of experiments may be related to mesoangioblasts.

When pericyte-derived cells taken from healthy human muscle tissue were given to mice missing the dystrophin protein (the cause of human Duchenne muscular dystrophy [DMD]) and also lacking an immune system, they showed a very high rate of maturation into muscle fibers.

They also improved the ability of these mice to grip a rotating rod and stay on a treadmill.

The pericyte-derived cells demonstrated that they could cross blood vessel walls into muscle tissue when injected into an artery, an important requirement if cells are to be delivered through the bloodstream in humans.

The investigators also took pericyte-derived cells from children with DMD and injected the cells with miniaturized dystrophin genes before giving them to dystrophin-deficient mice. These mice showed a similar improvement in functional performance compared to untreated mice, as did the animals that received cells from people without muscular dystrophy.

In eventual treatment, using a patient’s own muscle cells, altered to make a needed protein such as dystrophin, is probably preferable to using cells from a donor.

The mice that were given human cells from healthy people and from children with DMD both made significant numbers of muscle fibers and produced significant amounts of human dystrophin.

Cossu says his group plans a clinical trial using these cells in boys with DMD.

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Two anti-fibrosis drugs show promise in mice with DMD

Two drugs, losartan and pirfenidone, have shown promise in reducing fibrosis (scar formation) in mice that lack the muscle protein dystrophin and have a disease resembling Duchenne muscular dystrophy (DMD).

Both drugs target transforming growth factor beta (TGF-beta), a natural body compound that interferes with muscle fiber formation and promotes formation of scar tissue in response to injury, inflammation or disease.

Fibrosis, the result of excess deposition of connective tissue, is a major factor in muscle function impairment in human DMD.

Luc Gosselin, an MDA research grantee at the State University of New York at Buffalo, and colleagues, who published results of their work with pirfenidone in the February issue of Muscle & Nerve, found the drug was somewhat effective in reducing fibrosis in mice treated for four weeks, but they say more testing at higher doses is needed.

Pirfenidone is in development by Intermune of Brisbane, Calif., for the treatment of interstitial pulmonary fibrosis, a condition in which excess collagen interferes with lung function.

In a separate study, Ronald Cohn at Johns Hopkins University in Baltimore, and colleagues, who published their findings online Jan. 21 in Nature Medicine, had more success with losartan, which they tested in dystrophin-deficient, DMD-affected mice for six to nine months.

In the losartan-treated mice, the diaphragm muscles showed less scarring (fibrosis in 18 percent of the tissue, compared to 32 percent in untreated mice). The mice had significantly better front and back leg grip strength than did their untreated counterparts, showed less muscle fatigue when challenged, and had muscle fibers that looked more normal.

Losartan is approved to treat high blood pressure and is marketed by Merck of Whitehouse Station, N.J., under the brand names Cozaar and Hyzaar.

The investigators plan to test it in boys with DMD.

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Cyclosporine-like compound prevents cell death in mice with CMD

Abnormalities in mitochondria, the energy-producing units inside cells, appear to underlie the muscle degeneration seen in Ullrich congenital muscular dystrophy (CMD), a form of congenital muscular dystrophy (CMD), a form of MD caused by a lack of the protein collagen 6.

A few years ago, scientists at the University of Padua and other Italian institutions found that mutant mice unable to produce collagen 6 showed mitochondrial defects that lead to cell death. Specifically, a channel in the inner membrane surrounding each mitochondrion opens inappropriately, triggering a cell suicide program.

Now these researchers, who published their results in the Jan. 16 issue of Proceedings of the National Academy of Sciences, have studied muscle cells from five patients with Ullrich CMD, and found similar defects in their mitochondria, with similar results.

The muscle cell defects were reversed when the drug cyclosporine, which keeps the mitochondrial channel closed, was added to their environment, leading the investigators to think about this as a potential therapy for Ullrich CMD.

However, since cyclosporine is also a potent immune system suppressant, they decided to try the efficacy of a related compound, Debio 025. This compound, like cyclosporine, stabilizes mitochondria by keeping their inner membranes intact, but it doesn’t have immunosuppressive effects.

Debio 025 was shown to be equally effective in preventing mitochondrial defects and death of muscle cells from Ullrich CMD patients.

The researchers say their findings suggest new perspectives for treatment of people with collagen 6 disorders.

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