Details

Autor(en) / Beteiligte

• Kumar, Sandeep R.P.
• Xie, Jun
• Hu, Shilang
• Ko, Jihye
• Huang, Qifeng
• Brown, Harrison C.
• Srivastava, Alok
• Markusic, David M.
• Doering, Christopher B.
• Spencer, H. Trent
• Srivastava, Arun
• Gao, Guangping
• Herzog, Roland W.

Titel

Coagulation factor IX gene transfer to non-human primates using engineered AAV3 capsid and hepatic optimized expression cassette

Ist Teil von

• Molecular therapy. Methods & clinical development, 2021-12, Vol.23, p.98-107

Ort / Verlag

United States: Elsevier Inc

Erscheinungsjahr

2021

Link zum Volltext

Quelle

Free E-Journal (出版社公開部分のみ）

Beschreibungen/Notizen

• Hepatic gene transfer with adeno-associated viral (AAV) vectors shows much promise for the treatment of the X-linked bleeding disorder hemophilia B in multiple clinical trials. In an effort to further innovate this approach and to introduce alternative vector designs with potentially superior features into clinical development, we recently built a vector platform based on AAV serotype 3 because of its superior tropism for human hepatocytes. A vector genome with serotype-matched inverted terminal repeats expressing hyperactive human coagulation factor IX (FIX)-Padua was designed for clinical use that is optimized for translation using hepatocyte-specific codon-usage bias and is depleted of immune stimulatory CpG motifs. Here, this vector genome was packaged into AAV3 (T492V + S663V) capsid for hepatic gene transfer in non-human primates. FIX activity within or near the normal range was obtained at a low vector dose of 5 × 1011 vector genomes/kg. Pre-existing neutralizing antibodies, however, completely or partially blocked hepatic gene transfer at that dose. No CD8+ T cell response against capsid was observed. Antibodies against the human FIX transgene product formed at a 10-fold higher vector dose, albeit hepatic gene transfer was remarkably consistent, and sustained FIX activity in the normal range was nonetheless achieved in two of three animals for the 3-month duration of the study. These results support the use of this vector at low vector doses for gene therapy of hemophilia B in humans. [Display omitted] Hepatic AAV gene transfer shows much promise for the treatment of hemophilia. Here, a vector with AAV3 serotype-matched inverted terminal repeats expressing coagulation factor IX-Padua was designed using hepatocyte-specific codon bias and depletion of CpG motifs. FIX activity near the normal range was obtained at low vector dose in non-human primates.