Viral Gene Therapy for Menkes Disease

门克斯病的病毒基因疗法

基本信息

批准号：
10722806
负责人：
STEPHEN GERARD KALER
金额：
$ 129.82万
依托单位：
RESEARCH INST NATIONWIDE CHILDREN'S HOSP
依托单位国家：
美国
项目类别：
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/10722806
关键词：
Affect Age Animals Appearance Biochemical Biodistribution Biological Products Biological Sciences Birth Body Weight Budgets Capsid Cessation of life Child Childhood Clinical Clinical Research Clinical Trials Clinical Trials Design Codon Nucleotides Combined Modality Therapy Complement Copper Cyclic GMP Data Developmental Therapeutics Program Direct Costs Disease Dose Drug Kinetics Enrollment FDA approved Facial vein structure Feedback Future Genes Hemophilia A Hereditary Disease Histopathology Homologous Gene Human Human Development Incidence Infant Inherited Injections Innate Immune Response Intravenous Knowledge Label Laboratories Laboratory Research Licensing Life Link Mediating Menkes Kinky Hair Syndrome Metabolism Molecular Mus Mutant Strains Mice Mutation National Institute of Neurological Disorders and Stroke Natural History Neonatal Screening Neurodegenerative Disorders Neurologic Neurologic Symptoms New Drug Approvals New York Outcome Pediatric Hospitals Peripheral Nerves Phase Phase I/II Clinical Trial Pilot Projects Plasmids Qualifying Randomized Recombinants Recommendation Regimen Research Research Project Grants Residual state Safety Series Spinal Cord Spinal Ganglia Spinal Muscular Atrophy Technology Therapeutic Time Toxicology Transgenes Tropism United States National Institutes of Health Variant Viral Viral Genes Work animal safety beneficiary copper-transporting ATPase experience first-in-human gene therapy genome sequencing human subject improved infancy innovation interest loss of function male manufacture mortality mouse model new technology next generation sequencing novel therapeutics population based pre-Investigational New Drug meeting pre-clinical preclinical safety preclinical study premature prospective response small molecule subcutaneous success vector whole genome

项目摘要

URGenT Network U01 proposal will evaluate the preclinical safety, tolerability, and dosing of AAV9-codon-optimized, reduced-size ATP7A, which we propose to use in a first-in-human clinical trial for Menkes disease. Menkes disease is a X-linked recessive infantile-onset neurodegenerative disorder of copper metabolism, caused by mutations in a highly conserved copper-transporting ATPase, ATP7A. This condition has an estimated incidence of one in 35,000 live male births and is associated with high under-age three years mortality, if untreated. Based on two clinical trials that demonstrated safety and survival benefits, Cyprium Therapeutics, Inc. (New York, NY) began rolling submission of a CDER/FDA new drug application (NDA) for Copper Histidinate (CuHis, IND #34,166; NDA# 211,241) in December 2021. Pre-IND meeting responses from CBER/FDA regarding AAV9-codon-optimized, reduced- size ATP7A reflected the agency’s recognition of the need for more complete treatment of this illness, by combining CuHis with some working copies of ATP7A. This need is based on mixed results in survival and neurodevelopmental outcomes in over 130 human subjects treated with CuHis alone, as well as recent preclinical studies documenting a synergistic effect of CuHis and the AAV9-codon-optimized, reduced-size ATP7A in a reliable mouse model of Menkes disease. We previously demonstrated that CSF-directed AAV gene therapy rescued 23-53% of mice with a mutation in the human Menkes disease homolog (mottled-brindled) when combined with CSF or subcutaneous copper. More recently, based on the experience of others at Nationwide Children’s with systemic AAV9 treatment of mice and humans with spinal muscular atrophy, we evaluated intravenous (facial vein) administration of AAV9-corsATP7A combined with subcutaneous administration of CuHis. This regimen led to 95% long term rescue of mottled- brindled mutant mice (19 of 20), using an AAV9 dose of 2.6 x 1013 vg/kg body weight. We are seeking support from the innovative URGenT network at a highly opportune time with respect to Menkes disease. Advances in viral gene therapy and newborn screening technology make it feasible to envision altering the natural history of this rare fatal pediatric illness for several reasons. First, we anticipate FDA approval of the first (small molecule) treatment for Menkes disease, CuHis, in the coming year. Second, in combination with systemic AAV gene therapy to provide some working copies of the missing copper transporter, an even more complete correction of neurologic and other manifestations is anticipated. Third, we have proof of principle that newborn screening (NBS) for Menkes is feasible via targeted next-generation sequencing or whole genome sequencing and are embarking on population-based NBS pilot studies in the next year.

URGenT Network U01 提案将评估 AAV9 密码子优化的、尺寸减小的 ATP7A 的临床前安全性、耐受性和剂量，我们建议将其用于门克斯病的首次人体临床试验。与隐性婴儿发病有关的铜代谢神经退行性疾病有关，由高度保守的铜转运 ATP 酶 ATP7A 突变引起。这种情况的发病率估计较高。 35,000 名活产男性中就有 1 人患有这种疾病，如果未经治疗，该疾病与 3 岁以下儿童的高死亡率有关。根据两项证明安全性和生存益处的临床试验，Cyprium Therapeutics, Inc.（纽约州纽约市）开始滚动提交一份研究报告。组氨酸铜（CuHis，IND #34,166；NDA# 211,241）于 2021 年 12 月获得 CDER/FDA 新药申请 (NDA)。 CBER/FDA 对 AAV9 密码子优化、尺寸减小的 ATP7A 的预 IND 会议回应反映了该机构认识到需要通过将 CuHis 与 ATP7A 的一些工作副本相结合来更完整地治疗这种疾病。在超过 130 名单独使用 CuHis 治疗的人类受试者中，其生存和神经发育结果的结果好坏参半，而且最近的临床前研究记录了 CuHis 和我们之前在可靠的门克斯病小鼠模型中证明了 AAV9 密码子优化的、尺寸减小的 ATP7A，CSF 导向的 AAV 基因疗法拯救了 23-53% 具有人类门克斯病同源基因突变的小鼠。最近，根据全国儿童医院其他人对患有脊髓性肌萎缩症的小鼠和人类进行全身 AAV9 治疗的经验，我们评估了静脉注射。（面部静脉）施用 AAV9-corsATP7A 与皮下施用 CuHis 相结合，使用 2.6 x 1013 vg/kg 体重的 AAV9 剂量，该方案使斑纹突变小鼠（20 只中的 19 只）获得了 95% 的长期拯救。我们正在就门克斯病的病毒基因治疗和新生儿筛查技术的进展寻求创新的 URGenT 网络的支持。首先，我们预计 FDA 将在明年批准第一种治疗门克斯病的（小分子）药物 CuHis；其次，与全身治疗相结合，改变这种罕见致命儿科疾病的自然史是可行的。 AAV 基因疗法可以提供缺失的铜转运蛋白的一些工作副本，预计可以对神经系统和其他表现进行更完整的纠正。第三，我们有原理证明，通过靶向下一代测序对 Menkes 进行新生儿筛查 (NBS) 是可行的。或全基因组测序，并且是明年将开始以人口为基础的国家统计局试点研究。