Development of gene therapy product for treating MPS IIIB

开发治疗 MPS IIIB 的基因治疗产品

• 批准号: 10006261
• 负责人: HAIYAN FU
• 金额: $ 39.78万
• 依托单位: NEUROGT, INC.
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-04-15 至 2022-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10006261
• 关键词: Acute; Address; Advanced Development; Antibodies; Binding; Biological; Biological Assay; C57BL/6 Mouse; Cells; Cessation of life; Child; Chronic; Clinical; Clinical Trials; Codon Nucleotides; Complementary DNA; Cytotoxic T-Lymphocytes; Data; Defect; Dependovirus; Development; Disease; Disease Progression; Dose; Enrollment; Enzyme-Linked Immunosorbent Assay; Enzymes; Family; Gene Delivery; Gene Transduction Agent; Generations; Genes; Glycosaminoglycans; Goals; Guidelines; Hematopoietic Stem Cell Transplantation; Heparitin Sulfate; Human; Immune response; Injections; Lysosomal Storage Diseases; Mendelian disorder; Mind; Mission; Mucopolysaccharidoses; Mus; Neurologic; Neurologic Symptoms; Neuropathy; North Carolina; Organ; Patients; Phase; Plant Roots; Prevention; Recombinant adeno-associated virus (rAAV); Regimen; Reproducibility; Research Personnel; Safety; Serum; Services; Small Business Technology Transfer Research; Standardization; Symptoms; T cell response; Testing; Therapeutic; Toxic effect; Toxicology; Transgenes; Translating; Translations; Universities; adeno-associated viral vector; advanced disease; alpha-n-acetylglucosaminidase; assay development; clinical application; clinical development; commercialization; effective therapy; efficacy testing; enzyme replacement therapy; experience; experimental study; gene therapy; gene therapy clinical trial; immunotoxicity; improved; medical schools; mid-career faculty; neurogenetics; neurotropic; pre-clinical; premature; promoter; response; success; targeted treatment; transduction efficiency; vector; virtual

Project Summary NeuroGT, Inc is a new start-up company founded by Dr. Haiyan Fu, Associate professor in the Gene Therapy Center at University of North Carolina at Chapel Hill, with the mission of develop and commercialize effective gene therapy products to treat rare neurogenetic diseases in humans. The goal of this project is to develop an effective gene therapy product targeting the root cause for treating Mucopolysaccharidosis (MPS) IIIB in humans. MPS IIIB is a fatal lysosomal storage disease (LSD) caused by autosomal recessive defects in α-N-acetylglucosaminidase (NAGLU), leading to severe neurological manifestations, broad somatic disorders and premature death. No effective treatment is available for MPS IIIB. Gene therapy targeting the root cause has been demonstrated to be an ideal strategy for treating monogenic diseases including LSDs. Our previous studies have led to IND approvals for Phase 1/2 GT clinical trials in patients with MPS IIIA (NCT02716246), MPS IIIB (NCT03315182), and MPS II (IND# 17838), using the trans- BBB-neurotropic AAV9 vector via a systemic delivery. For improved therapeutic potential, we have developed three new 2nd-generation (2nd-gen) gene therapy products for MPS IIIB, using the AAV9 platform to deliver a codon-optimized human NAGLU gene (hNAGLUop) driven by different promoters. The codon-optimization resulted in enhanced rNAGLU secretion, indicating the potential of added by-stander effects. We have tested one of the 2nd-gen rAAV9-hNAGLUop vector in mice via an IV injection, and shown that the vector treatment was safe and effective for treating MPS IIIB, supporting the potential of further development towards clinical application in humans. In this proposed project, with human translation and commercialization in mind, we will expand our efforts to test the efficacy and safety of these rAAV9-hNAGLUop products in mice via systemic delivery to generate rigorous preclinical data to support the IND submission and clinical development.

项目概要 NeuroGT, Inc是一家新的初创公司，由基因治疗副教授付海燕博士创立 北卡罗来纳大学教堂山分校中心，其使命是开发有效性并将其商业化 基因治疗产品用于治疗人类罕见的神经遗传疾病。 该项目的目标是开发一种有效的基因治疗产品，针对治疗的根本原因 人类粘多糖贮积症 (MPS) IIIB 是一种致命的溶酶体贮积病 (LSD)。 α-N-乙酰氨基葡萄糖苷酶（NAGLU）的常染色体隐性缺陷，导致严重的神经系统疾病 MPS IIIB 没有有效的治疗方法。 针对根本原因的基因治疗已被证明是治疗单基因的理想策略 我们之前的研究已获得 1/2 期 GT 临床试验的 IND 批准。 MPS IIIA (NCT02716246)、MPS IIIB (NCT03315182) 和 MPS II (IND# 17838) 患者，使用反式 BBB-神经性 AAV9 载体通过全身递送。 为了提高治疗潜力，我们开发了三种新的第二代（2nd-gen）基因疗法 用于 MPS IIIB 的产品，使用 AAV9 平台提供密码子优化的人类 NAGLU 基因 (hNAGLUop) 由不同启动子驱动的密码子优化导致rNAGLU分泌增强，表明 我们已经在小鼠中测试了一种第二代 rAAV9-hNAGLUop 载体。 静脉注射，并表明载体治疗对于治疗 MPS IIIB 是安全有效的，支持 在这个拟议的项目中，进一步开发人类临床应用的潜力。 考虑到人工翻译和商业化，我们将加大力度测试其有效性和安全性 这些 rAAV9-hNAGLUop 产品通过全身递送在小鼠体内生成严格的临床前数据来支持 IND 提交和临床开发。