Intravenous AAV9- plus subcutaneous copper histidinate optimizes outcomes in a lethal Menkes disease mouse model.

Menkes disease is an X-linked recessive condition characterized by seizures, failure to thrive, and rapid, progressive neurodegeneration beginning within weeks after birth. Death usually occurs by 3 years of age. The disorder is caused by genetic variants in , an evolutionarily conserved copper transporter that is crucial for normal brain development. The mouse recapitulates salient features of the human illness. Affected male mice typically die by 14 postnatal days. We evaluated a single-dose intravenous adeno-associated virus gene therapy approach to deliver working copies of a codon-optimized version of ATP7A to male mice. In conjunction with subcutaneous injections of clinical-grade copper histidinate in the first month of life, 95% long-term survival was attained, which was correlated with improvements in serum and brain copper levels, brain neurochemical profiles, somatic growth, and neuromotor function. The notable results support a trial of this treatment combination in affected male newborns with Menkes disease.