Wolfgang Miesbach on Insights from Guy Young’s ASH2025 Session on Next-Generation Gene Therapy
Wolfgang Miesbach, Professor of Medicine at Frankfurt University Hospital, shared on LinkedIn:
”The Immunogenicity Challenge in Next-Generation Gene Therapy Dr. Guy Young‘s ASH2025 session “Deconstructing Gene Therapy in Haemophilia” highlighted a critical tension: the ASC618 Phase 1/2 trial shows both patients of the first cohort dosed with 2e12 vg/kg developed high-titer inhibitors to the ET3 transgene.
What is ASC618?
ASC618 uses ET3—a bioengineered BDD-FVIII chimera incorporating porcine sequences (A1/A3 domains) designed to enhance secretion 10–100x over native human FVIII, enabling lower doses.
The Problem:
These porcine residues could have acted as potent neo-antigens, breaking tolerance even in previously naive patients.
Both are now on emicizumab.
Predictive immunogenicity modeling for non-native constructs needs strengthening before clinical translation.”
All from ASH25 featured in Hemostasis Today.
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