Sustained enzymatic correction by rAAV-mediated liver gene therapy protects against induced motor neuropathy in acute porphyria mice.

摘要: Acute intermittent porphyria (AIP) is characterized by a hereditary deficiency of hepatic porphobilinogen deaminase (PBGD) activity. Clinical features are acute neurovisceral attacks accompanied overproduction porphyrin precursors in the liver. Recurrent life-threatening can be cured only liver transplantation. We developed recombinant adeno-associated virus (rAAV) vectors expressing human PBGD protein driven liver-specific promoter to provide sustained protection against induced predictive model for AIP. Phenobarbital injections AIP mice precursor accumulation, functional block nerve conduction, and progressive loss large-caliber axons sciatic nerve. Hepatocyte transduction showed no gender variation after rAAV2/8 injection, while rAAV2/5 lower efficiency females than males. Full phenobarbital-attacks was achieved animals showing over 10% hepatocytes high amounts PBGD. More importantly, expression hPBGD protected disturbances conduction velocity as recurrent phenobarbital administrations. These data show first time that generated interfere with motor function. rAAV2/5-hPBGD vector produced sufficient quantity an intended gene therapy trial patients attacks.