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.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Small Business Technology Transfer (STTR) Grants - Phase II (R42)
Project #
Application #
Study Section
Special Emphasis Panel (ZRG1-BDCN-A (11))
Program Officer
Fertig, Stephanie
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Athersys, Inc.
United States
Zip Code
Carroll, James (2012) Human cord blood for the hypoxic-ischemic neonate. Pediatr Res 71:459-63
Carroll, James E; Mays, Robert W (2011) Update on stem cell therapy for cerebral palsy. Expert Opin Biol Ther 11:463-71
Yu, Guolong; Borlongan, Cesar V; Stahl, Christine E et al. (2009) Systemic delivery of umbilical cord blood cells for stroke therapy: a review. Restor Neurol Neurosci 27:41-54
Chopp, Michael; Steinberg, Gary K; Kondziolka, Douglas et al. (2009) Who's in favor of translational cell therapy for stroke: STEPS forward please? Cell Transplant 18:691-3
Borlongan, Cesar V (2009) Cell therapy for stroke: remaining issues to address before embarking on clinical trials. Stroke 40:S146-8
Yasuhara, Takao; Hara, Koichi; Maki, Mina et al. (2008) Intravenous grafts recapitulate the neurorestoration afforded by intracerebrally delivered multipotent adult progenitor cells in neonatal hypoxic-ischemic rats. J Cereb Blood Flow Metab 28:1804-10
Carroll, James E; Borlongan, Cesar V (2008) Adult stem cell therapy for acute brain injury in children. CNS Neurol Disord Drug Targets 7:361-9
Hess, David C; Borlongan, Cesar V (2008) Cell-based therapy in ischemic stroke. Expert Rev Neurother 8:1193-201