Adenine base editing (ABE) to correct pathogenic variants in hematopoietic stem cells of patients with telomeropathies

Abstract

Telomeres are repetitive sequences of hexanucleotides located at the ends of linear chromosomes that, when critically short, can trigger chromosomal instability, senescence, or apoptosis. Pathogenic variants in genes involved in telomere biology can lead to excessive telomere shortening and diseases most frequently affecting the bone marrow, but also the skin, lungs, liver and predisposing to cancer, collectively called telomeropathies. The telomerase complex is crucial for maintaining hematopoietic stem cell homeostasis. Aging affects hematopoietic stem cells, diminishing their self-renewal capacity and ability to differentiate into lymphoid cells. Defects in the telomere maintenance system lead to premature depletion of the hematopoietic stem cell (HSC) pool, resulting in hypocellular or aplastic marrows. The most effective treatment for marrow failure in patients with telomeropathies is allogeneic HSC transplantation, but this is restricted by the limited availability of compatible donors, comorbidities, and conditioning complications. Autologous transplants offer a promising therapeutic approach by minimizing donor challenges, reducing rejection risks, lowering graft-versus-host disease (GVHD) incidence, and accerelating recovery. An alternative for overcoming limitations in cell proliferation arising from telomeric attrition and genetic instability involves correcting pathogenic variants in the patients' cells. This correction can enhance the in vitro expansion process using UM171, which has already demonstrated promise. In this collaborative study between the University of São Paulo (USP) and the Université de Montréal (UdeM), we plan to utilize base editing to revert specific mutations to the wild type in HSCs of individuals with telomeropathies. This collaborative study aims to strengthen the ongoing partnership between USP and UdeM in the field of hematology, contributing to novel therapeutic approaches for the treatment of patients with disorders related to telomere biology.