O.15 Engineering a Wnt7a-based protein therapeutic for the treatment of muscular dystrophy

Satellite stem cells represent the endogenous source of regenerative potential in adult muscle after injury and in the context of chronic degenerative diseases. Therefore, enhancing the ability of satellite cells to regenerate muscle tissue represents a promising approach to therapeutic intervention following muscle injury, irrespective of etiology. Recent evidence from the laboratory of Fate Therapeutics’ scientific founder Michael Rudnicki has demonstrated that treating rodent models of muscular dystrophy with WNT7a confers significant functional improvement in muscle force through a combination of satellite stem cell expansion and direct myofiber hypertrophic activity. Wnt proteins are developmental morphogens that drive embryogenesis, tissue repair and regeneration. Despite their potential as regenerative molecules, Wnt proteins have not been previously developed as therapeutics; primarily due to challenges in scaled protein manufacture and formulation. Building on the academic observations of WNT7a activity, we have used rational protein design and structural engineering to produce and select WNT7a analogs with preferred pharmaceutical, manufacturing and formulation properties. These WNT7a analogs induced significant myotube hypertrophy in cultures from murine myoblasts or myoblasts from patients with muscular dystrophy. The direct administration of the pharmaceutical candidate WNT7a proteins to the tibialis anterior (TA) muscle of either wild-type or dystrophic (MDX) mice resulted in significant satellite stem cell expansion and fiber hypertrophy. In MDX mice this was associated with reduced inflammation and muscle fiber necrosis, and a significant increase in muscle specific force. Together, these results underscore the therapeutic potential for WNT7a, demonstrate the engineering of a viable drug candidate and provide evidence for its therapeutic potential in the treatment of muscular dystrophy and potentially other neuromuscular diseases.