The primary objectives of this study were 1) to experimentally test our prediction that short dystrophins with altered structure in the Hinge 3 region have impaired cardiac function, and 2) to demonstrate the use of the leading exon skipping chemistry (Pip Chemistry) as a tool to study structure-function relationship of dystrophin disease in vivo in both cardiac and skeletal muscles.
Collaborative efforts with the MDEX consortium and the laboratories of Profs. Muntoni (University College London), Wood (Oxford University) and Gait (Cambridge University) have led us to conclude that the Pip chemistry can successfully target the heart and improve cardiac function in animal models of Duchenne muscular dystrophy. However, it requires further optimization before it can be successfully used in healthy animals to study structure-function relationships as proposed in our fellowship application. As a result, the MDEX consortium has established new collaborations with industry and academia to further develop the Pip chemistry as well as explore new chemistries.
Efforts directed at determining the cardio-protective properties of the Hinge 3 region of dystrophin have yielded important new knowledge. I have identified a specific region of dystrophin close to Hinge 3 that mediates a new association with caveolae, specialized membrane structures that play essential functions in cardiac contraction and whose disruption causes cardiac disease in animals and humans. I have shown that micro-dystrophin constructs for gene therapy that lack this region cannot interact with caveolae. In collaboration with the laboratory of Dr. Duan (University of Missouri), we have demonstrated that addition of this region to micro-dystrophin restores the association with caveolae and leads to normalization of cardiac contraction and protection from cardiac disease.
This work has resulted in a recent publication in Human Molecular Genetics (Wasala et al., 2018, Hum Gene Ther., PMID: 29433343) and I am preparing a second manuscript for submission to Circulation Research (a top leading journal in cardiac research). I have also presented the data as an invited speaker at the MRC neuromuscular centre seminar series, the Developmental Neurosciences seminar series, and the Myology forum conference. The research has also been disseminated in community outreach activities. In particular, it has been highlighted on the MDUK website that is accessed by scientists and lay members of the community, including patients and their families. I have also participated in a community outreach special initiative to introduce young children and families to science and neuromuscular disorders.
