Develop AAV9 gene replacement therapy for treating MPS I

开发 AAV9 基因替代疗法治疗 MPS I

• 批准号: 10545520
• 负责人: HAIYAN FU
• 金额: $ 37.89万
• 依托单位: NEUROGT, INC.
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-01 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10545520
• 关键词: 10 year old; Address; Advanced Development; Blood - brain barrier anatomy; Bone Marrow Transplantation; Cells; Cessation of life; Child; Codon Nucleotides; Complementary DNA; Data; Defect; Dependovirus; Deterioration; Development; Diffuse; Disease; Dose; Failure; Family; Future; GAG Gene; Gene Delivery; Goals; Human; In Vitro; Infusion procedures; L-Iduronidase; Lead; Lysosomal Storage Diseases; Mediating; Mendelian disorder; Mission; Mucopolysaccharidoses; Mucopolysaccharidosis I; Mucopolysaccharidosis I H; Mus; Neurologic; Neuropathy; North Carolina; Pathology; Patients; Peripheral; Phase; Plant Roots; Plasmids; Proteins; Recombinant adeno-associated virus (rAAV); Recombinants; Regimen; Reproducibility; Safety; Small Business Technology Transfer Research; Symptoms; Testing; Therapeutic; Toxic effect; Transfection; Transgenes; Translations; Universities; adeno-associated viral vector; clinical application; clinical development; clinically relevant; commercialization; effective therapy; enzyme replacement therapy; experience; experimental study; gene replacement therapy; gene therapy; in vitro testing; medical schools; mid-career faculty; miniaturize; mouse model; neurogenetics; neurotropic; novel; preclinical efficacy; preclinical safety; premature; product development; response; scale up; standard of care; success; targeted treatment; tissue culture; transduction efficiency; uptake; vector

Project Summary NeuroGT, Inc is a start-up company founded by Dr. Haiyan Fu, an 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) I is a fatal lysosomal storage disease (LSD) caused by autosomal recessive defects in α-L-iduronidase (IDUA). Severe form of MPS I (MPS IH, Hurler syndrome) represents the majority of known cases, with premature deaths usually before age 10 years, predominantly due to neurological deterioration and cardiorespiratory failure. No effective treatment is available for neurological indications of MPS IH. Because of the global diffuse neuropathy and the blood brain barrier (BBB), MPS IH is not amenable to either recombinant enzyme replacement therapy or bone marrow transplantation, which are the standard of care for treating somatic symptoms of MPS I. Gene replacement therapy targeting the root cause has been demonstrated to be an ideal strategy for treating monogenic diseases. Numerous studies have demonstrated successful in IV or intrathecal (IT) delivery of trans-BBB-neurotropic AAV9 for treating neurogenetic diseases. Importantly, the efficacy and safety profiles of IV and IT rAAV9 delivery have been demonstrated to be highly reproducible across different neurogenetic diseases, including LSDs. For optimal therapeutic potential, we have developed a novel self-complementary (sc) AAV vector, scAAV- mCMV-∆hIDUAop, to deliver a miniaturized human IDUA cDNA with codon-optimization. When tested in vitro in human MPS IH cells, this scAAV-∆hIDUAop vector construct was shown to express functional IDUA protein at a level 8-fold higher, than the single-stranded (ss) rAAV-hIDUAop vector. Importantly, the transduction with scAAV--∆hIDUAop vector also lead to 11-fold increase in the secretion of rIDUA, which can enter non- transduce MPS I cells and clear GAG storage there. Our preliminary data strongly support the potential of further development towards clinical application in humans. In this proposed project, for clinical relevance, we will test this new scAAV-∆hIDUAop vector in MPS I mouse model using AAV9, via IV, intrathecal (IT) and IV+IT delivery, to assess the therapeutic potential and determine the optimal regimen for treating MPS I. The proposed project will allow us to generate rigorous preclinical efficacy and safety data, to support the subsequent clinical development and commercialization.

项目概要 NeuroGT, Inc是一家由基因治疗副教授付海燕博士创立的初创公司 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 该项目的目标是开发一种治疗人类罕见神经遗传疾病的基因治疗产品。 有效的基因治疗产品针对根本原因进行治疗 粘多糖贮积症 (MPS) I 是一种由常染色体隐性遗传引起的致命性溶酶体贮积病 (LSD) α-L-艾杜糖醛酸酶 (IDUA) 缺陷占大多数 MPS I（MPS IH，Hurler 综合征）。 已知病例，通常在 10 岁之前过早死亡，主要是由于神经系统疾病 恶化和心肺衰竭没有有效的治疗方法。 由于全身弥漫性神经病变和血脑屏障 (BBB)，MPS IH 不适合。 重组酶替代疗法或骨髓移植，这是治疗的标准 护理治疗 MPS I 的躯体症状。针对根本原因的基因替代疗法已 大量研究表明，这是治疗单基因疾病的理想策略。 成功地通过静脉注射或鞘内 (IT) 递送反式 BBB 亲神经 AAV9 来治疗神经遗传性疾病。 重要的是，IV 和 IT rAAV9 递送的功效和安全性已被证明是高度 在不同的神经遗传疾病（包括 LSD）中可重复。 为了获得最佳的治疗潜力，我们开发了一种新型的自我互补 (sc) AAV 载体，scAAV- mCMV-ΔhIDUAop，在体外测试时提供经过密码子优化的小型化人类 IDUA cDNA。 人类 MPS IH 细胞中，这种 scAAV-ΔhIDUAop 载体构建体被证明可以在 水平比单链 (ss) rAAV-hIDUAop 载体高 8 倍。 scAAV--ΔhIDUAop载体还导致rIDUA的分泌增加11倍，rIDUA可以进入非 我们的初步数据强烈支持 MPS I 细胞的潜力。 在这个拟议的项目中，为了临床相关性，我们进一步开发人类临床应用。 将使用 AAV9 在 MPS I 小鼠模型中通过 IV、鞘内 (IT) 和 IV+IT 测试这个新的 scAAV-ΔhIDUAop 载体 递送，以评估治疗潜力并确定治疗 MPS I 的最佳方案。 拟议的项目将使我们能够生成严格的临床前疗效和安全性数据，以支持 随后的临床开发和商业化。