Project: Comparison of editing, complementing or replacement of defective RNA molecules as a novel treatment method to overcome early embryonic developmental arrest

2021-10-01 – 2023-09-14

Abstract

One out of seven couples experience difficulties to conceive. A subset of these infertility patients present with problems during the earliest stages of development when undergoing assisted reproductive technology, such as embryo developmental arrest (EDA) during the first cleavage stages, which is almost exclusively oocyte-driven. This indication has recently been associated with mutations in maternal effect genes, which implicates that defective mRNA molecules in the oocyte contribute to the arrest of the developing embryo. In this project proposal, we will develop a relevant mouse model for EDA and use it to investigate three techniques to either correct these defective mRNA molecules, complement them or replace them with functional molecules. In a first set of experiments, we will use a recently developed adaptation of the CRISPR/Cas editing technology enabling targeted base editing of mutant mRNA molecules present in the oocyte, during fertilization. Secondly, we will perform the more straightforward administration of wild type complementary RNA or recombinant protein molecules. As a third independent strategy, we will refresh the whole cytoplasm with the use of the novel nuclear transfer technology. Following optimization, assessment and comparison of these three strategies in terms of efficiency and safety in a mouse model, the ultimate goal is to further validate the most promising techniques in patients experiencing EDA, in a preclinical research context.