This grant builds upon the research from a prior grant: The role of TNF-mediated dopaminergic neurotoxicity in Parkinson's disease: Novel anti-TNF biologics as biochemical tools and new therapeutic agents
Because TNF inhibitors are not believed to cross the blood-brain barrier, an orally administered TNF-based therapy is not currently possible. The Foundation has awarded supplemental funding to drive investigation of a potential gene therapy TNF approach. The funding will allow Dr. Tansey to partner with a new collaborator who is an expert in viral vectors for gene therapy.
If the gene therapy experiments in animal models yield results as encouraging as those we saw with infusion, the Foundation will strongly consider additional ways to further pursue this promising avenue.
The studies funded by the second supplement (lenti-DN-TNF gene therapy) were performed in collaboration with Dr. Armin Blesch at UCSD and resulted in the development of new tools constitutive and tet-regulatable lentiviral vectors encoding DN-TNF to probe the role of TNF in vivo without the inherent limitation of chronic infusion of small proteins via osmotic pumps. Using the rat 6-OHDA striatal lesion model, we reported that a single injection of the constitutive lenti-DN-TNF afforded protection against 6-OHDA-induced death which was comparable to that achieved with chronic infusion of the DN-TNF inhibitor protein (McCoy et al., 2008 Molecular Therapy). The next critical question was to investigate whether delayed TNF signaling inhibition was neuroprotective against the progressive loss of nigral DA neurons in the Sauer/Bertel 6-OHDA model. In studies presently under review (Harms et al., Mol Therapy), we demonstrated that delaying the intranigral lenti-DN-TNF injection by two weeks still afforded neuroprotection and blocked the progressive phase of nigral DA neuron death. The Tet-ON lenti-DN-TNF vectors were found to be difficult to regulate in vivo.
Successful completion of the anti-TNF gene therapy studies also resulted in the High Q/CHDI Foundation inviting us to submit a proposal to validate TNF as a target in a pre-clinical model of HD in 2008. Technical limitations involving low transduction efficiency in striatal medium spiny neurons delayed initiation of those studies and prompted us to generate AAV-DN-TNF vectors. These studies will be completed by May 2010 and a manuscript will be submitted to Neurobiology of Disease.
We submitted an NIH R21 grant application in which we proposed to investigate the neuroprotective effects of DN-TNF inhibitor proteins, lenti-DN-TNF and AAV-DN-TNF in a non-human primate chronic MPTP model in collaboration with Dr. Erwan Bezard.