Most neuromuscular diseases are caused by genetic mutations, which at the moment cannot be corrected clinically. Accordingly, options for prevention and treatment of neuromuscular diseases are currently severely restricted. Experimentally, gene therapy using adeno-associated viral (AAV) vectors delivered encouraging results; however, many practical drawbacks and limitations still exist. In particular, systemic application, specific delivery, infection or expression in skeletal muscle and robust loss-of-function systems using small hairpin RNA (shRNA) are bottlenecks in the development of clinically useful vectors. Our project is geared towards the development of AAV vectors that overcome these limitations. We will validate our approach by generating gain- and loss-of-function mouse models for the peroxisome proliferator-activated receptor g coactivator 1 (PGC-1), both -1a and -1b, using these AAV vectors. PGC-1a and PGC-1b are strong promoters of mitochondrial biogenesis and function. Furthermore, both proteins are able to confer a high endurance muscle fiber phenotype even in untrained muscle. Interestingly, PGC-1a and PGC-1b employ different strategies to reach that goal. For PGC-1a, therapeutic efficacy against Duchenne muscular dystrophy, disuse-induced fiber atrophy, statin-induced muscle wasting and one form of a mitochondrial myopathy was shown in rodent models suggesting a broad applicability of therapeutic elevation of PGC-1a in a number of different contexts of muscle wasting. Elevation of PGC-1b might complement the beneficial effects of PGC-1a. Unfortunately, little is known about the therapeutic efficacy of PGC-1b in muscle wasting and dystrophies. Despite the promising data, pharmacological approaches to modulate PGC-1a and -1b gene expression have been disappointing.

We hope to achieve two goals that are significant for clinical application. First, the AAV vectors will obviously be useful for elevating or diminishing the levels of any gene and thus might provide an avenue to overcome some of the current bottlenecks in gene therapy using AAV. Second, our project will provide the means to elevate the PGC-1s in muscle; although the cause of muscle wasting is not addressed by this approach, the symptoms are alleviated and a broad number of different pathological contexts and diseases will be ameliorated by PGC-1-mediated increase in muscle function and fiber integrity.