Long-Term Follow-Up of the First in Human Intravascular Delivery of AAV for Gene Transfer: AAV2-hFIX16 for Severe Hemophilia B.
Full text not available from this repository.Item Type: | Article |
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Status: | Published |
Official URL: | https://doi.org/10.1016/j.ymthe.2020.06.001 |
Journal or Publication Title: | Molecular Therapy |
Volume: | 28 |
Number: | 9 |
Page Range: | pp. 2073-2082 |
Date: | 2020 |
Divisions: | Gene and Stem Cell Therapy |
Depositing User: | General Admin |
Identification Number: | 10.1016/j.ymthe.2020.06.001 |
ISSN: | 15250016 |
Date Deposited: | 04 Jan 2021 03:12 |
Abstract: | Adeno-associated virus (AAV) vectors are a leading platform for gene-based therapies for both monogenic and complex acquired disorders. The success of AAV gene transfer highlights the need to answer outstanding clinical questions of safety, durability, and the nature of the human immune response to AAV vectors. Here, we present longitudinal follow-up data of subjects who participated in the first trial of a systemically delivered AAV vector. Adult males (n = 7) with severe hemophilia B received an AAV2 vector at doses ranging from 8 × 1010 to 2 × 1012 vg/kg to target hepatocyte-specific expression of coagulation factor IX; a subset (n = 4) was followed for 12–15 years post-vector administration. No major safety concerns were observed. There was no evidence of sustained hepatic toxicity or development of hepatocellular carcinoma as assessed by liver transaminase values, serum -fetoprotein, and liver ultrasound. Subjects demonstrated persistent, increased AAV neutralizing antibodies (NAbs) to the infused AAV serotype 2 (AAV2) as well as all other AAV serotypes tested (AAV5 and AAV8) for the duration of follow-up. These data represent the longest available longitudinal follow-up data of subjects who received intravascular AAV and support the preliminary safety of intravascular AAV administration at the doses tested in adults. Data demonstrate, for the first time, the persistence of high-titer, multi-serotype cross-reactive AAV NAbs for up to 15 years post- AAV vector administration. Our observations are broadly applicable to the development of AAV-mediated gene therapy. |
Creators: | Creators Email George, Lindsey A. UNSPECIFIED Ragni, Margaret V. UNSPECIFIED Rasko, John E.J. UNSPECIFIED Raffini, Leslie J. UNSPECIFIED Samelson-Jones, Benjamin J. UNSPECIFIED Ozelo, Margareth UNSPECIFIED Hazbon, Maria UNSPECIFIED Runowski, Alexa R. UNSPECIFIED Wellman, Jennifer A. UNSPECIFIED Wachtel, Katie UNSPECIFIED Chen, Yifeng UNSPECIFIED Anguela, Xavier M. UNSPECIFIED Kuranda, Klaudia UNSPECIFIED Mingozzi, Federico UNSPECIFIED High, Katherine A. UNSPECIFIED |
Last Modified: | 04 Jan 2021 03:12 |
URI: | https://eprints.centenary.org.au/id/eprint/751 |
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