Abstract

Defects in genes involved in the immune response to infectious agents can cause genetic disorders known as autoinflammatory diseases (AIDs). Type I interferonopathies (T1I) constitute a subgroup of AIDs characterised by severe pulmonary and cutaneous complications that respond poorly to drug treatments. Gene therapy based on haematopoietic stem cells has shown the potential to become the treatment of choice for certain monogenic diseases; however, the vectors used may pose risks associated with insertion mutagenesis. 

Furthermore, gain-of-function mutations cannot be treated with conventional gene replacement strategies, as the simple addition of a ‘healthy’ version of the gene is insufficient to correct the phenotype. The recent development of genome editing (GE) technologies, which enable the precise correction of a locus of interest, offers the possibility of overcoming these challenges. The project involves the development of an in vitro model based on induced pluripotent stem cells (iPSCs) and 3D organoids to further our understanding of the mechanisms underlying SAVI, an autosomal dominant T1I characterised by severe systemic inflammation, skin ulcers and progressive pulmonary interstitial disease. 

We will use the generated iPS cell lines to assess the efficacy and feasibility of an approach based on base editing and prime editing. Finally, we will validate the optimised protocols in vivo using a humanised mouse model of SAVI, in which the endogenous locus has been replaced by the human homologue. Through this approach, we will deepen our understanding of the pathogenesis of the disease and provide a proof of concept useful for the development of future therapeutic strategies.