Amyotrophic lateral sclerosis (ALS) is a rapidly progressing degenerative disease that attacks motor neurons, leading to paralysis and death. Effective treatments for this devastating condition have evaded researchers for many years. Now, however, there is encouraging new evidence that direct delivery into the CNS of the neurotrophic factor vascular endothelial growth factor (VEGF) leads to a marked improvement in prognosis in a rat model of ALS.

The details of pathogenesis of ALS remain elusive, but Carmeliet and co-workers. recently reported that low VEGF concentrations cause motor neuron degeneration that resembles ALS in mice, and are associated with an increased risk of developing ALS in humans. This points to a role for VEGF in the pathogenesis of ALS, therefore making it a potentially attractive therapeutic candidate.

Systemic delivery of VEGF is beneficial to mice with ALS, but is associated with vascular side effects and an adverse immune response. Delivery of many recombinant neurotrophic factors, such as brain-derived neurotrophic factor and ciliary neurotrophic factor, have previously been shown to prolong survival in animal models of ALS, but, so far, these successes have not been replicated in human clinical trials.

In this new study, Carmeliet and co-workers showed that direct delivery of recombinant VEGF into the cerebrospinal fluid delayed the onset of paralysis by 17 days in rats with ALS. The treatment also improved motor performance and prolonged survival by 22 days. Importantly, there were no serious adverse consequences, in contrast to previously used systemic methods of VEGF delivery.

The therapeutic success of VEGF might rest on its direct involvement in the pathogenesis of ALS. By contrast, there is only limited evidence that other neurotrophic factors are involved in motor neuron degeneration. Alternatively, the intracerebroventricular mode of delivery might allow more rapid diffusion of VEGF into the spinal cord than systemic methods.

These results represent the most promising therapeutic effect of direct protein delivery observed so far in an animal model of ALS. However, it remains to be seen whether this can be translated into an effective therapy in human clinical trials.