Ricotti, V; (2016) Evolving natural history in Duchenne muscular dystrophy: implications for standard of care and experimental therapies. Doctoral thesis , UCL (University College London).

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Abstract

Duchenne muscular dystrophy (DMD) with an average global incidence of 1:5000 is an X-linked recessive disease, caused by mutations in the DMD gene encoding dystrophin. Lack of dystrophin isoforms results in progressive muscle weakness and cardiomyopathy, leading to loss of ambulation and premature death secondary to cardiac/respiratory complications. At present, there is no curative treatment. However, implementation of standards of care has significantly shifted life expectancy and the natural history of DMD has considerably evolved. Moreover, a number of promising therapeutic approaches are under development, some reaching phase II-III clinical trials. These experimental therapies will further contribute to the transformation of the disease trajectory. The projects of my thesis intended to address specific research questions, which have an impact not only on the clinical care of DMD patients, but also advice on clinical trial design. I studied the effect of steroid therapy on the motor function in DMD boys >7 years, more specifically profiling benefits and side effects of the most commonly used regimens: intermittent and daily prednisolone. I analysed the impact of starting steroids at an earlier age than what is standard of care. I explored the role of different dystrophin gene (DMD) genotypes in the motor progression of the disease, further defining the genotype-phenotype correlations. All results obtained are of particular interest for clinical trials of pharmaco-gene therapies targeting specific DMD mutations. Dystrophin isoforms also play an important role for the CNS and their lack causes morbidity in DMD. My investigations expanded the genotype-phenotype profile specifically in relation to neuropsychiatric co-morbidities in DMD. In conjunction with the CNS profile of DMD, I characterized abnormalities of retinal function and developed electroretinography as a potential and non-invasive CNS endpoint for future clinical trials. Addressing the non-ambulant DMD population, I studied quantitative magnetic resonance imaging and novel functional measures of the upper limb. These results allow for the first time to evaluate disease progression and response to treatment in non-ambulant DMD. All the results obtained in this thesis therefore enlarge our knowledge of the disease evolution under current standard treatment and contribute to trial readiness by developing new endpoints.

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