AUF1 gene therapy for traumatic skeletal muscle injury: significantly accelerated muscle regeneration in preclinical models


Translational Research

Poster Number: S23


Robert Schneider, PhD, Regerna Therapeutics, NYU Grossman School of Medicine, Dounia Abbadi, PhD, Regerna Tx, NYU School of Medicine, Riley McConnell, MS, NYU School of Medicine, Beth Walters, PhD, NYU School of Medicine, Olga Katsara, PhD, NYU School of Medicine, Sophie Dornbaum, BS, NYU School of Medicine, John Andrews, BS, NYU School of Medicine

Background. Traumatic skeletal muscle injuries are the most common debilitating injuries, whether in military service, sports, accidents and particularly in muscular dystrophies. Traumatic muscle injury can become muscle wasting disease, with unproductive cycles of muscle regeneration, exhaustion of muscle stem (satellite) cells, and continued degeneration of wounded muscle, representing a major unmet need for patients with muscular dystrophy.

Objective. There is, therefore, a large unmet need to develop therapeutic approaches that significantly activate satellite cells, promote successful muscle regeneration, reduce muscle atrophy, and reduce the extensive time for muscle regeneration following traumatic injury.

Results and Conclusions. AU-rich mRNA binding factor 1 (AUF1) is an RNA binding protein that binds repeated AU-rich elements (AREs) located in the 3’ untranslated region of approximately 3% of mRNAs. AUF1 targets ARE containing mRNAs for either rapid degradation, stabilization and/or increased translation. We previously showed that in skeletal muscle, the majority of key regulators of satellite cell activation, maintenance and muscle regeneration, are encoded by ARE-mRNAs regulated by AUF1. Here, in preclinical animal models, we used supplementation of AUF1 by either systemic muscle specific AAV8-tMCK-AUF1 or lentivirus vector-AUF1 direct muscle administration gene therapy, either prior to, during or 24 hours after injury. Following BaCl2 induced traumatic tibialis anterior traumatic muscle injury, we demonstrate that AUF1 gene therapy: (1) dramatically reduces muscle atrophy; (2) results in more rapid expression of satellite cell activation; (3) increases expression of myozenins, indicators of myofiber maturity and muscle regeneration progression; (4) increases the turnover of embryonic myosin (eMHC), a productive myogenesis marker; (5) enhances the size of differentiated and mature neo-synthesized myofibers; (6) dramatically reduces the time of post-injury muscle regeneration; and (7) protects muscle from loss of strength due to injury.
AUF1 supplemental gene therapy accelerates muscle regeneration following traumatic injury.