Sustained phenotypic correction of hemophilia B dogs with a factor IX null mutation by liver-directed gene therapy.
Hemophilia B is an X-linked coagulopathy caused by absence of functional coagulation factor IX (FIX). Using adeno-associated virus (AAV)-mediated, liver-directed gene therapy, we achieved long-term (> 17 months) substantial correction of canine hemophilia B in 3 of 4 animals, including 2 dogs with an FIX null mutation. This was accomplished with a comparatively low dose of 1 x 10(12) vector genomes/kg. Canine FIX (cFIX) levels rose to 5% to 12% of normal, high enough to result in nearly complete phenotypic correction of the disease. Activated clotting times and whole blood clotting times were normalized, activated partial thromboplastin times were substantially reduced, and anti-cFIX was not detected. The fourth animal, also a null mutation dog, showed transient expression (4 weeks), but subsequently developed neutralizing anti-cFIX (inhibitor). Previous work in the canine null mutation model has invariably resulted in inhibitor formation following treatment by either gene or protein replacement therapies. This study demonstrates that hepatic AAV gene transfer can result in sustained therapeutic expression in a large animal model characterized by increased risk of a neutralizing anti-FIX response.
Mount
Jane D
JD
Scott-Ritchey Research Center and Department of Clinical Sciences, College of Veterinary Sciences, Auburn University, AL, USA.
Herzog
Roland W
RW
Tillson
D Michael
DM
Goodman
Susan A
SA
Robinson
Nancy
N
McCleland
Mark L
ML
Bellinger
Dwight
D
Nichols
Timothy C
TC
Arruda
Valder R
VR
Lothrop
Clinton D
CD
High
Katherine A
KA
D000818:Animals; D000906:Antibodies / Q000097:blood; D004247:DNA / Q000032:analysis; D000229:Dependovirus / Q000235:genetics; D004285:Dogs; D016503:Drug Delivery Systems / Q000379:methods; D005164:Factor IX / Q000008:administration & dosage / Q000235:genetics* / Q000276:immunology; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000008:administration & dosage / Q000627:therapeutic use / Q000633:toxicity; D002836:Hemophilia B / Q000235:genetics* / Q000628:therapy*; D008099:Liver / Q000378:metabolism; D008297:Male; D009154:Mutation; D010641:Phenotype; D016896:Treatment Outcome
D000906:Antibodies; D005164:Factor IX; D004247:DNA