Genetically corrected human stem cells help mice with a disease resembling limb-girdle MD; cell membrane sealants are being studied in Duchenne and other forms of muscular dystrophy
A multinational team of scientists successfully transplanted genetically corrected muscle stem cells derived from people with type 2D limb-girdle muscular dystrophy (LGMD2D) into LGMD2D research mice and saw better muscle function in these mice than in similar mice that didn't receive the cells.
First, the scientists "reprogrammed" early-stage connective tissue cells and early-stage muscle cells taken from people with LGMD2D, making them into induced pluripotent stem cells, capable of becoming many cell types.
They then genetically corrected these induced stem cells, giving them functional genes for the muscle protein alpha-sarcoglycan, which is deficient in LGMD2D.
The cells were coaxed to multiply in the laboratory and to develop muscle-like characteristics, becoming a cell type that resembles muscle stem cells called mesoangioblasts. The mesoangioblast-like cells were able to produce the alpha-sarcoglycan protein because of the genetic correction procedure.
When the investigators gave these corrected stem cells to LGMD2D-like mice lacking alpha-sarcoglycan, the cells found their way to damaged skeletal muscle fibers, joined them, and formed fibers that produced the needed protein.
The mice that received these new cells were able to run longer on a treadmill than were their untreated counterparts.
The stem cells were injected both directly into muscle and into an artery, and both methods were effective. (The mice were also genetically modified to have deficient immune systems, which presumably helped them tolerate the human cells.)
The researchers say their results suggest that transplantation of genetically corrected mesoangioblast-like cells derived from LGMD2D patients could be useful for treating this form of MD and that similar strategies might be useful in other forms of muscular dystrophy. (Mesoangioblasts from donors are being tested in boys with Duchenne muscular dystrophy (DMD) in a phase 1-2 trial in Italy.)
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A naturally occurring protein called MG53, present inside skeletal and cardiac muscle cells, helps cell membranes reseal after they've been injured. Proteins like MG53 are particularly needed in Duchenne muscular dystrophy (DMD), where the absence of the muscle protein dystrophin makes the membranes of skeletal and cardiac muscle cells fragile and highly vulnerable to damage. Normal levels of these repair proteins aren't high enough to repair the constant injuries to cell membranes in this disease.
Now, new research has shown that extra MG53, delivered by injection from outside the cell, can improve the repair of torn cell membranes.
When mice missing the dystrophin protein and showing a disease resembling human DMD were given either intravenous or intramuscular injections of MG53, they showed reduced muscle damage and more normal-appearing muscle fibers than did dystrophin-deficient mice that didn't get this treatment.
Another possible advantage that MG53 may have over other treatment strategies is its status as a naturally occurring protein, reducing the likelihood that the immune system would reject it (as it might a "foreign"-appearing protein).
The researchers say their findings suggest that MG53 could be translated into a therapy for people with DMD and possibly other diseases in which fragile cell membranes play a prominent role. (For instance, Becker muscular dystrophy (BMD) and the forms of limb-girdle muscular dystrophy involving deficiencies of one of the sarcoglycan proteins or the dysferlin protein are in this category.)
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Phrixus Pharmaceuticals in Ann Arbor, Mich., has received funding from the U.S. National Institutes of Health to develop its experimental drug Carmeseal (also known as poloxamer 188 and P188) as a potential treatment for the heart-muscle degeneration associated with Duchenne muscular dystrophy (DMD). (The mechanism of heart muscle damage — a lack of the dystrophin protein — is the same in Becker muscular dystrophy as it is in DMD, so Carmeseal could have implications for this disease as well.)
Carmeseal is a synthetic compound that's designed to act like a molecular bandage and repair tears in the membrane that surrounds heart-muscle cells.
The drug has shown promise in animal models of DMD-related heart failure, and the company says it will now move closer to testing the drug in people.
The $623,000 grant from NIH is expected to allow Phrixus to develop Carmeseal as a drug that can be delivered on a daily basis by subcutaneous (under the skin) injection, instead of by intravenous infusion, which is the way it's been given in laboratory experiments.
MDA funded some of the early development of P188.
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