Department of Gene Therapy and Regenerative Medicine, Vrije Universiteit Brussel, Brussels, Belgium.
Catalyst Biosciences, South San Francisco, CA; and.
Blood. 2021 May 27;137(21):2902-2906. doi: 10.1182/blood.2020006005.
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.
腺相关病毒（AAV）载体基因治疗已能使乙型血友病患者实现治疗性因子 IX（FIX）水平的持续表达。然而，患者仍存在载体剂量限制毒性的风险，尤其是肝脏炎症，这证明需要更有效的载体和更低的给药方案。一种新型高活性 FIX（命名为 CB 2679d-GT），含有 3 个氨基酸取代（R318Y、R338E、T343R），在基因治疗后显著优于 R338L-Padua 变异体。与 AAV 载体基因治疗的 R338L-Padua 相比，CB 2679d-GT 在血友病小鼠中的凝血活性提高了约三倍，具有统计学意义。此外，与接受 R338L-Padua 治疗的小鼠相比，CB 2679d-GT 基因治疗显著减少了出血时间（约五倍至八倍）和总失血量（约四倍），从而实现了更快、更强的止血纠正。CB 2679d-GT 和 R338L-Padua 均可维持至少 20 周的 FIX 表达，而免疫原性没有显著增加。这是一项新型基因治疗研究，证明了 CB 2679d-GT 的优越性，突出了其在乙型血友病患者 AAV 靶向基因治疗后获得更高 FIX 活性水平和更优止血效果的潜力，优于目前 R338L-Padua 变异体所能达到的水平。
