Gene Editing for Duchenne Muscular Dystrophy: From Base Editing to Prime Editing in a Humanized Mouse Model
Speaker: Dr. Zhenya Ivakine
Duchenne muscular dystrophy (DMD) is a severe pediatric neuromuscular disorder caused by loss-of-function variants in the DMD gene. Unlike gene replacement strategies (e.g., micro-dystrophin AAV), gene editing technologies aim to permanently correct the underlying pathogenic variant at the DNA level. This presentation will introduce the key distinctions between gene replacement and gene editing approaches, including base editing and prime editing, and their respective translational considerations. Using a patient-specific nonsense variant (DMD c.9445C>T; p.Q3149X) as a model, we will present the development of a single AAV-compatible adenine base editor (ABE) optimized for myotropic delivery. In a novel fully-humanized D2.mdx-hDMD^Q3149X mouse model, a single low-dose systemic administration of MyoAAV4A-CK8e-ABE achieved ~85% dystrophin rescue in the heart and 20–40% across skeletal muscles, with significant improvements in cardiac function, grip strength, and muscle histopathology. Parallel optimization of a compact prime editor achieved comparable correction ex vivo, with proof-of-concept in vivo rescue in neonatal mice. This work establishes a versatile, clinically translatable gene editing platform for DMD and illustrates broader principles applicable to monogenic disorders.
At the end of the session, participants will be able to:
- Distinguish between gene replacement and gene editing therapeutic strategies.
- Describe how adenine base editing and prime editing can be applied to correct pathogenic point variants in inherited metabolic and neuromuscular disorders.
Target audience: Clinical Geneticists, Laboratory Geneticists, Genetic Counsellors, Trainees, Molecular Pathologists
CanMeds Roles: Medical Expert (the integrating role), Scholar
Dr. Evgueni (Zhenya) Ivakine is a scientist in the Genetics and Genome Biology Program at the Hospital for Sick Children and an Associate Professor at the Department of Molecular Genetics (University of Toronto). An overarching focus of his laboratory is development of clinically relevant, broadly translatable treatment strategies for individuals with devastating genetic disorders,
such as Niemann-Pick type C (NPC), Tay Sachs Disease, and Duchenne Muscular Dystrophy (DMD). He expertise lies in gene editing, genome engineering, and disease modelling in both cellular and animal models.
Speaker: Dr. Yannick Doyon
Yannick Doyon has been developing genome editing technologies for over 18 years. First in the biotechnology sector (Sangamo Therapeutics, California, USA; 2006-2013), then as a Professor at Université Laval (2013-now). He played a central role in developing the first proof-of-concepts for in vivo genome editing. His long-term objective is to develop and test if liver based enzyme replacement processes based on CRISPR-driven targeted integration of therapeutic transgenes and mutation specific correction can cure or ameliorate the symptoms associated with rare and severe monogenic diseases affecting children. More specifically, he couples systemic gene delivery using AAV to CRISPR-driven genome editing in neonatal mice modeling defects in amino acid catabolism, such as Hereditary tyrosinemia type 1 (HT1) and Glutaric acidemia I (GA1) and lysosomal storage disorders.
Event Timeslots (1)
Day 2
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Speakers: Dr. Yannick Doyon and Dr. Zhenya Ivakine
