Nampt/PBEF/Visfatin: a new molecular target for blocking axon degeneration

Lead Research Organisation: Babraham Institute
Department Name: UNLISTED

Abstract

We aim here to clarify the target of a drug that delays axon degeneration in primary culture. We have range of tools available including a conditional null allele, a second drug that inhibits a strong candidate enzyme and a mutation that confers drug resistance on this enzyme. Resolving this question will strongly support an external application to fund in vivo studies and disease and to identify more potent molecules. It will also help exploit the translational and commercial potential in collaboration with BBT, who are keen to provide additional support. First however, the target needs to be clear. Treating axon degeneration is a major unmet need. One in two of us will suffer its painful or disabling consequences through Alzheimer’s disease, multiple sclerosis, Parkinson’s disease, glaucoma, diabetic neuropathy or other disorders. We find that FK866, a pro- apoptotic cancer drug in Phase II trials (Holen et al., 2008), consistently protects injured axons in culture thus mimicking the slow Wallerian degeneration (WldS) phenotype. Unlike WldS, which substitutes for the labile NAD+ synthesising enzyme Nmnat2 (Gilley and Coleman, 2010), FK866 inhibits the previous enzyme in the NAD+ synthetic pathway, Nampt, depleting cells of NAD+. This is the basis of its anti-cancer action but whether Nampt also underlies the neuroprotective effect is not yet clear. This development is critically important for understanding the degenerative mechanism and the neuroprotective action of WldS. It is also an exciting basis for drug development in axonal disorders. For both purposes, the molecular target of FK866 has to be identified conclusively. Therefore, using pharmacological and genetic methods we will test the hypothesis that Nampt activity is necessary for Wallerian degeneration in vitro.

Publications

10 25 50
 
Description We identified a low molecular weight metabolite that has an important role in regulating axon longevity.
Exploitation Route Work is still progressing to understand the role of this metabolite in axon survival and whether axons can be preserved by drugs that target its action
Sectors Healthcare

 
Description Results reported to Takeda (Cambridge) Ltd in regular reports and in PhD thesis
First Year Of Impact 2010
Sector Pharmaceuticals and Medical Biotechnology
Impact Types Economic