Viral Gene Therapy for Menkes Disease

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.