Gene therapy for hemophilia B using CB 2679d-GT: a novel factor IX variant with higher potency than factor IX Padua.

Abstract

Sustained expression of therapeutic factor IX (FIX) levels has been achieved after adeno-associated viral (AAV) vector-based gene therapy in patients with hemophilia B. Nevertheless, patients are still at risk of vector dose-limiting toxicity, particularly liver inflammation, justifying the need for more efficient vectors and a lower dosing regimen. A novel increased potency FIX (designated as CB 2679d-GT), containing 3 amino acid substitutions (R318Y, R338E, T343R), significantly outperformed the R338L-Padua variant after gene therapy. CB 2679d-GT demonstrated a statistically significant approximately threefold improvement in clotting activity when compared with R338L-Padua after AAV-based gene therapy in hemophilic mice. Moreover, CB 2679d-GT gene therapy showed significantly reduced bleeding time (approximately fivefold to eightfold) and total blood loss volume (approximately fourfold) compared with mice treated with the R338L-Padua, thus achieving more rapid and robust hemostatic correction. FIX expression was sustained for at least 20 weeks with both CB 2679d-GT and R338L-Padua whereas immunogenicity was not significantly increased. This is a novel gene therapy study demonstrating the superiority of CB 2679d-GT, highlighting its potential to obtain higher FIX activity levels and superior hemostatic efficacy following AAV-directed gene therapy in hemophilia B patients than what is currently achievable with the R338L-Padua variant.

• Authors: Nisha Nair, Dries De Wolf, Phuong Anh Nguyen, Quang Hong Pham, Ermira Samara-Kuko, Jeff Landau, Grant E Blouse, Marinee K Chuah, Thierry VandenDriessche
• Journal: Blood (Blood) Vol. 137 Issue 21 Pg. 2902-2906 (05 27 2021) ISSN: 1528-0020 [Electronic] United States
• PMID: 33735915 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2021 by The American Society of Hematology.

Chemical References

• Recombinant Proteins
• factor IX-Padua
• Factor IX

Topics

• Amino Acid Substitution
• Animals
• Bleeding Time
• Dependovirus (genetics)
• Drug Evaluation, Preclinical
• Factor IX (chemistry, genetics, therapeutic use)
• Gain of Function Mutation
• Gene Dosage
• Genetic Therapy
• Genetic Vectors (therapeutic use)
• Hemophilia B (therapy)
• Humans
• Liver (metabolism)
• Mice
• Mice, Inbred C57BL
• Recombinant Proteins (therapeutic use)