Résumé :
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The Quebec/French DM network was created in 2005 to evaluate RNA-based gene therapy for DM1. We have characterized a mouse model of DM1 carrying 1200 CTG repeats (DMSXL mice) and validated a standardized protocol used for preclinical therapeutic trials. During the first 3 years, we explored an antisense RNA approach, based on the use of rAAV1. We showed that antisense RNA can silence mutant transcripts in vitro and in vivo after intramuscular but not after systemic injection. Because systemic injection of rAAV is not presently applicable in clinics, we have developed an alternative approach based on ASO. We showed that ASOs decreased up to 90% the levels of hmutant transcripts in vitro and following a single i.m. injection in DMSXL mice but only 25% following systemic injection, because of a poor penetration of ASO into the skeletal muscles. These data demonstrate the feasibility of the ASO approach and our efforts are presently focused on improvement of muscle delivery. The second goal of the network was to develop standardized assessment protocols for future multicentric clinical trials. Two protocols were designed and training of Quebec and French physiotherapists revealed excellent intra- and inter-observer reliability. The first protocol was the QMT of ankle dorsiflexors in a 5-years longitudinal study. A significant 12% decline in muscle strength was observed between initiation and 18-months and between 18- and 36 months in DM1 patients. A significant correlation was found between QMT and muscle MR imaging for the TA. In view of potential ASO trials by systemic injection, we have developed a second protocol, including the assessment of 8 muscle groups using handheld dynamometer, a 6-m walking test, timed-functional tests and quantification of myotonia. Preliminary results showed the feasibility of the protocol and the interest of the 6-m walk test in therapeutic trials. Because of the high prevalence of DM1 in Quebec, the last objective of the Network was to develop a Quebec DM registry, which is essential to both identify potential participants in clinical trials and to follow the natural history of the disease. The Quebec DM population-based registry contained: 1183 individuals including 892 patients with DM1 and 145 non-affected subjects. Among patients, 667 were clinically evaluated using a Quebec / French standardized grid, allowing the comparison of the Quebec and French DM1 population. No major difference in the frequency of manifestations was observed between the Quebec and French DM population. Conclusion, the AFM DM Network has significantly contributed not only to the development of a therapy for DM1 but also to the development of biomarkers that can be used in multicentric trials.
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