About 80% of the 7,000 rare diseases that have been identified so far are of genetic origin. In simple words, this means that a mutation in the genome (DNA) of the affected individual, often touching only one nucleotide of a target gene, is sufficient to induce the disease. Researchers survey rare disease-causing genes and mutations because they provide reliable information for diagnosis. This is important because patients often report seeing an average of 4 to 7 physicians before being diagnosed, a serious burden on the lives of the patients and their families.

However, identification of target genes and mutations is not enough to really understand the defects that cause diseases nor to develop drugs that can correct them. Understanding the molecular basis and mechanisms that lead to these diseases is thus of the utmost importance in order to progress towards finding cures. In recent years, researchers have found that mutations in some rare disease protein-coding genes cause non-proper folding of their protein products, leading to significant impairment in their stability or ability to interact with other proteins to form protein complexes and networks.

This is true for hypomyelinating leukodystrophies, as our group demonstrated in collaboration with Dr. Geneviève Bernard from the McGill University Health Centre, but also for many other rare diseases. One approach we favor is now to screen for small chemical molecules which are able to correct the defects in mutated proteins and restore their stability and ability to form proper protein-protein interactions. This work is currently in progress.

To further improve our understanding of the mechanisms of rare disease onset and progression, and to accelerate drug and biomarker discovery, our Translational Proteomics laboratory at the Montreal Clinical Research Institute launched the ambitious initiative to build a cell map consisting of the entire network of protein-protein interactions involving rare disease-causing gene products, as well as the effect of disease-causative mutations on network architecture (something we call Differential Interactomes). This “Rare Disease Cell Map” will reveal the blueprint of the cell’s machinery and mechanisms at the origin of rare genetic diseases. We are currently discussing with international partners, from both the academic and private sectors, to develop a high-profile multidisciplinary research team that will seek funding to support this ambitious initiative.

To further accelerate the development of cures for rare diseases, we elected to adopt an Open Science strategy where our data and reagents are made freely and publicly available to the research community as quickly as possible. Our Open for Rare web site presents the results of the Rare Disease Cell Map. Rapid communication and sharing of data and reagents are key and we have engaged in accelerating this aspect of our work.

Approved treatments are only available for 5% of all rare diseases, but the quest for novel drugs has been relatively successful in the last few years, with more than half of the 59 new drugs approved by the FDA in 2018, and 21 out of the 48 approved in 2019, being for the treatment rare diseases. These numbers are very encouraging but far from satisfying. We hope that our Open for Rare and Rare Disease Cell Map initiatives will help accelerate the development of new cures for rare diseases.