Amyotrophic lateral sclerosis (ALS) has become an increasingly attractive area for the pharmaceutical industry, the most experimentally tractable of the
neurodegenerative diseases. Mechanisms underlying cell death in ALS are likely to be important in more common but more complex disorders.
Riluzole, the only
drug launched for treatment ALS is currently undergoing industrial trials for Alzheimer's, Parkinson's,
Huntington disease,
stroke and
head injury. Other compounds in Phase III testing for ALS (mecamserin,
xaliproden,
gabapentin) are also in trials for other
neurodegenerative disorders. Mechanisms of action of these advanced compounds are limited to
glutamate antagonism, direct or indirect
growth factor activity, as well as
GABA agonism and interaction with
calcium channels. A broader range of mechanisms is represented by compounds in Phase I trials:
glutamate antagonism (dextramethorphan/p450 inhibitor;
talampanel),
growth factors (
leukemia inhibiting factor;
IL-1 receptor; encapsulated cells secreting
CNTF) and
antioxidants (TR500, a
glutathione-repleting agent; recombinant
superoxide dismutase;
procysteine.) An even broader range of mechanisms is being explored in preclinical discovery programs. Recognition of the difficulties associated with delivery of
protein therapeutics to the CNS has led to development of small molecules interacting either with
neurotrophin receptors or with downstream intracellular signalling pathways. Other novel
drug targets include caspaces,
protein kinases and other molecules influencing apoptosis. High-throughput screens of large libraries of small molecules yield lead compounds that are subsequently optimized by chemists, screened for toxicity, and validated before a candidate is selected for clinical trials. The net is cast wide in early discovery efforts, only about 1% of which result in useful drugs at the end of a decade-long process. Successful discovery and development of novel drugs will increasingly depend on collaborative efforts between the academy and industry.