Our work with Duchenne Muscular Dystrophy is focused on the role of dysfunctional autophagy in disease progression. Our earlier work pointed to impaired activation of autophagy as well as impaired degradation of autophagosomes. Of interest, we also noted a reduction in lysosome abundance, which may be driven by nuclear exclusion of TFEB, a major transcription factor leading to lysosome biogenesis. In an independent research line we discovered that PGC-1α gene transfer attenuated disease severity. In these muscles we discovered that PGC-1α gene transfer caused increased nuclear translocation of TFEB, increased lysosome biogenesis, and caused changes in muscle consistent with increased degradation of autophagosomes. We are currently pursuing several lines of inquiry related to these discoveries. In the first, we are interested in repurposing drugs with current FDA approval that will activate this transcription factor, increase autophagy, and decrease disease severity. In the second, we are interested in better understanding the interplay between PGC-1α and TFEB.
We are also interested in the role of obesity and insulin resistance as a mediator of disease progression. It is well recognized that most humans with DMD are overfat/obese and develop insulin resistance over time. Unfortunately, most animal models used to study DMD are lean. This disconnect prevents the study of the disease in the appropriate physiological context, which may limit applicability of research findings and predictability of preclinical therapeutic outcomes.
In addition, we joined a team that had recently discovered a spontaneously occurring pig dystrophinopathy model. We have since bred this mutation onto a minipig line and are in the process of performing the initial characterizations of this model with the hope that it can be inserted into the preclinical pipeline. Use of these large animal models would allow the testing of drugs in human sized models with many physiological systems more similar to humans than either the currently available mouse or dog models.