Mechanosensitive Channel based Pressure-Modulating Gene Therapy for Glaucoma Treatment

基于机械敏感通道的压力调节基因疗法治疗青光眼

• 批准号: 10384600
• 负责人: ADNAN Ismail DIBAS
• 金额: $ 71.69万
• 依托单位: NANOSCOPE TECHNOLOGIES, LLC
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-30 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10384600
• 关键词: Address; African American population; Aftercare; Age; American; Americas; Anti-Inflammatory Agents; Antibodies; Aqueous Humor; Biodistribution; Biology; Biomedical Engineering; Biometry; Blindness; Capsid; Cell Size; Cell Volumes; Cells; Clinical; Clinical Pathology; Closure by clamp; DNA; DNA analysis; Development; Disease; Dose; Dose-Limiting; Drainage procedure; Elderly; Electrophysiology (science); Energy-Generating Resources; Engineering; Enzyme-Linked Immunosorbent Assay; Equipment Malfunction; Extracellular Space; Eye; Eye Infections; FDA approved; Family; Genes; Glaucoma; Goals; Government; Guidelines; Healthcare; Hispanic Populations; Histopathology; Homo; Immune; Immunohistochemistry; Impairment; Inflammatory; Injections; Legal patent; Life; Lipid Bilayers; Liquid substance; Measurement; Measures; Membrane; Molecular; Mus; Ocular Hypertension; Operative Surgical Procedures; Ophthalmology; Optic Nerve; Organ; Outcome; Pathway interactions; Patient Noncompliance; Peripheral Blood Mononuclear Cell; Persons; Pharmaceutical Preparations; Pharmacology; Phase; Physiologic Intraocular Pressure; Physiological; Plasma; Primary Open Angle Glaucoma; Production; Proteins; Quality of life; Rattus; Reaction; Recording of previous events; Research; Residual state; Retina; Rodent Model; Safety; Sampling; Serum; Signal Transduction; Small Business Innovation Research Grant; Stretching; Suction; Taxes; Technology; Therapeutic; Therapeutic Effect; Toxic effect; Transgenes; Transgenic Organisms; Variant; Viral; Visual Cortex; aqueous humor flow; base; cytokine; demographics; diabetic; gene therapy; improved; in vivo; mechanical force; mouse model; nerve damage; novel; pressure; response; sensor; sex; side effect; success; systemic toxicity; ultrasound; vector

Glaucoma is recalcitrant to treatment and the resulting optic nerve damage is irreversible. All demographics are susceptible to glaucoma, especially the elderly, African-Americans, Hispanics, diabetics and families with a history of glaucoma. About three million Americans have glaucoma and the US government loses an estimated 3 billion USD each year in lost tax revenue, benefit payouts and healthcare subsidies needed to support these citizens. There is great need for a long-lasting treatment for glaucoma, because vision loss due to glaucoma is the second leading cause of blindness in America. The currently available pharmacological and surgical treatments for glaucoma have significant limitations and side-effects, which include, systemic reactions to medications, patient non-compliance, eye infections, surgical device failure, and damage to the eye. Primary Open Angle Glaucoma (POAG) is common and is characterized by poor drainage of aqueous humor through the conventional outflow pathway. Here, we put forth a novel commission for virally delivered Engineered Mechanosensitive Channel (EMC) as a pressure modulator in the impaired TM of glaucomatous eyes. Using this patent pending technology, we have demonstrated that EMC is: (i) functional in cultured TM cells, (ii) successfully transduced in vivo in TM cells; and (iii) effective in lowering the IOP in a mouse model of ocular hypertension without (i) non-targeted expression (measured by QPCR); (ii) ocular damage (assessed by OCT); (iii) inflammatory cytokines in plasma (detected by ELISA); or (iv) immune cell response and (v) loss of viability of targeted cells expressing EMC over long period. EMC is an engineered version of the bacterial stretch- activated channel, which directly senses tension in the membrane lipid bilayer of cells and in response, transiently opens its large non-specific pore for trans/paracytosis. At its pressure threshold, EMC can release fluid from TM cells to be cleared through SC. Additionally, the resulting decrease in cell volume and size will widen intercellular spaces and facilitate the paracellular flow of aqueous humor. EMC acts as an ideal drainage valve for TM cells, because it is a relatively small homo-oligomeric channel and does not need any associated proteins or energy sources to assemble and function. We have identified optimal EMC variant that is activated at physiologically relevant pressures using pressure clamp. The goal of the proposed research is to further develop the product based on the self-complementary AAV carried engineered mechanosensitive EMC channel (scEMC) for gene therapy of POAG. The objective of this phase-II SBIR project will be accomplished through three specific aims. Aim 1: Quantify long-term stability of scEMC and safety of scEMC in wild type rats; Aim 2: Evaluate scEMC-enabled long-term IOP lowering Efficacy in rodent models of POAG and Aim 3: GLP Study of toxicity and Biodistribution of intracamerally-injected scEMC in wild-type NHPs. The development of a safe effective single-dose long-lasting treatment for glaucoma via the success of this proposal would improve the lives of many Americans.

青光眼难以治疗，造成的视神经损伤是不可逆的。所有的人口