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

In vivo genome editing for inborn errors of metabolism
Speaker: Dr. Yannick Doyon

The liver is a highly desirable target for the development of gene transfer approaches (e.g. AAV) but treatment of infants faces a major challenge because the corrective gene is lost during liver growth resulting in the rapid extinction of the therapeutic effect. This problem could be circumvented by driving the site-specific integration of therapeutic transgenes using CRISPR-Cas9 systems to create a permanent somatic genetic correction of liver cells. In mouse models of Mucopolysaccharidosis type I (MPS1; OMIM 607014) and Glycogen storage disease II (GSD2 aka Pompe), we show that creating therapeutic fusion proteins by targeting the transferrin gene locus enhances secretion and tissue bioavailability of lysosomal enzymes. In addition, defects in amino acid catabolism [Hereditary tyrosinemia type 1 (HT1; OMIM 27670) and Glutaric acidemia I (GA1; OMIM 231670)] can be rescued by targeting the 5’UTR of the albumin gene. Our long-term objective is to develop a liver-based enzyme replacement process to treat rare metabolic diseases affecting children.

At the end of the session, participants will be able to:

• describe how genome editing can be used to correct genetic mutations in vivo

Target audience: Trainees
CanMeds Roles: Scholar