Sustained enzymatic correction by rAAV-mediated liver gene therapy protects against induced motor neuropathy in acute porphyria mice.
Acute intermittent porphyria (AIP) is characterized by a hereditary deficiency of hepatic porphobilinogen deaminase (PBGD) activity. Clinical features are acute neurovisceral attacks accompanied by overproduction of porphyrin precursors in the liver. Recurrent life-threatening attacks can be cured only by liver transplantation. We developed recombinant adeno-associated virus (rAAV) vectors expressing human PBGD protein driven by a liver-specific promoter to provide sustained protection against induced attacks in a predictive model for AIP. Phenobarbital injections in AIP mice induced porphyrin precursor accumulation, functional block of nerve conduction, and progressive loss of large-caliber axons in the sciatic nerve. Hepatocyte transduction showed no gender variation after rAAV2/8 injection, while rAAV2/5 showed lower transduction efficiency in females than males. Full protection against induced phenobarbital-attacks was achieved in animals showing over 10% of hepatocytes expressing high amounts of PBGD. More importantly, sustained hepatic expression of hPBGD protected against loss of large-caliber axons in the sciatic nerve and disturbances in nerve conduction velocity as induced by recurrent phenobarbital administrations. These data show for the first time that porphyrin precursors generated in the liver interfere with motor function. rAAV2/5-hPBGD vector can be produced in sufficient quantity for an intended gene therapy trial in patients with recurrent life-threatening porphyria attacks.
Unzu
Carmen
C
Gene Therapy and Hepatology Area, Centre for Applied Medical Research, University of Navarra, Pamplona, Spain.
Sampedro
Ana
A
Mauleón
Itsaso
I
Alegre
Manuel
M
Beattie
Stuart G
SG
de Salamanca
Rafael Enríquez
RE
Snapper
Jolanda
J
Twisk
Jaap
J
Petry
Harald
H
González-Aseguinolaza
Gloria
G
Artieda
Julio
J
Rodríguez-Pena
María Sol
MS
Prieto
Jesús
J
Fontanellas
Antonio
A
D000818:Animals; D000229:Dependovirus / Q000235:genetics*; D005260:Female; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000235:genetics*; D006801:Humans; D011163:Hydroxymethylbilane Synthase / Q000235:genetics; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D010634:Phenobarbital / Q000633:toxicity; D017094:Porphyrias, Hepatic / Q000201:enzymology / Q000503:physiopathology / Q000628:therapy*; D020426:Sciatic Neuropathy / Q000139:chemically induced / Q000628:therapy*
D011163:Hydroxymethylbilane Synthase; D010634:Phenobarbital