Highlights From the ASGCT 2026 Annual Meeting
Improved hFIX and hFVIII expression with ITR-modified AAV vectors in hemophilic mice
Presenting Author: Radek Kaczmarek, PhD
Radoslaw Kaczmarek1, Jakob Shoti2, Keyun Qing2, Roland Herzog1, Arun Srivastava2
1 Indiana University School of Medicine, Pediatrics, Indianapolis, United States; 2 University of Florida College of Medicine, Pediatrics, Gainesville, United States
At ASGCT 2026, a preclinical study evaluated a novel AAV vector design in which the native inverted terminal repeat (ITR) sequence was modified to incorporate a glucocorticoid receptor-binding element (GRE). This modification was designed to enhance transgene expression and improve vector efficiency for hemophilia gene therapy. In mouse models of hemophilia A and B, vectors containing the GRE-modified ITR achieved up to 3-fold higher FVIII activity and approximately 2-fold higher FIX-Padua expression compared with vectors containing wild-type ITRs over 8 weeks of follow-up. In hemophilia A mice, FVIII activity reached normal to near-normal levels with the GRE-ITR vector. These findings suggest that modifying the ITR sequence may improve vector potency and transgene expression, potentially supporting effective factor expression at lower vector doses and representing a promising strategy to optimize future hemophilia gene therapies.
Figure Legend: hFVIII expression mediated by ssAAV8 vectors either with (green) or without (black) a GRE site inserted in the 5'-ITR upstream of the TTR promoter
