Essential stem cell maintenance genes, including Pax7, a transcription factor fundamental to preserving the high regenerative capacity of muscles, is induced via targeting DNA secondary structures.

Tissue restoration is essential to maintain skeletal muscles after injury. Skeletal muscle regeneration is exclusively achieved by the bona fide residential stem cells known as muscle stem cells (MuSCs). External cues, such as muscle trauma, activate the quiescent MuSCs to undergo rapid expansion and differentiation to reconstruct damaged muscle. Aging, diabetes, obesity, cancer cachexia, and several muscle diseases, including muscular dystrophies, are associated with a loss of MuSC function and a significant decline in skeletal muscle regenerative capacity.

MuSCs are essential for muscle maintenance and growth throughout life; exploiting the critical molecular regulators of these cells is vital to harness their remarkable potential for preserving skeletal muscles. Paired box protein (Pax7) is a critical transcription factor that supports muscle regeneration.

Pax7 is currently considered the universal stem cell marker for the myogenic lineage. Pax7 is expressed by all MuSCs in adult muscles and it is an essential protein in preserving their population and maintaining their myogenic properties. Depletion of Pax7 in MuSCs reduces stem cell number and results in a substantial regeneration defect following injury. The inventors uncover that telomeric repeat-binding factor 2 (TRF2) binds to G-quadruplex DNA sequences within the regulatory regions of the Pax7 gene, as well as other essential stem cell maintenance genes and supports their transcriptional activity. Through this mechanism, the inventors demonstrate that stem cell maintenance is druggable via the DNA G-quadruplex-binding drug PhenDC3.

• A truly regenerative therapy for improved muscle repair
• Broad therapeutic target demographic (especially for treatment of aging and exercise-induced injury)
• PhenDC3 is already a commercially available (scalable) drug