finnish disease heritage
The Finnish disease heritage contains almost forty monogenic, hereditary diseases that are clearly enriched in Finland. These all are rare diseases, which are more prevalent in Finland than elsewhere in the world due to Finnish population history favoring high carrier frequency matches. Despite the great advances made in identifying the genetic mutations causative for these diseases in 1990-2000, the research of biochemical and cellular mechanisms has not really advanced understanding of disease-specific symptom.
Finnish Disease Heritage to model rare diseases
This national FinnDisMice research consortium established in 2020 focuses on modeling a set of Finnish disease heritage in mouse. The goal of the project is to facilitate understanding of disease pathomechanisms that are causative for these rare diseases. Faithful recapitulation of disease-causing mutations in mouse, their primary phenotyping and research at the organ and tissue level are essential for development of novel therapeutic strategies for these diseases. In the future, the disease models generated within FinnDisMice consortium will provide valuable preclinical validation instruments for potential new therapies, thus facilitating bench-to-bedside research result transfer. Finally, the in vivo disease modelling of rare diseases is expected to facilitate understanding of the pathomechanisms in more common diseases affecting the same cell and tissue types, e.g. amyotrophic lateral sclerosis (ALS), Parkinson’s disease and other degenerative disorders.
Diseases in mouse models
Generation of knockout mice has greatly advanced understanding of essential genetic requirements for life. However, human diseases are disappointingly seldom recapitulated in knockout mice, and thus full inactivation of gene function has served as inadequate in vivo models for human monogenic diseases. The next task in the in vivo modeling field is to recapitulate specific human disease-causing mutations in animal models. Through a national pilot project aiming at modeling the selected Finnish Heritage Diseases in mice (FinnDisMice) we are committed to utilize CRISPR/Cas9 genome editing in mimicking total of nine different rare syndromes in animal models. The diseases were selected based on the lack of an existing animal model (knockout not studied or does not phenocopy the given disease), clinical relevance (patients regularly seen at hospitals) and potential for therapeutic solution. The modelled diseases include rare human fetal/pediatric syndromes (hydrolethalus, LCCS1 and LCHAD), pediatric on-set epilepsies (EPMR, PEHO and Salla disease) and an adult-onset motoneuron disease (Jokela type of spinal muscular atrophy), degenerative amyloidosis (FAF) and growth disorder with defective immunity (CHH). Generation of these new in vivo disease models is expected to facilitate development of diagnostic, prognostic and therapeutic strategies these diseases, as previously exemplified by GRACILE success story (Levéen 2011, Rajemdran 2018, Purhonen 2020). This project also serves as a pilot study for designing future strategies and efforts by international consortiums deciding on successful approach for next era of mouse genome editing.
Project coordinator: Satu Kuure, GM-Unit, HiLIFE, University of Helsinki
Partners: Reetta Hinttala, TG unit, BCO, University of Oulu and Petra Sipilä, TCDM, University of Turku