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

Molecular Therapy: Methods & Clinical Development

Guangping Gao¹  Alok Srivastava²  H. Trent Spencer³  Christopher B. Doering³  Sandeep R.P. Kumar⁴  David M. Markusic⁴  Arun Srivastava⁵  Harrison C. Brown⁶  Roland W. Herzog⁷  Jun Xie⁷  Qifeng Huang⁷  Shilang Hu⁷  Jihye Ko⁷ 

[1] Corresponding author: Arun Srivastava, PhD, Division of Cellular and Molecular Therapy, Departments of Pediatrics and Molecular Genetics and Microbiology, Powell Gene Therapy Center, University of Florida College of Medicine, Gainesville, FL 32611, USA.;Department of Haematology, Christian Medical College and Centre for Stem Cell Research (a Unit of inStem, Bengaluru), Vellore, Tamil Nadu, India;Department of Pediatrics, Aflac Cancer and Blood Disorders Center, Emory University School of Medicine, Atlanta, GA, USA;Department of Pediatrics, Herman B Wells Center for Pediatric Research, Indiana University, Indianapolis, IN, USA;Division of Cellular and Molecular Therapy, Departments of Pediatrics and Molecular Genetics and Microbiology, Powell Gene Therapy Center, University of Florida College of Medicine, Gainesville, FL, USA;Expression Therapeutics, Tucker, GA, USA;Horae Gene Therapy Center, Department of Microbiology and Physiological Systems, University of Massachusetts Medical School, Worcester, MA, USA;

关键词: adeno-associated virus;    AAV;    hemophilia;    factor IX;    liver;    non-human primate;   

DOI  :  

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown