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UMass Medical details promising ALS treatment

WORCESTER, Mass. — You may never have heard of the SOD 1 gene, but it’s been part of Dr. Robert Brown’s life for almost 30 years.

In 1993, Brown, a professor of neurology and director of the neurotherapeutics program at the University of Massachusetts Medical School, was part of the team that identified mutant SOD1 genes as causing one form of Amyotrophic Lateral Sclerosis, or ALS.

"What's pretty clear, and now there are several ALS genes, they cause ALS by having some form of toxic effect," Dr. Brown said. "It's not that they're not doing their normal job, it is that they've, with their mutation, now have acquired a toxic effect."

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One of the goals in developing therapies for ALS, which causes, in the end, near-total paralysis, is to “shut off” such defective genes.

“In SOD we were able to do that in a petri dish in 1994, one year after finding the gene,” Brown said. “The question is how do you do it safely in humans?”

Now, Brown and some colleagues believe they have answered that question. They injected a therapeutic virus into the spinal cords of two ALS patients.

“A virus that goes into the spinal fluid and the spinal cord and releases what’s called a micro RNA that turns off, in this case, the SOD-1 gene,” Brown explained. “And it looks like it does turn it off pretty effectively as it’s measured in the spinal cord. Whether it will have an enduring clinical effect remains to be seen...but we think it will.”

One of the patients did develop a significant immune reaction to the virus. The second was pre-treated with an immunosuppressant drug, the same type used by organ transplant patients.

“It seemed to dampen down the adverse immune response,” Brown said, acknowledging that it’s difficult to draw conclusions from a data sample size of one.

The goal of the study was to assess safety; the next step will be to see whether the novel therapy can actually slow the progress of the disease, which affects perhaps 30,000 Americans.

About 10% of ALS patients have a familial form, meaning they inherit the disease from one or both parents, including those with the disease caused by a defective SOD1 gene. And the SOD1 group is even smaller, making up just about 2% of the total ALS patient population.

Still, Brown said the delivery system demonstrated in this study should, in theory, benefit not only familial ALS patients but the other 90% of ‘sporadic’ ALS patients.

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"There are probably several other genes whose suppression can be beneficial in ALS other than just SOD1," Dr. Brown said. "So we think just knowing you can put something into the spinal fluid that can turn down this gene - that'll turn down a gene in the spinal cord - probably has broader ramifications than just SOD1."

One concern with suppressing any gene is can you go too far? In the case of SOD 1, the gene normally produces Superoxide Dismutase 1, an enzyme.

“Its normal function is thought to be a free radical scavenger, and, in that capacity, it turns out to be very protective for nerves in particular when they are injured,” Dr. Brown said. “One of the concerns is, ‘if you shut it off too much will that be adverse?’ And that’s one of the things we’re trying to learn from these kinds of studies.”

The new research appears in The New England Journal of Medicine.