Viral Gene Therapy for Menkes Disease

URGenT Network U 01提案将评估AAV 9密码子优化的、尺寸减小的ATP 7A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连锁隐性遗传的铜代谢神经退行性疾病，由高度保守的铜转运ATP酶（ATP 7A）突变引起。据估计，这种疾病的发病率为每35 000名活产男婴中就有一名，如果不加以治疗，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. (New约克，纽约）于2021年12月开始滚动提交组氨酸铜（CuHis，IND #34，166; NDA#211，241）的CDER/FDA新药申请（NDA）。CBER/FDA关于AAV 9-密码子优化的、尺寸减小的ATP 7A的IND前会议答复反映了该机构认识到需要通过将CuHis与ATP 7A的一些工作拷贝组合来更完整地治疗这种疾病。这种需求是基于超过130名单独用CuHis治疗的人类受试者的存活和神经发育结果的混合结果，以及最近的临床前研究，这些研究记录了CuHis和AAV 9密码子优化的、尺寸减小的ATP 7A在可靠的Menkes病小鼠模型中的协同作用。我们以前证明，CSF导向的AAV基因治疗与CSF或皮下铜联合使用时，可挽救23-53%的人门克斯病同源物突变小鼠（斑点状）。最近，基于Nationwide Children's的其他人对患有脊髓性肌萎缩症的小鼠和人进行全身性AAV 9治疗的经验，我们评估了AAV 9-corsATP 7A的静脉内（面部静脉）施用与CuHis的皮下施用的组合。使用2.6x 1013 vg/kg体重的AAV 9剂量，该方案导致95%的斑驳斑纹突变小鼠（20只中的19只）的长期拯救。我们正在寻求创新的URGenT网络在非常合适的时间对门克斯病的支持。病毒基因治疗和新生儿筛查技术的进步使人们有可能设想改变这种罕见的致命儿科疾病的自然史，原因有几个。首先，我们预计FDA将在明年批准第一种（小分子）治疗Menkes病的药物CuHis。第二，结合系统性AAV基因治疗以提供缺失的铜转运蛋白的一些工作拷贝，预期神经学和其他表现的甚至更完全的校正。第三，我们有原则证明，通过有针对性的下一代测序或全基因组测序进行新生儿筛查（NBS）是可行的，并将在明年开展基于人群的NBS试点研究。

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.