CRISPR prime editing as a promising therapeutic avenue for Menkes disease: the next step in correcting ATP7A mutations.

Menkes disease is a life-threatening X-linked disease caused by mutations in ATP7A, an ATPase that mediates copper transport and is vital for copper homeostasis in the nervous system and the whole body. Existing therapies, such as copper histidinate injections, have limited neurological effects because of inefficient brain copper uptake. CRISPR prime editing (PE) provides a very powerful alternative since it can accurately correct single-base substitutions or small errors efficiently without inducing double-strand breaks. Compared to conventional gene therapy, PE also overcomes vector size restrictions and reduces off-target concerns. In this letter, we will discuss ATP7A variants that may be prime-editable and suggest an ex vivo approach for correction in induced pluripotent stem cells generated from Menkes patients with validation of function to follow. There is currently no literature that demonstrates PE for Menkes disease to the best of our knowledge and therefore represents a unique approach for a novel gene-level intervention for this fatal disease.