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Long-term correction of inhibitor-prone hemophilia B dogs treated with liver-directed AAV2-mediated factor IX gene therapy

Scott-Ritchey Research Center, College of Veterinary Medicine, Auburn University, AL, USA.
Blood (Impact Factor: 10.43). 11/2008; 113(4):797-806. DOI: 10.1182/blood-2008-10-181479
Source: PubMed

ABSTRACT Preclinical studies and initial clinical trials have documented the feasibility of adenoassociated virus (AAV)-mediated gene therapy for hemophilia B. In an 8-year study, inhibitor-prone hemophilia B dogs (n = 2) treated with liver-directed AAV2 factor IX (FIX) gene therapy did not have a single bleed requiring FIX replacement, whereas dogs undergoing muscle-directed gene therapy (n = 3) had a bleed frequency similar to untreated FIX-deficient dogs. Coagulation tests (whole blood clotting time [WBCT], activated clotting time [ACT], and activated partial thromboplastin time [aPTT]) have remained at the upper limits of the normal ranges in the 2 dogs that received liver-directed gene therapy. The FIX activity has remained stable between 4% and 10% in both liver-treated dogs, but is undetectable in the dogs undergoing muscle-directed gene transfer. Integration site analysis by linear amplification-mediated polymerase chain reaction (LAM-PCR) suggested the vector sequences have persisted predominantly in extrachromosomal form. Complete blood count (CBC), serum chemistries, bile acid profile, hepatic magnetic resonance imaging (MRI) and computed tomography (CT) scans, and liver biopsy were normal with no evidence for tumor formation. AAV-mediated liver-directed gene therapy corrected the hemophilia phenotype without toxicity or inhibitor development in the inhibitor-prone null mutation dogs for more than 8 years.

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    • "The fact that we are able to resume hFIX protein injections in tolerized animals without relapse of inhibitors or allergic reactions has additional implications for human treatment, as supplementary protein therapy may be required on occasion even in patients with mild disease. Although a number of studies have now shown that liver‐ directed transgene expression from an AAV vector results in transgene tolerance, until now few data had been available on gene transfer with pre‐existing immunity against the transgene product (Cao et al, 2007; LoDuca et al, 2009; Mingozzi et al, 2003; Niemeyer et al, 2009). A recently published study showed inhibitor reversal following AAV liver gene transfer of canine F.VIII to haemophilia A dogs with low‐titre inhibitors (Finn et al, 2010). "
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