24 October 2003. Jeff Rothstein of Johns Hopkins University last Monday chaired a symposium on animal models of neurologic diseases at the American Neurological Association, held in San Francisco from October 19 to 22. Two talks were particularly relevant to this audience.
Dale Schenk reviewed the PDAPP mouse from its original discovery in 1995 up through its current use in the study of candidate therapeutics for Alzheimer's disease. He discussed two strategies in some detail: an Elan/Lilly γ-secretase inhibitor LY411575 and the 1792 Aβ vaccine.
Both were shown to have important effects on amyloid plaque load in the PDAPP mouse, and no toxicity for either in the mouse was described. Schenk reviewed the development of acute autoimmune encephalitis in about five percent of subjects in the Phase II 1792 trial. By now, a total of three vaccinated patients have died (none directly from vaccine-related toxicity) and have been subjected to postmortem examination. All three had unexpectedly few amyloid plaques in the frontal lobes, consistent with a possible partial response to 1792 vaccination (see ARF related news story). It should be noted that three is still a small number, that no such diminution was observed in other brain regions, and that tangle pathology did not appear to have been modulated, i.e., the tangle density was just as one would expect from the stage of disease. On the subject of passive transfer as a more controllable intervention, Schenk noted that an IND application has been filed with the FDA for passive transfer of immune IgG, but did not describe the details of this preparation.
Merit Cudkowicz, University of California, San Francisco, reviewed the status of mouse models of ALS and their use in identifying potential therapeutics. The most studied is the G93A superoxide dismutase (SOD) mouse. Two rat models have also recently been created of the G93A and H46R SOD mutants. Recently, several new ALS genes have been identified: Alsin, a novel molecule of unknown function that is responsible for a juvenile form of ALS; dynactin, a protein involved in axonal transport; and a VEGF promoter deletion. More than 100 drugs have been screened in mutant SOD mice with some modest extension of life (a maximum of 30 percent; e.g., see ALS-TDF), and interesting crosses have been made with molecules relevant to apoptosis and glutamate transport.
AAV delivery to muscles of IGF1 has shown the longest prolongation of life in rodents (see ARF related news story). Riluzole (which extends life by about 10 percent) remains the only drug that has been proven effective and approved by the FDA for use in humans. Topiramate has been recently tried in humans and failed; a Celebrex trial is underway and the results will be available in July 2004.
Others that have shown some efficacy in rodents are Celebrex; the antibiotic minocycline (see ARF related news story); TCH386; nitric oxide synthase modulators; coenzyme Q; and IGF. A combination of minocycline and creatine showed additive efficacy of 25 percent.
The recent report by Don Cleveland (see ARF related news story) that neighboring cells can affect the viability of neurons bearing pathogenic mutations and destined to degenerate was highlighted as support for the notion that stem cell strategies might be beneficial for ALS, extending life by about 30 percent.
NINDS recently completely a screen in ALS rodents of 1,000 FDA-approved compounds: Four hits were cephalosporins; three hits were tetracyclines. Fifteen other compounds gave two hits each: some were COX-2 inhibitors and some were AMPA antagonists.
Concern has been expressed that the mouse mutant diseases may be overly aggressive and that some potentially useful drugs might be missed. Prior to moving into humans, drugs ought to be shown effective in more than one rodent model.—Sam Gandy.