Long-term follow-up of liver-directed, adeno-associated vector-mediated gene therapy in the canine model of hemophilia A.

Questions remain concerning the long-term efficacy, safety, and site(s) of transgene expression following adeno-associated vector (AAV) therapy. We report a long-term follow-up of 8 (male = 4, hemizygous, and female = 4, homozygous) dogs with severe hemophilia A treated with a single portal vein infusion of a B-domain-deleted (BDD)-canine FVIII (cFVIII) AAV vector (median dose = 1.25 × 1013 vg/kg, AAV2 = 4, AAV6 = 3, and AAV8 = 1). After a median follow-up of 10.8 years (8.2-12.0 years), persistent FVIII:C (median one-stage = 12.7%, chromogenic = 7.2%) was seen in all responding dogs (n = 6), with improvement in annualized bleed rates (pre = 3.9 vs post = 0.3 event per year; P = .003). Anti-AAV capsid neutralizing antibodies (nAbs) toward the dosed capsid were detected throughout the study, with limited cross-reactivity to other capsids. nAb titers for all capsid serotypes declined with time, although they remained at levels precluding redosing with the same capsid. AAV-BDD-cFVIII DNA was detected in the liver of all dogs (median = 0.15 vg per diploid genome), with lower levels in the spleen in 4 dogs (median = 0.005 vg per diploid genome). Consistent with the liver-specific promoter, BDD-cFVIII mRNA was only detected in the liver. Postmortem examination demonstrated no evidence of chronic liver disease or liver malignancy. Persistent FVIII expression and an improved bleeding phenotype was seen for more than a decade after vector delivery. This is the longest follow-up reported in a preclinical model supporting long-term efficacy and safety of AAV-mediated gene therapy.

Batty P ，Mo AM ，Hurlbut D ，Ishida J ，Yates B ，Brown C ，Harpell L ，Hough C ，Pender A ，Rimmer EK ，Sardo Infirri S ，Winterborn A ，Fong S ，Lillicrap D ... -  《-》

Multiyear therapeutic benefit of AAV serotypes 2, 6, and 8 delivering factor VIII to hemophilia A mice and dogs.

Jiang H ，Lillicrap D ，Patarroyo-White S ，Liu T ，Qian X ，Scallan CD ，Powell S ，Keller T ，McMurray M ，Labelle A ，Nagy D ，Vargas JA ，Zhou S ，Couto LB ，Pierce GF ... -  《BLOOD》

Efficacy and safety of long-term prophylaxis in severe hemophilia A dogs following liver gene therapy using AAV vectors.

Sabatino DE ，Lange AM ，Altynova ES ，Sarkar R ，Zhou S ，Merricks EP ，Franck HG ，Nichols TC ，Arruda VR ，Kazazian HH Jr ... -  《-》

Phenotype correction of hemophilia A mice with adeno-associated virus vectors carrying the B domain-deleted canine factor VIII gene.

Ishiwata A ，Mimuro J ，Kashiwakura Y ，Niimura M ，Takano K ，Ohmori T ，Madoiwa S ，Mizukami H ，Okada T ，Naka H ，Yoshioka A ，Ozawa K ，Sakata Y ... -  《THROMBOSIS RESEARCH》

Liver-restricted expression of the canine factor VIII gene facilitates prevention of inhibitor formation in factor VIII-deficient mice.

Ishiwata A ，Mimuro J ，Mizukami H ，Kashiwakura Y ，Takano K ，Ohmori T ，Madoiwa S ，Ozawa K ，Sakata Y ... -  《-》