Viral Gene Therapy for Menkes Disease

门克斯病的病毒基因疗法

• 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
• 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

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密码子优化的小尺寸ATP7A的临床前安全性、耐受性和剂量，我们建议将其用于Menkes病的首次人体临床试验。Menkes病是一种x连锁隐性婴儿性铜代谢神经退行性疾病，由高度保守的铜转运atp酶ATP7A突变引起。这种情况的发生率估计为每35000例活产男婴中有1例，如果不加以治疗，则与3岁以下儿童的高死亡率有关。基于两项证明安全性和生存益处的临床试验，Cyprium Therapeutics, Inc. （New York， NY）于2021年12月开始向CDER/FDA提交组氨酸铜（CuHis, IND #34,166; NDA# 211,241）的新药申请（NDA）。CBER/FDA关于aav9密码子优化、缩小尺寸的ATP7A的Pre-IND会议反应反映了该机构认识到需要通过将CuHis与一些ATP7A的工作拷贝结合来更彻底地治疗这种疾病。这一需求是基于130多名单独接受CuHis治疗的人类受试者的生存和神经发育结果的混合结果，以及最近在可靠的Menkes病小鼠模型中记录CuHis和aav9密码子优化的缩小尺寸的ATP7A的协同作用的临床前研究。我们之前证明，CSF导向的AAV基因治疗在与CSF或皮下铜联合使用时，可挽救23-53%的人类门克斯病同源基因突变（斑驳-斑纹）小鼠。最近，基于全国儿童医院其他全身性AAV9治疗小鼠和脊髓性肌萎缩症患者的经验，我们评估了静脉（面静脉）给药AAV9- corsatp7a联合皮下给药CuHis。该方案使用2.6 x 1013 vg/kg体重的AAV9剂量，对斑点斑纹突变小鼠（20只中的19只）的长期挽救率为95%。我们正在寻求创新的URGenT网络在非常适当的时候对门克斯病的支持。病毒基因治疗和新生儿筛查技术的进步使得改变这种罕见致命儿科疾病的自然史成为可能。首先，我们预计FDA将在明年批准Menkes病的首个（小分子）治疗药物CuHis。其次，结合系统性AAV基因治疗，提供一些缺失铜转运体的工作拷贝，有望更彻底地纠正神经系统和其他表现。第三，我们有原则证据表明，通过有针对性的下一代测序或全基因组测序，新生儿筛查（NBS）对Menkes是可行的，并将在明年开展基于人群的NBS试点研究。