Cas-mediated genome editing technology holds great promise as a curative treatment for a number of genetic diseases. Conventional CRISPR-Cas genome editing induces DNA damage (double stranded DNA breaks) and relies on the cellular DNA repair system to yield the desired repair outcome. This works quite well in cells with a fully operational DNA repair machinery. However, in Fanconi Anemia (FA), a genetic disorder associated with bone marrow failure and cancer predisposition, DNA repair is defective due to the gene mutations causing the disorder. Homology directed repair (HDR)-based editing strategy as an option to correct FA mutations is pretty inefficient (Richardson et al. Nature Genetics 2018). But is it possible to avoid DNA cleavage, and instead use recently developed genome editing systems such as base editing? Can base editing reverse the effects of FA mutations? New work led by a postdoc Erman Karasu (co-corresponding author) and PhD student Sebastian Siegner together with Alexandra Clemens at ETHZ and Laura Ugalde from Paula Rio’s lab shows that this is possible, even in bone marrow stem cells from FA patients.

In this proof-of-concept study, we find that base editing can indeed restore the function of FA bone marrow stem cells. First, the team went through cycles of optimization for the conditions (base editor construct, vector type, guide RNA format, delivery) in cell lines from multiple FA patients. The developed approach effectively corrected FA mutations in both patient-derived cell lines and bone marrow stem cells from FA patients, leading to restored FANCA expression and functional FA pathway and phenotypic resistance to crosslinking agents.

An obvious question that comes up: how safe is this editing approach? To answer this question, the team predicted possible off-targets and measured the editing outcomes in > 60 sites across multiple base editors. Unintended modifications were detected at a single site with one guide RNA, but a guide RNA targeting the most prevalent FA mutation had no detected off-targets.  Nevertheless, un-biased off- target identification using genome or RNA-sequencing will be the next step in the preclinical validation of base editing as an approach to cure FA.

Altogether, this work highlights base editors as a feasible editing strategy in FA and brings us one step closer to the future clinical implementation of base editing not only in FA, but also in other genetic diseases.

Check out our paper, now out in Nature Communications!


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