TitleCoagulation factor IX gene transfer to non-human primates using engineered AAV3 capsid and hepatic optimized expression cassette.
Publication TypeJournal Article
Year of Publication2021
AuthorsKumar SRP, Xie J, Hu S, Ko J, Huang Q, Brown HC, Srivastava A, Markusic DM, Doering CB, H Spencer T, Srivastava A, Gao G, Herzog RW
JournalMol Ther Methods Clin Dev
Date Published2021 Dec 10

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 × 10 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.

Alternate JournalMol Ther Methods Clin Dev
PubMed ID34631930
PubMed Central IDPMC8476648
Grant ListR01 AI051390 / AI / NIAID NIH HHS / United States
R01 GM119186 / GM / NIGMS NIH HHS / United States
R01 HL097088 / HL / NHLBI NIH HHS / United States
P01 HL131471 / HL / NHLBI NIH HHS / United States
U19 AI149646 / AI / NIAID NIH HHS / United States
R01 NS076991 / NS / NINDS NIH HHS / United States
R01 HL131093 / HL / NHLBI NIH HHS / United States
UG3 HL147367 / HL / NHLBI NIH HHS / United States