Antisense Reduces SOD1, Prolongs
Survival In ALS Rats

Researchers at several California institutions have shown that blocking the production of abnormal SOD1, the cause of of 1 percent to 2 percent of all cases of amyotrophic lateral sclerosis (ALS), extends survival in rats with the disease and that the compound is a good candidate for near-future testing in patients.

Don Cleveland, Timothy Miller and Richard Smith of the University of California-San Diego (UCSD) and colleagues, in partnership with Isis Pharmaceuticals, announced their findings online July 27 in the Journal of Clinical Investigation.

After developing an SOD1 “antisense” compound, which targets the genetic instructions for the SOD1 protein and interferes with protein synthesis, they administered it to rats bred with multiple copies of abnormal SOD1 genes and therefore destined to develop ALS. Humans have only one copy of the abnormal SOD1 gene.

The rats survived an average of 132 days if they received the antisense treatment, compared with 122 days if they didn’t, a survival difference of 8 percent.

Timothy Miller, a UCSD neurologist and neuroscientist, notes that when the researchers looked at how long the rats survived after the onset of ALS symptoms, at about day 95, the treated rodents lived on average another 37 days, compared to 27 in the untreated group. That 10-day, 37 percent difference, he says, means the disease slowed significantly after onset with the antisense treatment.

The beginning stage of disease in the animals was not affected, since the drug requires about 30 days to start decreasing SOD1, and treatment was started 30 days before the animals typically get the disease. The researchers have not yet tested whether earlier treatment of the animals increases the survival benefit.

Miller says that if all the right pieces fall into place, including assurance of safety through further animal testing and approval from the Food and Drug Administration, his group plans to test SOD1 antisense therapy in patients with SOD1-related ALS. He estimates there are 300 to 400 SOD1 ALS patients in the United States.

The rats were given antisense directly into the cerebral spinal fluid (CSF) that circulates throughout the brain and spinal cord. For the human trial, the investigators plan to infuse it into the CSF in the lumbar spinal cord area, via an implantable pump. If unwanted effects occur, the treatment can easily be stopped.