MSCs engineered to produce Brain-Derived Neurotrophic Factor for the Treatment of Huntington's disease

亨廷顿舞蹈症（HD）是一种严重的神经退行性疾病，无法治愈，有一种

Huntington's disease (HD) is a brutal neurodegenerative disorder with no cure, and there is a critical unmet need for disease-modifying treatments. We are developing a novel therapy for HD: intrastriatal implantation of human Mesenchymal Stem/Stromal Cells (MSCs) engineered to secrete Brain-Derived Neurotrophic Factor (MSC/BDNF), a growth factor needed in the degenerating striatal regions of the brain. BDNF is low in humans and mice with HD, and up- regulation of BDNF in the brains of transgenic rodent models of HD has ameliorated the disease phenotype. Due to pro-survival effects in striatal neuropathology, BDNF is a strong candidate for neuroprotective therapies. The challenge is delivery into the brain, since BDNF does not cross the blood-brain barrier. MSC/BDNF combines the beneficial effects of MSC administration to the striata with the benefits of BDNF production. Unlike BDNF delivery via direct vector injection or protein administration into the brain, MSCs migrate into the areas of damage and have numerous beneficial effects. Although optimized MSCs will not persist longer than several months, we hypothesize that the neurorestorative effects of BDNF will outlast the survival of MSCs. This is supported by animal data from our laboratory and others. In our double-blinded efficacy studies, intrastriatal delivery of human MSC/BDNF significantly reduced anxiety and significantly increased neurogenesis in immune suppressed HD mice, with increased survival, in comparison to vehicle treated HD mice. Treatment with MSC/BDNF decreased striatal atrophy as compared to vehicle treated HD mice (PMID:26765769). This recovery may be due to the stimulation of endogenous neurogenesis promoted by BDNF, and enhanced by the secretion of various complementary therapeutic factors by the MSCs. In the planned studies, we will perform the following studies in support of an investigational new drug filing to the FDA (RAC and Pre- IND meetings already completed): in Aim 1 we will determine effective in vitro potency assays for MSC/BDNF and will define in vivo outcomes for each assay, in Aim 2 we will complete dose- finding efficacy and biosafety studies, and in Aim 3 we will perform MSC/BDNF striatal implantation studies in a porcine model. Our studies will define reproducible techniques and methods, at the level of Good Laboratory Practice, for evaluation of cell and gene therapy candidates to be used in neurodegenerative disorders. We will be positioned to move the MSC/BDNF candidate into clinical trials for HD initially, and to assist others in using the product for additional disorders in the future. We will better define mechanism of action of MSC/BDNF and will define potency assays, using promotion of in vivo neurogenesis as a readout.