PROMOT

Documenting natural history study in rare diseases is complex due to several challenges including: 1) restricted sample size for each disease; 2) complex relationship of all the processes influencing the genotype-phenotype relationship leading to a myriad of clinical portraits modulating in a patient-specific way the evolution of the disease over time; 3) difficulty of having access to cohorts of patients allowing the discovery or the prospective validation of biomarkers; 4) heterogeneity of evaluation protocols in the context of prospective studies and therapeutic trials limiting the aggregation of data and the possibility of carrying out systematic reviews and meta-analysis ; and 5) limited availability of biological material collected concurrently with standardized phenotypic evaluation.
To counter these challenges, a recent scientific report highlighted the need to integrate the most complete genotypic and phenotypic portrait possible, accompanied by standardized assessments, in an interdisciplinary and patient-centered perspective. This could permit to further understand the interplay between genome, transcriptome, proteome, metabolome, epigenome, microbiome, and additional factors that, taken together, could facilitate the understanding of their interactions. In addition, the report underlined the need to obtain high-quality longitudinal data to improve our understanding of these complex biological interactions and to combine the data collected from several rare diseases to target common biological pathways and, consequently, common treatments.To face these daunting challenges and be able to support patients, families and optimize clinical trial readiness, we propose an unprecedented model in the field of rare diseases by adapting a new approach: the Master Observational Trial (MOT). This approach is supported by several key stakeholders including the Food and Drug Administration, particularly for COVID-19 and oncology. The MOT follows a clinical study design defined as a prospective interdisciplinary observational study including several data sources (e.g. multiomics, biomarkers, data from the medical file, data from therapeutic trials) in addition with a common MOT highly standardized protocol, making it possible to simultaneously answer several questions nested in a structure of long-term multilevel intervention/therapeutic trials (e.g., basket trial).
This research project aims to generate a learning and mobilization platform allowing the development of a precision medicine approach adapted to rare diseases and based on an innovative natural history study design with a  Master Observational Trial and using artificial intelligence (AI).  It will support the integration of clinical, research, interventional and patient generated knowledge to support biomarkers discovery, refinement of clinical prognosis, development of interventions and optimizing clinical trial readiness in rare diseases. 
The proposal will support the identification of biomarkers/predictors for prognosis and evolution of a group of five neuromuscular disorders as well as a common MOT protocol for natural history study and clinical trials. This project will allow to demonstrate a proof of concept in a group of rare neuromuscular diseases with strong commonalities: oculopharyngeal muscular dystrophy, myofibrillar myopathies, congenital myopathies, congenital myasthenia and RyR1 central myopathies. 
The objectives are to develop a MOT approach using oculopharyngeal muscular dystrophy as a flagship disease; to conduct a pilot MOT in five neuromuscular disorders with patient-centered endpoints/outcome measures; to document the feasibility of conducting a MOT approach in these vulnerable populations and across different legislations. 
This proposal will permit us to respond to several unmet needs in this population regarding prognosis and clinical trial readiness. The MOT approach is an innovative way to speed up clinical trials readiness by providing an umbrella protocol and have the potential to decrease the burden associated with multiple therapeutic trials that may come soon. It will permit to identify potential biomarkers amenable to treatment, to have a common protocol ready for clinical trials of basket or umbrella type in a group of five neuromuscular diseases.