CRISPR-dependent base editing as a therapeutic strategy for rare monogenic disorders.

Abstract

Rare monogenic disorders are caused by mutations in single genes and have an incidence rate of less than 0.5%. Due to their low prevalence, these diseases often attract limited research and commercial interest, leading to significant unmet medical needs. In a therapeutic landscape where treatments are targeted to manage symptoms, gene editing therapy emerges as a promising approach to craft curative and lasting treatments for these patients, often referred to as "one-and-done" therapeutics. CRISPR-dependent base editing enables the precise correction of genetic mutations by direct modification of DNA bases without creating potentially deleterious DNA double-strand breaks. Base editors combine a nickase version of Cas9 with cytosine or adenine deaminases to convert C·G to T·A and A·T to G·C, respectively. Together, cytosine (CBE) and adenine (ABE) base editors can theoretically correct ∼95% of pathogenic transition mutations cataloged in ClinVar. This mini-review explores the application of base editing as a therapeutic approach for rare monogenic disorders. It provides an overview of the state of gene therapies and a comprehensive compilation of preclinical studies using base editing to treat rare monogenic disorders. Key considerations for designing base editing-driven therapeutics are summarized in a user-friendly guide for researchers interested in applying this technology to a specific rare monogenic disorder. Finally, we discuss the prospects and challenges for bench-to-bedside translation of base editing therapies for rare monogenic disorders.