Parkinson's disease (PD) is a progressive neurodegenerative disease that is currently incurable with significantunmet medical needs. In the US, over a million people suffer from this disease with an estimated cost of $27billion per year. The mainstay of PD management is symptomatic treatment with drugs that increase dopaminein the striatum. However, the utility of these drugs is significantly curtailed by waning efficacy and debilitatingside effects. Since PD stems from the degeneration of a single cell type, dopaminergic (DA) neurons thatsupply dopamine to a defined location the striatum, PD patients have been viewed as optimal candidate for celltransplantation therapy. Preclinical and clinical studies have demonstrated that transplantation of primary fetalmidbrain DA neurons into the striatum, provide significant and sustained restoration of function. Howeverethical, practical and safety issues with using fetal aborted tissue and the recent progress in inducedpluripotent stem cells (iPSCs), grafting trials in PD are beginning to re-emerge world-wide with a new focus onpluripotent stem cell technologies. However, clinical studies to date suggest that critical refinements in thecellular product, in the delivery method, and in the clinical protocol by considering the incorporation ofadjunctive therapies, are essential to realize the potential of cell therapy in PD. NeoNeuron LLC has developedintellectual property on scalable and effective technologies for generating an unlimited supply of DA neuronsfrom iPSCs and an image-guided methodology for delivering the cells into the target area of the brain enablingfunctional recovery in the rat and in the nonhuman primate models of PD. In preparation for our InvestigationalNew Drug (IND) submission, NeoNeuron met with the U.S. Food and Drug Administration (FDA) and receivedrecommendations to conduct optimal dose range for the cellular product, iPSC-DA neurons, in theimmunocompromised rat model of PD. The company has established standard operating procedures toexpand this product under current good manufacturing practice (cGMP), and to produce DA neurons that willbe available as an off-the-shelf product. This feature is desirable for the development of the intended productfor clinical use and for commercialization. In Aim 1 we will show evidence of dose-response and adequatelevels of DA cell engraftment and survival for a 6-month duration in the hemi- parkinsonian rat model of PD.Aim 2 will assess the impact of adjunctive physical and cognitive training on motor and cognitive functions inthe grafted animals. We will leverage single cell spatial transcriptomics profiling of the grafted cells to gaininsights into the mechanisms of actions of our product and of the adjunctive training intervention in enhancingfunctional recovery. This Phase 1 will enable us to respond to the FDA recommendations by identifying theoptimal dose level of iPSC-DA cell engraftment and durable effects in the PD model and to proceed with ourplanned Phase II SBIR proposal to establish the chemistry, manufacturing and controls, additional safetytoxicology studies and device testing in nonhuman primates for the IND filing.
Public Health Relevance Statement: Project narrative:
Parkinson's disease (PD) is a progressive neurodegenerative disease
that is currently incurable and with
significant unmet medical needs. In this application
NeoNeuron LLC proposes to conduct U.S. Food and Drug
Administration (FDA) requested IND-enabling studies to develop promising cell therapy approach for PD.
NeoNeuron met with the FDA and received comments and recommendations to determine the optimal dose
level range for the intended cellular product, DA neurons, in an immunocompromised rat model of PD. The
proposed study is designed to demonstrate levels of DA neuron engraftment and survival for a 6-month duration
and robust evidence of the durable effects of the intended product in vivo.
Project Terms: <21+ years old>
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