Development of a Clinical Candidate AAV3 Vector for Gene Therapy of Hemophilia B
Highlights from the ASGCT 23rd Annual Meeting

Development of a Clinical Candidate AAV3 Vector for Gene Therapy of Hemophilia B

Harrison Brown1, Christopher B. Doering1, Roland W. Herzog2, Chen Ling3, David M. Markusic2, H. Trent Spencer1, Alok Srivastava4, Arun Srivastava5

1Pediatrics, Emory University, Atlanta, GA

2Pediatrics, Indiana University of School of Medicine, Indianapolis, IN

3Genetic Engineering, Fudan University, Shanghai, China

4Hematology, Christian Medical College, Vellore, India

5Pediatrics, University of Florida, Gainesville, FL

Key Data Points

Comparison of the structures of FIX expression cassettes used in the first successful clinical trial for hemophilia B (scAAV8-LP1-FIX-WT-CO, red), and the one used in the current studies (scAAV3-HSh-TTR-Padua-FIX-LCO, blue). Optimization of the promoter from LP1 to HSh-TTR lead to a 2-3 fold increase in expression and codon optimization to the Padua variant produced a 3-3-8 fold increase in expression, leading to an overall increase in expression of 40-50 fold.

Results from patients with or without consecutive DFPP cycles using bright luciferase transduction inhibition assay (BL-TIA). Consecutive cycles were more effective than non-consecutive cycles in reducing Nab titres. Regression analysis predicted that 5 cycles would reduce the starting AAVS3 NAb titre by 94%, which would enable treatment of 60% of patients.



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Supported by educational grants from Bayer, BioMarin, CSL Behring, Freeline Therapeutics Limited, Pfizer Inc., Spark Therapeutics, and uniQure, Inc.

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