Nathwani, AC, Gray, JT, McIntosh, J, Ng, CYC, Zhou, J, Spence, S 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: 10.45). 03/2007; 109(4):1414-21. DOI: 10.1182/blood-2006-03-010181
Source: PubMed


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 G Tuddenham
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    • "This and the very effective liver transduction by AAV 8 and 5 in non-human primates, indicates that of these two serotypes seem preferable candidates for in vivo gene therapy in CN patients. In addition, the availability of several suitable vectors does allow switching to another serotype for treating patients with pre-existing NAb towards one of these serotypes [12]. Furthermore, due to the episomal persistence of AAV vectors the correction may diminish in time. "
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    ABSTRACT: Preclinical studies in mice and non-human primates showed that AAV serotype 5 provides efficient liver transduction and as such seems a promising vector for liver directed gene therapy. An advantage of AAV5 compared to serotype 8 already shown to provide efficient correction in a phase 1 trial in patients suffering from hemophilia B, is its lower seroprevalence in the general population. Our goal is liver directed gene therapy for Crigler-Najjar syndrome type I, inherited severe unconjugated hyperbilirubinemia caused by UGT1A1 deficiency. In a relevant animal model, the Gunn rat, we compared the efficacy of AAV 5 and 8 to that of AAV1 previously shown to be effective. Ferrying a construct driving hepatocyte specific expression of UGT1A1, both AAV8 and AAV1 provided an efficient correction of hyperbilirubinemia. In contrast to these two and to other animal models AAV5 failed to provide any correction. To clarify whether this unexpected finding was due to the rat model used or due to a problem with AAV5, the efficacy of this serotype was compared in a mouse and two additional rat strains. Administration of an AAV5 vector expressing luciferase under the control of a liver specific promoter confirmed that this serotype poorly performed in rat liver, rendering it not suitable for proof of concept studies in this species.
    Full-text · Article · Dec 2013 · PLoS ONE
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    • "In 2010, a third AAV-FIX trial in humans was initiated by St Jude Children’s Research Hospital and University College London, and capitalized on previous research by introducing several novel features which made a key difference in the overall efficacy. The vector was encapsulated using an alternate AAV serotype (AAV8) which less frequently causes natural infection in humans,46 less efficiently transduces professional antigen-presenting cells (leading to reduce CTL responses to capsid in animal models),47 and has increased liver tropism, which enabled peripheral vein infusion of the vector.48 Patients exhibiting detectable neutralizing antibody titer were excluded. "
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    ABSTRACT: Hemophilia B is a genetic disorder that is characterized by a deficiency of clotting factor IX (FIX) and excessive bleeding. Advanced understanding of the pathophysiology of the disease has led to the development of improved treatment strategies that aim to minimize the acute and long-term complications of the disease. Patients with hemophilia B are ideal candidates for gene therapy, mostly because a small increase in protein production can lead to significantly decreased bleeding diathesis. Although human clotting FIX was cloned and sequenced over 30 years ago, progress toward achieving real success in human clinical trials has been slow, with long-term, therapeutically relevant gene expression only achieved in one trial published in 2011. The history of this extensive research effort has revealed the importance of the interactions between gene therapy vectors and multiple arms of the host immune system at multiple stages of the transduction process. Different viral vector systems each have unique properties that influence their ability to deliver genes to different tissues, and the data generated in several clinical trials testing different vectors for hemophilia have guided our understanding toward development of optimal configurations for treating hemophilia B. The recent clinical success implementing a novel adeno-associated virus vector demonstrated sufficient FIX expression in patients to convert a severe hemophilia phenotype to mild, an achievement which has the potential to profoundly alter the impact of this disease on human society. Continued research should lead to vector designs that result in higher FIX activity at lower vector doses and with reduced host immune responses to the vector and the transgene product.
    Full-text · Article · Oct 2013 · The Application of Clinical Genetics
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    • "AAV1 has been reported to efficiently transduce muscle2425, while AAV5 is efficient in transducing lungs and muscle tissue2627. Both AAV1 and AAV5 are also known to be efficient in liver directed gene transfer in pre-clinical models102328 and have low cross-reactivity with AAV2 neutralizing antibodies242729. Indeed, pseudotyped AAV1 and AAV5 vectors are already in Phase I/II clinical trials for treating alpha-1 antitrypsin deficiency ( "
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    ABSTRACT: Despite significant advancements with recombinant AAV2 or AAV8 vectors for liver directed gene therapy in humans, it is well-recognized that host and vector-related immune challenges need to be overcome for long-term gene transfer. To overcome these limitations, alternate AAV serotypes (1-10) are being rigorously evaluated. AAV5 is the most divergent (55% similarity vs. other serotypes) and like AAV1 vector is known to transduce liver efficiently. AAV1 and AAV5 vectors are also immunologically distinct by virtue of their low seroprevalence and minimal cross reactivity against pre-existing AAV2 neutralizing antibodies. Here, we demonstrate that targeted bio-engineering of these vectors, augment their gene expression in murine hepatocytes in vivo (up to 16-fold). These studies demonstrate the feasibility of the use of these novel AAV1 and AAV5 vectors for potential gene therapy of diseases like hemophilia.
    Full-text · Article · May 2013 · Scientific Reports
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