Cell Based Therapy for Treatment of Traumatic Brain Injury
DESCRIPTION (provided by applicant): Previously performed and published studies have demonstrated that MultiStem(R), Athersys' patented adult adherent stem cell product, modulates the inflammatory component of secondary brain injury in rodent models of traumatic brain injury (TBI). Further, there are supporting published data illustrating the efficacy of MultiStem in other CNS injury models including stroke, hypoxic-ischemic injury, and spinal cord injury among others. Athersys, Inc., and the University ofTexas Medical School at Houston have a collaborative research agreement in place for the development of proof-of-concept studies in vivo and in vitro for the treatment of TBI and stroke. The ultimate goal of this relationship is to translate these initialpositive findings into clinical trials and novel therapeutic approaches for neurological injury. The specific objective of this SBIR Fast-Track Research Proposal is to define and successfully execute pivotal pre-clinical safety and efficacy studies required for a successful Investigational New Drug submission to the FDA for an optimized cellular therapy regimen for treatment of TBI and its related outcomes. This application proposes an initial GLP toxicity study in Phase 1, followed by sequential studies to address clinically relevant translational issues in progenitor cell therapy for neurological injury/disease. The specific aims are: Phase 1: Define the safety profile of MultiStem delivered intravenously after TBI with both short and long-term GLP toxicity/pathology-necropsy evaluation. The rationale for the proposed groups is that safety must be defined in naive and injured animals, since injury affects biodistribution secondary to chemo-attractant signals from injured tissues. NO GO decision will be based principally on the development of ectopic tissue in any organ (not just cell presence), or significant exacerbation of inflammation/organ function. Phase 2a: The goal of Phase 2a is the completion of comprehensive toxicity studies in TBI, with doses shown to be efficacious in our previous proof-of-concept efficacy testing in rodents. Comprehensive toxicity and anatomic pathology studies will need to be completed at higher doses/multiple doses based on previous proof- of-concept studies. GO/NO GO decisions will be made by assessing the dose toxicity profiles (compared to Controls) relative to previous proof-of-concept efficacy data. Phase 2b: The goal of the Phase 2b portion of the proposal is to establish the optimal dosing scheme based on primary and secondary outcomes measures, after clearing safety studies in Phase 1 and Phase 2a. Translational issues of catheter delivery systems and osmolarity of the cell infusion environment will be evaluated in terms of affecting cell survival and potency. Phase 2c:The primary goals of this sub-phase are (1) IND submission for both adult and pediatric protocols using intravenous MultiStem for severe TBI, and (2) addressing/revising the submissions in response to any critiques, and (3) approval and local IRB submission to allow initiation of the clinical trials. PUBLIC HEALTH RELEVANCE The treatment of traumatic brain injury (TBI) is an unmet medical need of significance in the United States, especially for children under the age of 5, young male adults aged 15-25, elderly men and women aged 75 and older and military personnel in active combat zones (NINDS Website). According to the National Institutes of Neurological Disorders and Stroke there are currently more than 5 million Americans living with permanent deficitsresulting from TBI that require daily help or assistance, with a resulting burden in direct and indirect costs to the United States health care system of 56 Billion annually. Although cell-based therapies have emerged as experimental treatments for a number of other neurological and cardiovascular disorders, there is currently no treatment for TBI other than post-injury supportive care. The specific objective of this research project is to develop an optimized cellular therapy regimen for treatment of patients suffering TBI.
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