Human Trials Of SOD1 Blocker Expected Soon

Neuroscientist and neurologist Timothy Miller of the University of California-San Diego says recent MDA funding has allowed his group to move closer to human trials of an experimental compound that blocks abnormal SOD1 genetic instructions, a genetic cause of amyotrophic lateral sclerosis (ALS).

ALS is caused by a mutated SOD1 gene only about 1 percent to 3 percent of the time. Nevertheless, it’s perhaps the best-understood form of the disease and almost the only form used in animal-based ALS studies.

Miller says a recent meeting with the Food and Drug Administration (FDA) assured him that he’s on the right track with preclinical testing of the compound’s possible toxicities in animals, a prerequisite for a human trial.

The anti-SOD1 compound makes use of recent developments in the field of gene blocking with so-called “antisense,” pieces of genetic information that keep other genetic information from being processed.

Miller and colleagues Don Cleveland at UCSD, Richard Smith at the Center for Neurologic Study in La Jolla, Calif., Merit Cudkowicz at Harvard University and Isis Pharmaceuticals in Carlsbad, Calif., are using antisense to block the abnormal RNA instructions that would otherwise result in ALS-causing superoxide dismutase 1 (SOD1) protein molecules. (When cells process a genetic recipe for a protein, they first convert DNA to RNA.)

When Miller and colleagues infused SOD1 antisense molecules into the brains of rats destined to develop ALS because they have mutated SOD1 genes, they saw an 8 percent increase in overall survival in these rodents compared to their untreated counterparts. But when the researchers looked specifically at survival after disease onset, they saw a 30 percent difference between the treated and untreated rodents.

“We’re very encouraged about the extension of survival after onset,” Miller says. “For patients who are symptomatic [show symptoms], I do think this therapy will provide benefit.”

In fact, he believes the benefits in human patients might be even better than in the rodents, because the animals produce about 15 times the normal amount of SOD1, while humans, though they make abnormal SOD1, don’t overproduce it.

One potential problem is that the antisense compound can’t distinguish between normal and abnormal SOD1 RNA and therefore blocks both. (People with SOD1-related ALS nearly always have one normal SOD1 gene and one mutated one.) Miller, however, isn’t overly concerned.

“With antisense therapy, you’re not going to reduce the level to zero,” Miller notes. “You’re likely to get about a 50 percent knockdown, which may be a very appropriate level to decrease the toxicity of SOD1 but still maintain enough of the function of the enzyme.”

The human trial will involve infusing SOD1 antisense compounds through an electronic pump into the fluid surrounding the spinal cord. Pending the outcome of the toxicity studies and approval from the FDA, Miller hopes to begin late this year.