Mesenchymal Stem Cells Engineered To Overexpress Brain-Derived Neurotrophic Factor As A Proposed Therapeutic For Huntington'S Disease

Objective: To describe the effects of genetically-modified mesenchymal stem/stromal cells (MSC) over-expressing BDNF (MSC/BDNF) in two strains of Huntington’s disease (HD) transgenic mice.Background: HD is an autosomal dominant disorder caused by an expanded CAG trinucleotide repeat that causes progressive degeneration of neurons in the striatum. Survival and function of striatal neurons is dependent on BDNF, and levels of this trophic factor are significantly reduced in HD patients. Transplantation of bone marrow-derived MSC show considerable therapeutic promise through stimulation of endogenous neuronal growth, decreased neuronal apoptosis, regulation of inflammation, and the secretion of trophic factors. MSC are readily available, easily expanded in vitro, have immunomodulatory properties, and can be easily engineered to over-produce trophic factors.Design/Methods: We tested a novel therapeutic approach using stem cell-based delivery of BDNF. Striatal implantation of MSC/BDNF was tested in two murine HD models. The MSC/BDNF product was manufactured following Good Manufacturing Practices Standard Operating Procedures to facilitate translation to future clinical trials. Double-blinded studies were performed to examine the effects of intracranially transplanted MSC/BDNF on disease progression in two strains of HD transgenic mice: YAC 128 and R6/2.Results: No alterations in cell growth, differentiation capacity, cell size or phenotype were observed after transduction by the BDNF vector, and the karyotype remained stable. MSC/BDNF treatment decreased striatal atrophy in YAC128 mice and significantly reduced anxiety as measured in the open field assay. Both MSC and MSC/BDNF treatments induced a significant increase in neurogenesis-like activity and MSC/BDNF increased the mean lifespan of the R6/2 mice.Conclusions: This data indicates that intrastriatal BDNF delivery via MSC can prevent behavioral manifestations and neuropathological abnormalities in rodent HD models. Definitive dose-finding, biosafety, biodistribution, and large animal neurotransplantation targeting studies are currently underway in preparation for submission for regulatory approval for a Phase 1 safety and tolerability trial. Disclosure: Dr. Wheelock has nothing to disclose. Dr. Pollock has nothing to disclose. Dr. Dahlenberg has nothing to disclose. Dr. Nelson has nothing to disclose. Dr. Fink has nothing to disclose. Dr. Cary has nothing to disclose. Dr. Hendrix has nothing to disclose. Dr. Annett has nothing to disclose. Dr. Torrest has nothing to disclose. Dr. Deng has nothing to disclose. Dr. Gutierrez has nothing to disclose. Dr. Nacy has nothing to disclose. Dr. Pepper has nothing to disclose. Dr. Kalomoiris has nothing to disclose. Dr. Anderson has nothing to disclose. Dr. McGee has nothing to disclose. Dr. Gruenloh has nothing to disclose. Dr. Fury has nothing to disclose. Dr. Bauer has nothing to disclose. Dr. Duffy has nothing to disclose. Dr. Tempkin has received personal compensation for activities with Lundbeck Pharmaceuticals. Dr. Nolta has nothing to disclose.