Sustained expression of therapeutic level of factor IX in hemophilia B dogs by AAV-mediated gene therapy in liver.
We demonstrate that a single intraportal vein injection of a recombinant adeno-associated virus (rAAV) vector encoding canine factor IX (cFIX) cDNA under the control of a liver-specific enhancer/promoter leads to a long-term correction of the bleeding disorder in hemophilia B dogs. Stable expression of the therapeutic level of cFIX (5% of normal level) was detected in the plasma of a dog injected with an AAV vector at a dose of 4.6 x 10(12) particles/kg for over 7 months. Both whole-blood clotting time (WBCT) and activated partial thromboplastin time (aPTT) of the treated dogs have been greatly decreased since the treatment. No anti-canine factor IX antibodies have been detected in the treated animals. Importantly, no bleeding has been observed in the dog that expresses a therapeutic level of cFIX for 7 months following vector administration. Moreover, no persistent significant hepatic enzyme abnormalities were detected in the treated dogs. Thus, a single intraportal injection of a rAAV vector expressing cFIX successfully corrected the bleeding disorder of hemophilia B dogs, supporting the feasibility of using AAV-based vectors for liver-targeted gene therapy of genetic diseases.
Laboratory of Genetics, The Salk Institute, La Jolla, California 92037, USA.
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L
Wang
T C
TC
Nichols
M S
MS
Read
D A
DA
Bellinger
I M
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Verma
D000410:Alanine Transaminase / Q000097:blood; D000469:Alkaline Phosphatase / Q000097:blood; D000818:Animals; D001219:Aspartate Aminotransferases / Q000097:blood; D001663:Bilirubin / Q000097:blood; D018076:DNA, Complementary / Q000378:metabolism; D000229:Dependovirus / Q000235:genetics*; D004285:Dogs; D004742:Enhancer Elements, Genetic; D005164:Factor IX / Q000096:biosynthesis* / Q000235:genetics*; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000235:genetics; D002836:Hemophilia B / Q000235:genetics / Q000628:therapy*; D008099:Liver / Q000378:metabolism*; D010314:Partial Thromboplastin Time; D011401:Promoter Regions, Genetic; D013997:Time Factors; D014914:Whole Blood Coagulation Time; D005723:gamma-Glutamyltransferase / Q000097:blood
D018076:DNA, Complementary; D005164:Factor IX; D005723:gamma-Glutamyltransferase; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase; D000469:Alkaline Phosphatase; D001663:Bilirubin