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.

编码这种功能障碍酶的一个有缺陷的aga基因会导致一种严重的进行性遗传性神经疾病--天冬氨酸氨基葡萄糖尿症(agu，OMIM#208400)。这种功能酶是分解细胞溶酶体中糖蛋白所必需的。缺乏酶活性会导致溶酶体功能受损，并在各种组织和体液的溶酶体中积聚天冬氨酸氨基葡萄糖(GlcNAc-ASN)。底物堆积的主要后果是溶酶体肥大，表现为智力障碍，以及其他相关症状，包括骨骼和关节异常。患者在整个童年期间精神运动发育缓慢/倒退，在生命的第三个十年左右恶化，变得精神和身体严重受损，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性基金会--稀有特质希望基金资助的努力，格雷博士的实验室已经产生了临床前数据，支持启动一项治疗AGU的I/II期基因治疗试验。2018年1月，与FDA就此举行了B型PreIND会议，会议为人工翻译制定了明确的道路。这种方法将使用鞘内注射的AAV9/AGA载体，遵循Gray博士之前的努力开创的先例，即2015年在NIH临床中心启动针对巨大轴索神经病的类似I期试验，并于2021年在达拉斯儿童医学中心启动针对CLN7 Batten病的类似I期试验。可用于AGU的丰富的疾病特异性生物标志物(包括AGA酶底物在离散脑区的局部成像)以及潜在的大治疗窗口，使AGU成为快速和全面评估鞘内AAV9作为治疗许多其他神经系统疾病的“平台”方法的完整疗效和/或缺点的理想疾病。我们建议进行必要的IND研究，以启动AGU的I/II期临床试验。