Manno, CS, Pierce, GF, Arruda, VR, Glader, B, Ragni, M, Rasko, JJ et al.. Successful transduction of liver in hemophilia by AAV-Factor IX and limitations imposed by the host immune response. Nat Med 12: 342-347

The Children's Hospital of Philadelphia, 3615 Civic Center Boulevard, Philadelphia, Pennsylvania, 19104, USA.
Nature Medicine (Impact Factor: 27.36). 04/2006; 12(3):342-7. DOI: 10.1038/nm1358
Source: PubMed


We have previously shown that a single portal vein infusion of a recombinant adeno-associated viral vector (rAAV) expressing canine Factor IX (F.IX) resulted in long-term expression of therapeutic levels of F.IX in dogs with severe hemophilia B. We carried out a phase 1/2 dose-escalation clinical study to extend this approach to humans with severe hemophilia B. rAAV-2 vector expressing human F.IX was infused through the hepatic artery into seven subjects. The data show that: (i) vector infusion at doses up to 2 x 10(12) vg/kg was not associated with acute or long-lasting toxicity; (ii) therapeutic levels of F.IX were achieved at the highest dose tested; (iii) duration of expression at therapeutic levels was limited to a period of approximately 8 weeks; (iv) a gradual decline in F.IX was accompanied by a transient asymptomatic elevation of liver transaminases that resolved without treatment. Further studies suggested that destruction of transduced hepatocytes by cell-mediated immunity targeting antigens of the AAV capsid caused both the decline in F.IX and the transient transaminitis. We conclude that rAAV-2 vectors can transduce human hepatocytes in vivo to result in therapeutically relevant levels of F.IX, but that future studies in humans may require immunomodulation to achieve long-term expression.

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    • "A human codon-optimized acid a-glucosidase cDNA (coGAA) (GeneArt; Life Technologies) was cloned into a desmin promoter construct (pTR-DES) previously described (Pacak et al., 2009; Falk et al., 2013). The liver-specific promoter (LSP) (GeneArt; Life Technologies) contains the apolipoprotein E-hepatocyte control region (Miao et al., 2000; Manno et al., 2006; Cao et al., 2007), the human a 1 -antitrypsin promoter (Cresawn et al., 2005), and 5¢ untranslated region (UTR) and was subcloned into pTR-DES-coGAA in lieu of the DES promoter (BglII and SalI). "
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