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Neural Stem Cell Therapy for Severe Traumatic Brain Injury

Description:

TECHNOLOGY AREA(S): Bio Medical 

OBJECTIVE: Develop and demonstrate a neural stem cell transplantation treatment protocol using human neural stem cells that will satisfy FDA mandated requirements for a Phase I/II, open-label, neural stem cell transplantation trial for the treatment of severe traumatic brain injury (TBI). Investigate the safety and effectiveness of this product as a neurorestorative therapy in promoting wound healing and recovery to injured brain. 

DESCRIPTION: The Department of Defense (DoD) and the military services require solutions to fill the capability gap to treat traumatic brain injury (TBI) which affects not only soldiers during wartime, but during training exercises as well. Currently, there are no clinically proven and FDA-approved pharmacological therapies for traumatic brain injury (TBI). Severe TBI results in widespread delayed focal and global neuronal loss causing significant disability or persistent vegetative state of the effected individual. Since these processes have proven resistant to numerous therapies, there is renewed interest in strategies to replace or endogenously regenerate these lost neurons following TBI. This interest has been driven by the realization that neural stem cells (NSC) possess a remarkable ability to integrate into the injured brain in either a targeted or widespread manner. In the central nervous system, they are capable of forming both neuronal and glial phenotypes, dependent largely upon the micro milieu of the host environment. In support of the concept of cellular transplantation for severe TBI, numerous studies have been performed to prove the concept that precursor cells of embryonic, fetal or mesenchymal origin can be transplanted into the brain, can integrate with the host brain architecture, and improve functional outcome in various animal models of stroke, neurodegenerative diseases and TBI. However, mesenchymal origin stem cells (MSC), though able to differentiate and express some neural markers, have not been shown to form synaptic connections, or integrate well with host tissues and are assumed to exert their beneficial effect through trophic factor modulation (1-2). Moreover, cells delivered via intravenous administration lose the majority (~95%) of the cells during lung passage (3). Intra-arterial injection carries the risk of causing embolic brain infarction and fails to deliver sufficient cells across the vascular wall barrier to the brain parenchyma (4). Thus, the choice of cell type, injection dose and technique of injection is clearly critical to success. To meet the objective of this topic, the company will evaluate existing human stem cell lines that give rise to a neuronal phenotype; these cell lines must not be on the Federal moratorium list for funding, must be ultimately be produced under good manufacturing practice (GMP) conditions, and must ultimately meet FDA guidelines for cellular therapies. This topic asks for an innovative approach to develop a human neural stem cell product that is capable of being delivered directly to the injured brain. The transplanted cells need to target brain tissue; the cells should survive and integrate into the host brain and be maintained for a sufficient duration of time to reach the desired efficacy. The desired end product would consist of a human neural stem cell replacement therapy that complies with the FDA regulatory pathway. Early FDA consideration is encouraged. 

PHASE I: The SBIR Performer must identify a human neural stem cell line that can address the technical challenges on this topic. The effort should clearly analyze and define the properties of any materials used for culturing the stem cells and define methods for intraparenchymal delivery of the cells in a rodent model of traumatic brain injury. If immunosuppression is required, the composite immunosuppressant therapy and treatment regimen should be defined. 

PHASE II: The SBIR Performer will design and perform pre-clinical in vivo studies to demonstrate and validate safety and therapeutic efficacy of neural stem cell transplantation in a rat model of TBI. The small business will develop, demonstrate, validate, and show feasibility of the selected stem cell therapy in an established animal model of severe TBI. Additionally, the small business will provide details regarding delivery of the cells and any required immunosuppressant regimen. TBI rodent models should demonstrate reduction in neurological deficits; including motor and cognitive deficits. The Performer will provide evidence of product safety by testing for long-term tumorigenicity of the stem cell transplants in immune-compromised athymic nude rats, who undergo TBI. For this purpose, athymic nude (rnu-/rnu-) rats represent an FDA-approved animal model of choice for general, pre-clinical tumorigenicity studies and are recommended by regulatory agencies specifically for the evaluation of tumorigenicity. All research involving animals, shall comply with the applicable federal and state laws and agency policy/guidelines for animal protection. The U. S. Army Medical Materiel Development Activity, Division of Regulated Activities & Compliance (USAMMDA/DRAC) may provide regulatory assistance. The FDA approval pathway will be outlined and considered at each developmental stage. The offeror shall initiate contact with FDA representatives and provide a clear plan on how FDA clearance will be obtained. 

PHASE III: Once the product successfully completes Phase II, the small business can seek partnership with a commercial entity for the production of prototypes using Good Manufacturing Practice (GMP) processes. Dose escalation studies using clinical grade GMP cells in swine or non-human primate TBI models may be recommended. A detailed analysis of the predicted performance pertaining to engraftment, survival and safety indications including, but not limited to bioavailability, bio-distribution, phenotypic differentiation, formation should be provided. It is recommended, although not required, to establish an independent advisory committee to review protocols and clinical trial design, planned endpoints, and statistical analysis. Ideally, the small business will sponsor the clinical studies necessary to demonstrate selective, targeted delivery to the brain, as well as clinical safety and efficacy. The small business should have a plan to continue to systematically collect and report data on safety, efficacy and utility after clinical use; therefore, plans to conduct long-term monitoring should be included in study protocols. The small business should seek FDA approval for the validation of the human neural stem cell delivery platform and tests conducted with it. 

REFERENCES: 

1: Xiong Y, Mahmood A, Chopp M. Neurorestorative treatments for traumatic brain injury. Discovery medicine 2010

2:  10(54): 434-42.

3:  Zhang Y, Chopp M, Meng Y, Katakowski M, Xin H, Mahmood A et al. Effect of exosomes derived from multipluripotent mesenchymal stromal cells on functional recovery and neurovascular plasticity in rats after traumatic brain injury. Journal of neurosurgery 2015

4:  122(4): 856-67.

5:  Pendharkar AV, Chua JY, Andres RH, Wang N, Gaeta X, Wang H et al. Biodistribution of neural stem cells after intravascular therapy for hypoxic-ischemia. Stroke

6:  a journal of cerebral circulation 2010

7:  41(9): 2064-70. 54.

8:  Yavagal DR, Lin B, Raval AP, Garza PS, Dong C, Zhao W et al. Efficacy and dose-dependent safety of intra-arterial delivery of mesenchymal stem cells in a rodent stroke model. PloS one 2014

9:  9(5): e93735.55. NCT01273337. Study of ALD-401 Via Intracarotid Infusion in Ischemic Stroke Subjects. In, 2014. 56.

10:  Giusto E, Donega M, Cossetti C, Pluchino S. Neuro-immune interactions of neural stem cell transplants: from animal disease models to human trials. Experimental neurology 2014

11:  260: 19-32.

KEYWORDS: Neural Stem Cells, Traumatic Brain Injury, TBI, Neurotransplantation, Cellular Replacement, Neurorestorative 

CONTACT(S): 

Dr. Deborah Shear 

(301) 319-7208 

deborah.a.shear.civ@mail.mil 

Dr. Janice Gilsdorf 

(301) 319-9376 

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