Optogenetic control over transgene expression for the therapy of brain and spine Abstract Gene modified stem cells are a powerful tool for the production of secretable therapeutic proteins in the body. Yet, there is a valid concern over their safety since there is no way to control them once they have been transplanted. We propose to utilize optogenetic control of transcription (ORT) to externally control secretion of the therapeutic protein using red light. ORT would improve the efficacy and safety of the therapy by repeated remote activation of transgene synthesis with red light delivered noninvasively. For a specific disease application, we propose to use intrathecally delivered ORTdriven stem cells to produce antiinflammatory antiTNF hybrid antibodies in the subarachnoid cavity for the therapy of neuroinflammation in the brain. The ORT option would allow us to externally induce production of the antiinflammatory antibody using red light as needed. At this initial phase of the project, we propose the conceptual evaluation of the ORT system genetically embedded into bone marrow stem cells. This testing is proposed in cell culture (Aim 1) and the mouse cerebral subarachnoid cavity (Aim 2). The proposed method aims to improve the safety and efficiency of the therapy of chronic CNS disorders with episodic neuroinflammatory components by providing the benefit of remote control of the timing and dosage of the therapy.
Public Health Relevance Statement: Narrative Gene modified stem cells offer promise for the therapy of central nervous disorders. However, the current methods of delivery and dosage adjustment are not sufficiently safe. This proposal offers to test a novel concept of producing a biological drug in the subarachnoid cavity of the brain under repetitive induction by red light. In this phase, we propose to perform the initial evaluation of this technology in cell culture and a mouse model. The option of control over gene modified cell activity would improve the efficacy and safety of central nervous system therapy, opening new opportunities for treatment of brain and spinal cord disorders. The proposed technology has the potential to facilitate the therapys dosage adjustment and administration timing, thus improving the quality of life and comfort of neuropsychiatric patients.
Project Terms: accomplished suicide; Adverse effects; Alpha Cell; Alzheimer's Disease; Anti-inflammatory; Anti-Inflammatory Agents; Antibodies; AP 1903 reagent; Automobile Driving; Benchmarking; Biological; Bipolar Disorder; Blood - brain barrier anatomy; Bone Marrow Stem Cell; Brain; Brain Injuries; CASP9 gene; Cell Culture Techniques; Cell Cycle Kinetics; Cell Therapy; Cell Transplants; Cells; Central Nervous System Diseases; Cerebrospinal Fluid; Cerebrum; Characteristics; Chronic; Crohn's disease; Disease; Disease model; dosage; Drug Delivery Systems; Epilepsy; Etanercept; Evaluation; Flow Cytometry; Gene-Modified; Genetic Transcription; genetically modified cells; Helmet; Human; Humira; hybrid antibody; Immunity; improved; in vivo; in vivo imaging; Infection; Injectable; Injury; innovation; Intrathecal Injections; irradiation; Kinetics; Light; Major Depressive Disorder; Measures; Mediating; Mental disorders; Messenger RNA; Methods; Microscopy; mouse model; Multiple Sclerosis; Mus; Neuraxis; neuroinflammation; neuropsychiatric disorder; neuropsychiatry; novel; novel strategies; optogenetics; Parkinson Disease; Patients; Performance; Peripheral; Pharmaceutical Preparations; Phase; Procedures; Production; Proteins; Psoriasis; Quality of life; Regulation; Reporter; response; Rheumatoid Arthritis; Risk; Safety; Self Administration; small molecule; Spinal Cord Diseases; Stem cells; stroke; Suicide; suicide gene; Surface; synthetic biology; System; Technology; Testing; therapeutic protein; TNF gene; tool; Transcriptional Regulation; transgene expression; Transgenes; Transplantation; Vertebral column
