A research team led by MDA grantee Douglas Kerr at Johns Hopkins University in Baltimore has developed a multistep regimen that improves the functional effect of transplanted stem cells in paralyzed rats and could have implications for motor neuron diseases like spinal muscular atrophy (SMA) and amyotrophic lateral sclerosis (ALS).
Deepa Deshpande at Hopkins, with colleagues at Upstate Medical University in Syracuse, N.Y., and Curis Inc. of Cambridge, Mass., describe in their June 26  online publication in Annals of Neurology how their strategy restored functional nerve-to-muscle connections and movement in the back legs of rats that had been paralyzed by a virus.
In a four-step process, the investigators transplanted mouse embryonic stem cells and injected the nerve growth factor GDNF into the sciatic nerve near the spinal cord. At the same time, they infused two compounds that counteract the effects of myelin, a normal substance that ensheathes nerve fibers but which has been found to interfere with the growth of new fibers.
“I do see these findings as a preliminary step that could ultimately apply to either or both ALS or SMA,” Kerr said, adding that he was particularly optimistic about the implications for infantile SMA. He noted that “the environment is less hostile [than in ALS], because the disease is [limited] to motor neurons; infants have a short distance to bridge between spinal cord and muscle; the peripheral nerve components remain primed to receive new axonal input because of the rapid nature of motor neuron death in infants; and there is no or little myelin to inhibit growth in infants.”
Better understanding of muscle atrophy — the wasting of muscle tissue that occurs in various disease states or when weight bearing doesn’t occur for some time — may reveal new targets for muscular dystrophy treatment, say researchers at Purdue University in West Lafayette, Ind., and the University of Pittsburgh.
Xun Wang and colleagues, who published their results online May 24 in the FASEB Journal, found that activation of the protein Merg1a may set off an atrophy program in muscle cells.
When mice that had been prevented from bearing weight on their back legs for seven days were given the drug astemizole, which blocks Merg1a function, they experienced significantly less atrophy than mice that didn’t get the drug.
Amber Pond and Kevin Hannon at Purdue’s School of Veterinary Medicine, who led the study, said their group has since experimented with mice affected by a disorder resembling Duchenne muscular dystrophy (DMD). “We have tested mdx [DMD-affected] mice for the Merg1 protein, and cursorily, it appears to be more abundant in the mdx mice than in control mice,” Pond said.
Pond emphasized that astemizole can’t be safely used in humans because of its dangerous effects on cardiac muscle. She noted, however, that in the heart, it’s believed that there are two different Merg1 proteins — Merg1a and Merg1b — whereas in skeletal muscle, there’s only Merg1a. That might make it possible, she said, to target the skeletal muscle form without af-fecting the heart protein.
Spinal-bulbar muscularatrophy (SBMA) is caused by an extra-long androgen receptor protein and a loss of normal androgen receptor protein function, say MDA grantee Albert La Spada at the University of Washington-Seattle and colleagues.
The extra-long androgen (male hormone) receptor (docking site) occurs because of an extra-long stretch of DNA on the X chromosome and has been known for years to cause neurodegeneration in SBMA. The question of whether the loss of androgen receptor activity is a cause of SBMA symptoms has until now been controversial.
In fact, therapies to reduce androgens have been proposed and even tested, on the theory that if receptors aren’t functioning normally, it might be better to have less androgen for them to receive.
|Albert La Spada|
In a series of experiments, mice bred without normal androgen receptor function and only with SBMA-affected androgen receptors had more severe symptoms of nerve cell degeneration and hormonal abnormalities than did mice with some normal receptor function and some SBMA-affected receptors.
Patrick Thomas Jr. and colleagues (in La Spada’s group), who published their results online June 13  in Human Molecular Genetics, caution that treatments based on knocking out abnormal genetic information might actually make SBMA worse, since remaining androgen receptor function might be lost in the process. La Spada, who was on the team that identified the SBMA-causing genetic mutation in 1991, later commented that blocking androgen activity with medications also might be detrimental.
In another paper, published online June 4 in Nature Neuroscience, Gerardo Morfini at the University of Illinois-Chicago and the Marine Biological Laboratory at Woods Hole, Mass., with colleagues at these institutions and the University of Texas Southwestern Medical Center in Dallas, identified activation of a protein known as JNK as an important downstream effect of the underlying genetic mutation that leads to SBMA.
Activation of JNK, they say, may turn on a cell death program in the nervous system. The investigators say blocking JNK is a promising SBMA therapeutic target.
The Friedreich's Ataxia Research Alliance (FARA) has launched a Web-based patient registry to identify and recruit potential participants with Friedreich's ataxia for future clinical trials.
To participate, see www.CureFA.org/registry, where you’ll be asked to agree to an online consent and enter some basic demographic and clinical data. For more information, go to www.CureFA.org, or call FARA in Arlington, Va., at (703) 426-1576.