Moderate and severe TBI can cause significant neuronal death and dysfunction, resulting in cognitive disability. The best strategy to restore neurologic function in TBI patients is to preserve existing neurons and to stimulate neurogenesis to replace lost neural tissue. Many therapeutics have sought to accomplish these goals, but none have succeeded, resulting in a lack of FDA-approved treatments for the restoration of cognitive disabilities that result from TBI. The exact cause of failure is not known, but we do know that brain injury induces secondary cascades that elevate levels of a transcriptional repressor of neural genes known as REST. Upregulation of REST in mature neurons prevents them from functioning properly and eventually ends in their death and increased levels of REST in stem cells and neural progenitor cells prevent them from becoming new neurons or oligodendrocytes. Previous therapeutic strategies as well as current approaches all work upstream of REST and do not account for this transcriptional block. To address this challenge, we have developed a lead biologic that promotes REST degradation and clears the injury induced transcriptional repression of neuronal genes. To engineer this lead biologic into a drug candidate for an Investigational New Drug (IND) application with the FDA we will carry out the following objectives: I. Optimize the activity, tissue targeting and intracellular transport of our drug candidate. II. Assess in vitro efficacy in human induced pluripotent stem (iPS) cells. III. Assess in vivo efficacy using a rodent model of TBI. To accomplish these objectives, Alcamena Stem Cell Therapeutics is collaborating with field leading academic scientists at Johns Hopkins University (JHU), and the Uniformed Services University of the Health Sciences (USHS/DoD). Cumulatively, these studies will inform us on the degree to which our drug candidate improves neuron and oligodendrocyte regeneration, survival and cognitive function. Additionally, the use of both human induced pluripotent stem cells and an in vivo rodent model of brain injury ensure that our results are translatable towards our long-term goal of addressing the unmet therapeutic needs of TBI patients.
Public Health Relevance Statement: Narrative. Traumatic brain injury (TBI) causes significant neuronal death resulting in motor and cognitive disability. To date, all targeted therapies to improve neuronal growth and viability in TBI patients have proved ineffective. To address this challenge, we have developed a biologic that overcomes the obstacles encountered by other approaches: a TBI-induced brake on neuronal genes. Our lead biologic is both neuroprotective and neurogenic and has the potential to restore cognitive functions such as learning and memory. Our approach offers the greatest promise yet for patients who suffer from cognitive disability caused by TBI. In this proposal, we describe our strategy for optimization and nonclinical assessment of our drug candidate.
NIH Spending Category: Acquired Cognitive Impairment; Behavioral and Social Science; Brain Disorders; Genetics; Injury (total) Accidents/Adverse Effects; Injury - Trauma - (Head and Spine); Injury - Traumatic brain injury; Neurosciences; Regenerative Medicine; Stem Cell Research; Stem Cell Research - Induced Pluripotent Stem Cell; Stem Cell Research - Induced Pluripotent Stem Cell - Human
Project Terms: Address; Affect; Affinity; American; Animal Model; Automobile Driving; Autopsy; base; Behavior; Binding; Biological; Biological Assay; Brain; Brain Injuries; C-terminal; Cell Death; Cell Membrane Permeability; Cell Nucleus; Cells; Cessation of life; Cognitive; cognitive disability; cognitive function; cognitive recovery; combinatorial; Cytoplasm; design; Dose; drug candidate; Drug Controls; Drug Design; economic cost; Engineering; Ensure; experience; experimental study; Failure; Family; FDA approved; Gene Expression; gene repression; Genes; Genetic Transcription; Goals; Health Sciences; Human; improved; In Vitro; in vivo; Individual; induced pluripotent stem cell; inhibitor/antagonist; Injury; International; Intracellular Transport; Investigational New Drug Application; Lead; Learning; Legal patent; Lesion; Libraries; Memory; mimetics; Monitor; Motor; mutant; Natural regeneration; Nerve Degeneration; Nerve Regeneration; nerve stem cell; Nervous System Physiology; neurogenesis; neuron loss; Neuronal Dysfunction; neuronal growth; Neuronal Injury; Neurons; novel; off-patent; Oligodendroglia; Oregon; overexpression; Patients; Peptides; Permeability; Phase; Phosphoric Monoester Hydrolases; Phosphorylation; Plasmids; pluripotency; preservation; prevent; Protein Dephosphorylation; Publishing; Randomized; Rattus; relating to nervous system; restoration; Ribosomes; Rodent Model; Safety; Scientist; screening; Site; Small Business Innovation Research Grant; stem cell therapy; stem cells; targeted treatment; Technology; Testing; Therapeutic; Therapeutic Intervention; Time; Tissues; Transcription Repressor; Traumatic Brain Injury; United States National Academy of Sciences; Universities; University Health Services; Up-Regulation; Work
