SBIR-STTR Award

The emergence of technologies enabling isolation of adult stem cells has allowed evaluation of cell therapeutics for central nervous system disorders with a path for clinical development. Much promise has been shown using stem cells in acute disease models such as stroke or hypoxic injury to the brain, and as well to chronic degenerative diseases such as Parkinson's or spinal cord fracture. We will evaluate physiological benefit derived from treatment of injured animals receiving multi-potent progenitor cells (MPC) derived from bone marrow. We propose to extend pre-clinical efficacy data in a rat model neonatal hypoxic-ischemic injury. Our preliminary data supports a model in which administration of therapeutic cell populations soon after injury provides benefit through trophic influences regulating local inflammatory responses and vascular permeability, vasculogenesis, neurogenesis or recruitment of endogenous stem or progenitor cells. MPC can be isolated from animal and human bone marrow, and using both in vivo and in vitro models produce differentiated progeny of the CMS. Because these cells can be expanded to large cell number, and do not readily stimulate an allogeneic immunological reaction when in a non-differentiated state, they are ideal candidates as an "off-the-shelf clinical product. In our Phase I proposal, we will test both interstitial injection and intra-arterial delivery of stem cells to animals subjected to hypoxic- ischemic injury. We will evaluate route of delivery showing most benefit and test for cell fate and long-term persistence, allowing transition to a Phase II pre-clinical disease model for safety and benefit testing in primates. It is our intention to commercialize a stem cell therapeutic product for acute ischemic injury to the brain.

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The specific objective of this STTR Phase II research and development project is to provide an optimized cellular therapy regimen for treating hypoxic-ischemic (HI) injury and its related outcomes in neonates. Pre- clinical studies performed in a rat pup model of HI injury as part of the funded Phase I STTR grant, point to benefit when Multipotent Adult Progenitor Cells (MAPC), a pluripotent adult stem cell, are administered intravenously (IV) or intracerebrally (IC) one week post-HI injury. Syngeneic and allogeneic MAPC demonstrated statistically significant efficacy in the absence or presence of immunosuppression, thereby resolving key clinical issues for using MAPC as an off-the-shelf allogeneic product. After receiving feedback from the FDA following a Type B pre-IND discussion, this Phase II proposal aggressively pursues those preclinical issues required to advance the application of MAPC based therapy to treat HI injury in neonates. This Phase II STTR submission has 4 specific aims, which will complete the pre-clinical report package required for IND submission. Aim 1: Determine that the anticipated clinical product, human MAPC processed under cGMP conditions, exhibits therapeutic behavioral and histological benefit equivalent to those previously observed with allogeneic rat MAPC in the rat neonatal HI injury model. Dosing experiments will include: Aim 1.1: IV dose ranging to determine optimal dose of human MAPC; Aim 1.2: Optimal timing of delivery, post-HI injury; and Aim 1.3: Benefit of multiple IV dose administrations. Aim 2: Demonstrate stable and long-term therapeutic behavioral and histological benefits of MAPC grafts in the rat HI injury model, i.e., 6 months post-transplantation with safety component in both male and female neonatal rats, using optimized conditions from Aim 1 (as per FDA recommendation). Aim 3: Determine the relative efficacy benefit of cell therapy in minimal, moderate and severe HI injury models. These data will help determine the appropriate inclusion criteria and clinical endpoints for Phase I and Phase II clinical development (as per discussion with FDA). Aim 4: Characterize stem cell histocompatibility, inflammation and tumor/ectopic tissue formation in rat and human MAPC to support safety of IV MAPC in rat neonatal HI model. The overarching goal of this STTR Phase II study is to provide the optimal regimen of MAPC transplantation in an HI model that addresses the feasibility, safety and efficacy criteria within the standards of FDA regulations, thereby realizing a smooth translation of this cell based therapy from the laboratory to the clinic