Nathwani, AC, Gray, JT, McIntosh, J, Ng, CY, Zhou, J, Spence, Y et al.. Safe and efficient transduction of the liver after peripheral vein infusion of self-complementary AAV vector results in stable therapeutic expression of human FIX in nonhuman primates. Blood 109: 1414-1421

Department of Surgery, St. Jude Children's Research Hospital, Memphis, Tennessee, United States
Blood (Impact Factor: 10.43). 03/2007; 109(4):1414-21. DOI: 10.1182/blood-2006-03-010181
Source: PubMed

ABSTRACT The safety and efficacy of peripheral venous administration of a self-complementary adeno-associated viral vector encoding the human FIX gene (scAAV-LP1-hFIXco) was evaluated in nonhuman primates for gene therapy of hemophilia B. Peripheral vein infusion of 1x10(12) vg/kg scAAV-LP1-hFIXco pseudotyped with serotype 8 capsid, in 3 macaques, resulted in stable therapeutic expression (more than 9 months) of human FIX (hFIX) at levels (1.1+/-0.5 microg/mL, or 22% of normal) that were comparable to those achieved after direct delivery of the same vector dose into the portal circulation (1.3+/-0.3 microg/mL, or 26% of normal). Importantly, the pattern of vector biodistribution after systemic and portal vein administration of scAAV-LP1-hFIXco was almost identical. Additionally, comparable levels of gene transfer were achieved in macaques with preexisting immunity to AAV8 following peripheral vein administration of 1x10(12) vg/kg AAV5-pseudotyped scAAV-LP1-hFIXco. This confirms that alternative serotypes can circumvent preexisting naturally acquired immunity to AAV. Thus, peripheral venous administration of AAV5 and AAV8 vectors is safe and as effective at transducing the liver in nonhuman primates as direct vector administration into the portal circulation. These results should make vector administration to patients, especially those with a severe bleeding diathesis, significantly easier and safer.

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Available from: Edward Tuddenham, Aug 20, 2015
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    • "Furthermore, studies in DO11.10 mice transgenic for the ovalbumin (OVA) T cell receptor, showed that hepatic gene transfer of an AAV-OVA vector induces antigen-specific CD4 + CD25 + regulatory T cells [Cao et al., 2007; Dobrzynski et al., 2004]. Similar results have been confirmed by several labs using a variety of transgenes, delivery vectors, and animal models [Nathwani et al., 2007; Wang et al., 2005]. Finally, beyond hemophilia, the "
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    ABSTRACT: Findings in the first clinical trial in which an adeno-associated virus (AAV) vector was introduced into the liver of human subjects highlighted an issue not previously identified in animal studies. Upon AAV gene transfer to liver, two subjects developed transient elevation of liver enzymes, likely as a consequence of immune rejection of transduced hepatocytes mediated by AAV capsid-specific CD8(+) T cells. Studies in healthy donors showed that humans carry a population of antigen-specific memory CD8(+) T cells probably arising from wild-type AAV infections. The hypothesis formulated at that time was that these cells expanded upon re-exposure to capsid, i.e. upon AAV-2 hepatic gene transfer, and cleared AAV epitope-bearing transduced hepatocytes. Other hypotheses have been formulated which include specific receptor-binding properties of AAV-2 capsid, presence of capsid-expressing DNA in AAV vector preparations, and expression of alternate open reading frames from the transgene; emerging data from clinical trials however fail to support these competing hypotheses. Possible solutions to the problem are discussed, including the administration of a short-term immunosuppression regimen concomitant with gene transfer, or the development of more efficient vectors that can be administered at lower doses. While more studies will be necessary to define mechanisms and risks associated with capsid-specific immune responses in humans, monitoring of these responses in clinical trials will be essential to achieving the goal of long-term therapeutic gene transfer in humans.
    Current Gene Therapy 08/2011; 11(4):321-30. DOI:10.2174/156652307782151425 · 4.91 Impact Factor
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    • "Natural infections with AAVs establish a broad scope of neutralizing responses in both human and nonhuman primates. Others have attempted to simulate host antibody responses to natural infections by immunizing animals with AAV capsid (Nathwani et al., 2007). However, the breadth of the humoral response seen in primates after natural infections contrasts with the narrow serotype-specific response elicited in nonprimate animal models after exposure to AAV vectors (Brantly et al., 2009). "
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    • "This result is of critical importance as we have shown that serotype-specific neutralizing antibodies preclude successful hepatocyte transduction (Davidoff et al., 2005; Hurlbut et al., 2010). Clearance of AAV8 from the systemic circulation in macaques was also significantly quicker than with other serotypes (Nathwani et al., 2007), and AAV8 was shown to have reduced heparin binding, which reduced cytotoxic capsid-specific T cell activation (Vandenberghe et al., 2006). Last, AAV8 vectors have distinct biological properties that enable them to uncoat and release their genome more rapidly than other AAV serotypes (Thomas et al., 2004). "
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