Jan. 28, 2009

New Treatment Ideas Eyed in CMD

Recently published findings from two independent groups have suggested possible treatment development pathways for the merosin-deficient and integrin-deficient forms of congenital muscular dystrophy (CMD).

Doxycycline fights cell death and lessens disease severity in merosin-deficient mice

The first finding, published online Dec. 11 in Annals of Neurology, shows doxycycline, normally used as an infection-fighting antibiotic but known to have other properties, increased survival time, improved growth and delayed the onset of paralysis of the back legs in merosin-deficient mice with a CMD-like disease.

MDA grantee Jeffrey Boone Miller of Harvard Medical School in Boston and Boston Biomedical Research Institute in Watertown, Mass., coordinated the merosin-deficient CMD research team, which also included Mahasweta Girgenrath, lead author on the report and an MDA grantee at Boston University.

This type of CMD is caused by mutations in the gene for laminin alpha 2, a protein strand in a larger protein called merosin, which helps connect muscle fibers to their surrounding tissue.

Earlier research has shown that at least one mechanism by which merosin-deficient CMD leads to weakness, paralysis and premature death is the inappropriate induction of a "cell death program" (apoptosis) in skeletal muscles and the nerve cells controlling them.

Because doxycycline and related antibiotics have been reported to interfere with apoptosis, Girgenrath and colleagues decided to see how it might affect disease progression in merosin-deficient CMD mice.

They randomly assigned some of the CMD mice to receive doxycycline in their drinking water starting one to three days after birth and others to receive water without doxycycline.

In the doxycycline-treated group, half the mice were still alive at about 70 days after birth, while in the untreated group, half had died at about 32 days.

And in marked contrast to the back leg paralysis seen in all the untreated mice four to six weeks after birth, the majority of the treated mice didn't have this paralysis at age 10 to 12 weeks.

Laminin 111 restores muscle repair process in integrin-deficient mice

A different research team, coordinated by Dean Burkin at the University of Nevada School of Medicine in Reno, has found a way to improve muscle repair in a mouse model of integrin-deficient CMD, publishing its findings in the January issue of the American Journal of Pathology.

Like merosin, integrins help anchor muscle fibers to their surroundings. Some integrin proteins, such as alpha 7 integrin, are also apparently needed to maintain normal levels of merosin and to activate the muscle repair and regeneration process.

Children with mutations in the gene for alpha 7 integrin have a deficiency of this protein, with muscle abnormalities, delayed developmental milestones and impaired mobility. Mice lacking alpha 7 integrin develop a CMD-like disease with muscle and blood-vessel defects.

To see whether alpha 7 integrin is important for skeletal muscle regeneration and repair, Burkin, with colleagues at the University of Nevada and the University of Washington-Seattle, purposely damaged muscle tissue in alpha-7-integrin-deficient mice and found that regeneration in response to injury was defective.

They say the regenerative capacity of skeletal muscle depends on an "intricate interplay" between cells that carry out muscle repair and their normally laminin-rich environment, leading them to test the hypothesis that injecting a laminin protein might improve muscle repair.

When prior to injury they injected integrin-deficient mouse muscle with laminin 111, normally produced in muscle during embryonic development, post-injury repair was restored to normal.

They also note that, because loss of regenerative capacity has been implicated in a variety of muscular dystrophies, including merosin-deficient CMD and Duchenne muscular dystrophy they're now investigating whether laminin 111 protein therapy might also be beneficial in other forms of MD.