PgmNr W4075: Nematode disease model of Niemann-Pick C yields pharmacological bypass suppressors.

Authors:
E. O. Perlstein

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Institutes
Perlstein Lab PBC, San Francisco, CA.

Keyword: Other ( drug discovery )

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Abstract:
Perlstein Lab PBC (PLab) has built an automated model-organism-based drug discovery platform for rare genetic diseases, starting with Niemann-Pick Type C/NPC. Using CRISPR we generated null alleles of NPC1 orthologs in nematodes and flies, resulting in mutant animals that exhibit developmental delay and larval lethality, respectively. We then screened those models against a 50,000-compound library to identify small molecules that reverse disease phenotypes in whole animals. In less than a year, we discovered and validated a novel pharmacological bypass suppressor called PERL101. PERL101 is one of 14 unoptimized primary screening hits that modifies developmental phenotypes in ncr-1 null worms and cholesterol-storage phenotypes NPC patient fibroblasts. At the same time, PERL101 has excellent pharmaceutical properties such as 100% oral bioavailability, CNS penetration and tolerability in mice. Based on preliminary mechanism-of-action studies in both worms and mammalian cells, PERL101 modulates autophagy, an evolutionarily conserved pathway that has been implicated in NPC disease and other lysosomal storage disorders.