A compound known as "activated protein C" (APC) that is already in use to treat severe bloodstream infections also may have benefit in ALS, according to a recently published report.
APC reduced production of a toxic protein, reduced inflammation in the nervous system, and prolonged survival by 10 percent to 13 percent in mice with a disease resembling human amyotrophic lateral sclerosis (ALS), a team of researchers reported online Oct. 19, 2009, in the Journal of Clinical Investigation. Hristelina Ilieva, an author on the study, is a current MDA grantee at the University of California-San Diego, and co-principal investigator Don Cleveland has received MDA funding for ALS research at UCSD.
The research was done in mice with mutations in the SOD1 gene. These mutations result in the production of toxic, defective SOD1 protein molecules. Found in people with a form of familial (inherited) ALS, SOD1 mutations are responsible for about 1 percent to 3 percent of all ALS cases. However, some reports suggest that abnormal and toxic SOD1 protein molecules may play a role in other forms of ALS besides the SOD1-related familial form.
In the APC study, researchers waited until the SOD1 mice displayed ALS-like symptoms and then administered various forms of APC via injections into the abdomen. The team found that APC markedly diminished production of mutated SOD1 not only in the motor neurons (the cells thought to be the most affected in ALS), but also in immune-system cells and support cells in the nervous system.
Along with the lowered SOD1 levels, inflammation seen in the nervous system of the mice was reduced as well. Moreover, the normal barrier between the bloodstream and the spinal cord, which is disrupted in mice with mutated SOD1 genes, was restored, apparently because inflammation was decreased.
APC is currently used to treat severe blood infections ("sepsis") and is being tested in clinical trials to see if it has benefit in people with strokes. However, the APC currently in use has blood-thinning properties and may not be safe for use in people with ALS. Variants of this drug are being studied to determine whether there is a version that could be safely tested in ALS.
Meaning for people with ALS
APC has not been tested in people with ALS. It isn't clear if APC-based drugs would be effective for human ALS that is not related to the SOD1 gene, or whether the drug would have beneficial anti-inflammatory effects not related to its lowering of SOD1 levels. Inflammation in the nervous system is believed to be a major contributor to all forms of ALS, but it is not commonly believed to be the primary cause of the disease.
On the plus side, it’s encouraging that the APC compounds were effective when administered after disease symptoms began, and that they were beneficial even when not injected directly into the nervous system.