Gene Transduction Therapy in Neurodegenerative Disorders

Lead Inventor: Robert Burke, M.D. Tech Ventures Reference: IR CU12241 Induction of axonal regeneration in neurodegenerative disease utilizing viral transduction Neurodegenerative conditions such as Parkinson's Disease, Huntington's Disease, and Alzheimer's Disease are devastating neurological diseases which have a high rate of prevalence and effect millions of people worldwide. They are associated with significant and progressive decline in cognitive and motor function secondary to neurodegeneration. Current therapies for such diseases are unable to halt or reverse this associated neurodegeneration and instead focus on neurotransmitter signaling, as in the case of L-Dopa in Parkinson's Disease. In addition to many adverse effects of these therapies, including dyskinesias and cognitive impairment, deterioration of neuronal function continues to progress, and functional deficits are not repaired. In contrast, this technology seeks to promote regeneration of neuronal axons, thereby reversing deficits of motor and cognitive function. Regeneration of damaged neurons presents a viable therapeutic method, restoring function by promoting cell growth. Constitutively active p70S6K induces axonal regeneration within cells damaged in neurodegenerative disorders. The p70S6K gene has been discovered to induce axonal growth when in a constitutively active state. In order to simulate Parkinson's disease in a mouse model, the Substantia Nigra (SN) was lesioned. Constitutively active p70S6K was introduced into the SN utilizing viral vector induction three weeks after lesioning. These mice showed significant axonal regeneration in this area 12 weeks following introduction of the constitutively active p70S6k gene. Applications • Treatment of neurodegenerative disorders such as Parkinson's, Alzheimer's, and Huntington's disease • Potential for axonal regeneration in ischemic, infectious, or traumatic neuron damage Advantages • Stimulates direct regeneration of the axons of damaged neurons • Avoids potential adverse effects of exogenous neurotransmitter delivery

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Licensing Status: Available for licensing and sponsored research support Related Publications: • Kim SR, Chen X, Oo TF, Kareva T, Wang C, During M, Kholodilov N, Burke RE. Dopaminergic pathway reconstruction by Akt/Rheb-induced axon regeneration. Annals of Neurology, Volume 70, Issue 1, 2011: pp 110-120. • Burke RE. Inhibition of mitogen-activated protein kinase and stimulation of Akt kinase signaling pathways: Two approaches with therapeutic potential in the treatment of neurodegenerative disease. Pharmacology and Therapeutics. Volume 114, Issue 3, 2007: pp 261-277. • Kim SR, Kareva T, Yarygina O, Kholodilov N, Burke RE. AAV transduction of dopamine neurons with constitutively active Rheb protects from neurodegeneration and mediates axon re-growth. Molecular Therapy, 2012, 20:275-286. (PMCID: PMC3277224).