Therapeutic Vaccine for ALS?

Abstract & Commentary 

Source: Angelov DN, et al. Therapeutic vaccine for acute and chronic motor neuron diseases: Implications for amyotrophic lateral sclerosis. Proc Natl Acad Sci USA. 2003;100:4790-4795.

This article reports the novel observation that therapeutic vaccination with Copaxone (glatiramer acetate, Cop-1), protects motor neurons against acute and chronic neurodegenerative conditions. Angelov and colleagues examined acute degeneration after facial nerve axotomy. They found that the number of surviving motor neurons was 2-fold greater in Cop-1 vaccinated mice as compared to nonvaccinated mice. Furthermore, they found that administration of Cop-1 to transgenic mice with the G93A mutation in copper zinc superoxide dismutase significantly improves life span as compared to unmatched controls. They found an increase in life span of approximately 25% in low-expressing mice. There was also a delay in the disease onset as assessed by motor performance. An increase in life span and a high-expressing G93A SOD1 mouse line, however, did not exceed 10%. Angelov et al conclude that they have induced protective autoimmunity and that Cop-1 vaccination boosts the local immune response needed to combat destructive self-compounds associated with motor neuron death.

Commentary

These results are unprecedented and certainly of interest. Angelov et al have a long-standing interest in the possibility that the initial immune response may be neuroprotective rather than neurodestructive. They have examined a number of other models previously with vaccination and have demonstrated that preimmunization prior to insults, such as mechanical crush injury or axotomy or biochemical insults with glutamate or oxidative stress, results in a neuroprotective response. They, therefore, hypothesized that the protective T-cell mediated response might be boosted without risk of an autoimmune disease induction by administrating Copolymer-1 (Copaxone), a synthetic polypeptide consisting of the amino acids tyrosine, glutamate, alanine, and lysine. This compound is presently in clinical use for multiple sclerosis. It has been shown to activate a wide range of self-reactive T cells. In a model of a chronic neurodegenerative disorder associated with optic nerve neuropathy induced by experimental glaucoma, Cop-1 vaccination significantly increased neuronal survival. The present results demonstrating that vaccination produced protection against motor neuron degeneration induced by acute facial nerve axotomy are of considerable interest. Angelov et al also found that immunization of Cop-1 at the age of 60 days into low-expressing transgenic mouse models of ALS significantly improved survival by 25%. This is a relatively good increase. However, a caveat is that this was in the low-expressing mice, which show a bigger response to a variety of therapies than the high-expressing mice. The improvement in the high-expressing mice was not impressive. Angelov et al also demonstrated that administration of Cop-1 significantly delayed the onset of impaired motor performance. The present results, therefore, suggest that Cop-1 might be a useful treatment for ALS. This is consistent with other evidence that certain immune modulators exert protective effects in transgenic mouse models of ALS. For instance, minocycline has been shown to delay the progression of symptoms in a mouse model of ALS in 3 different studies. This drug has anti-inflammatory activities, which may be related to its beneficial effects, and has now entered clinical trials. The present results are of considerable interest but need further experimental studies before they can be applied to humans. — M. Flint Beal

Dr. Beal is Professor and Chairman; Department of Neurology; Cornell University Medical College, New York, NY.