IND-enabling studies for Aspartylglucosaminuria (AGU) to support the initiation of an AAV9/AGA gene transfer clinical trial

天冬氨葡萄糖胺尿症 (AGU) 的 IND 启用研究，以支持 AAV9/AGA 基因转移临床试验的启动

• 批准号: 10722310
• 负责人: Steven J Gray
• 金额: $ 63.17万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10722310
• 关键词: Aspartylglucosaminuria; Behavioral; Biochemical; Biological Assay; Biological Markers; Blood; Body Fluids; Brain region; Caregivers; Child; Childhood; Clinical; Clinical Trials; Clinical Trials Data Monitoring Committees; Code; Cognitive; Communication; Data; Deformity; Deterioration; Development; Disease; Dose; Enzymes; Feasibility Studies; Foundations; Functional disorder; Funding; Gene therapy trial; Genes; Genetic; Glycoproteins; Histopathology; Human; Hypertrophy; Image; Immune response; Impairment; Individual; Inherited; Institutional Review Boards; Intellectual functioning disability; Investigational Drugs; Investigational New Drug Application; Joints; Lead; Life; Longevity; Lysosomes; Magnetic Resonance Spectroscopy; Measurement; Measures; Medical center; Methodology; Motor; Mus; Nerve Degeneration; Neurodegenerative Disorders; Nonprofit Organizations; Online Mendelian Inheritance In Man; Outcome; Parents; Patients; Pharmaceutical Preparations; Phase; Phase I/II Clinical Trial; Pre-Clinical Model; Psyche structure; Psychomotor Performance; Publishing; Rattus; Research Personnel; Resources; Sampling; Spastic Paraplegia; Spielmeyer-Vogt Disease; Supportive care; Symptoms; Technology; Technology Transfer; Tissues; Toxicology; Translations; United States National Institutes of Health; Urine; associated symptom; clinical biomarkers; clinical center; design; enzyme activity; enzyme substrate; first-in-human; gene therapy; gene therapy clinical trial; giant axonal neuropathy; good laboratory practice; imaging biomarker; in vivo; institutional biosafety committee; large scale production; lead candidate; manufacture; meetings; nervous system disorder; novel therapeutics; phase I trial; pre-clinical; preclinical study; safety assessment; safety testing; skeletal; specific biomarkers; therapeutic candidate; trait; vector

A faulty AGA gene coding for the dysfunctional enzyme results in a severe and progressive genetic neurological disorder, Aspartylglucosaminuria (AGU, OMIM # 208400). The functional enzyme is required for the breakdown of glycoproteins in the cellular lysosomes. Absence of enzymatic activity results in impaired lysosomal function and accumulation of aspartylglucosamine (GlcNAc-Asn) in the lysosomes of various tissues and body fluids. The key consequence of the substrate accumulation is lysosomal hypertrophy that manifests as intellectual disability, and other associated symptoms including skeletal and joint abnormalities. Patients have slowed/regressive psychomotor development throughout childhood, deteriorating around the third decade of life to become severely impaired mentally and physically, highly dependent on supportive care thereafter. The median lifespan of AGU patients is approximately 40-50 years. Through efforts primarily funded through a parent-organized non-profit foundation, the Rare Trait Hope Fund, Dr. Gray’s lab has generated preclinical data supporting the initiation of a Phase I/II gene therapy trial to treat AGU. A Type B preIND meeting was held with the FDA regarding this in January 2018, which has charted a clear path forward for human translation. This approach would use an AAV9/AGA vector injected intrathecally, following a precedent set by Dr. Gray’s previous efforts to initiate similar Phase I trials for Giant Axonal Neuropathy at the NIH Clinical Center in 2015 and for CLN7 Batten disease at Children’s Medical Center Dallas in 2021. The wealth of available disease-specific biomarkers for AGU (including localized imaging of the AGA enzyme substrate in discrete brain regions) along with a potentially large treatment window, make AGU an ideal disease to rapidly and fully assess the complete efficacy and/or shortcomings of intrathecal AAV9 as a “platform” approach to treat many other neurological diseases. We propose to conduct the necessary IND-enabling studies to initiate a Phase I/II clinical trial for AGU.

一个错误的阿加基因编码的功能障碍酶的结果在一个严重的和渐进的遗传神经系统疾病，天冬氨酸氨基葡萄糖尿症（AGU，OMIM # 208400）。这种功能性酶是细胞溶酶体中糖蛋白分解所必需的。酶活性的缺乏导致溶酶体功能受损，并导致不同组织和体液的溶酶体中乙酰氨基葡萄糖（GlcNAc-Asn）蓄积。底物蓄积的关键后果是溶酶体肥大，表现为智力残疾和其他相关症状，包括骨骼和关节异常。患者在整个童年期的精神发育缓慢/倒退，在生命的第三个十年左右恶化，在精神和身体上严重受损，此后高度依赖支持性护理。AGU患者的中位寿命约为40-50岁。通过主要由父母组织的非营利基金会Rare Trait Hope Fund资助的努力，Gray博士的实验室已经产生了临床前数据，支持启动I/II期基因治疗试验来治疗AGU。2018年1月与FDA就此举行了B类preIND会议，为人类翻译制定了明确的前进道路。这种方法将使用鞘内注射的AAV 9/阿加载体，这是继格雷博士之前在2015年在NIH临床中心启动类似的巨轴突神经病I期试验和2021年在达拉斯儿童医学中心启动CLN 7巴滕病I期试验的先例。AGU可用的疾病特异性生物标志物的丰富性（包括阿加酶底物在离散脑区域中的局部成像）沿着潜在的大治疗窗，使得AGU成为快速和全面评估鞘内AAV 9作为治疗许多其他神经系统疾病的“平台”方法的完整功效和/或缺点的理想疾病。我们建议进行必要的IND使能研究，以启动AGU的I/II期临床试验。