Effect of UM171 on the in vitro expansion of hematopoietic stem cells from patients with telomeropathies

• Grant number: 21/08755-7
• Support Opportunities: Scholarships in Brazil - Doctorate
• Start date: January 01, 2022
• End date: March 31, 2026
• Field of knowledge: Health Sciences - Medicine - Medical Clinics
• Principal Investigator: Rodrigo do Tocantins Calado de Saloma Rodrigues
• Grantee: Vinícius Silva de Carvalho
• Host Institution: Hemocentro de Ribeirão Preto. Hospital das Clínicas da Faculdade de Medicina de Ribeirão Preto da USP (HCMRP). Secretaria da Saúde (São Paulo - Estado). Ribeirão Preto , SP, Brazil
• Associated research grant: 13/08135-2 - CTC - Center for Cell-Based Therapy, AP.CEPID
• Associated scholarship(s): 24/00289-5 - Adenine base editing (ABE) to correct pathogenic variants in hematopoietic stem cells of patients with telomeropathies, BE.EP.DR

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 most effective treatment for marrow failure in patients with telomeropathies is allogeneic bone marrow transplantation, but this is restricted by the limited availability of compatible donors, comorbidities, and conditioning complications. The UM171 molecule is capable of ex vivo expanding umbilical cord hematopoietic stem cells (CTHs) in the laboratory and has already been used safely in transplants of human patients. We have recently obtained promising results from the preclinical use of UM171 in the expansion of CTHs from the bone marrow of patients with immune aplastic anemia. In these acquired cases of immune mechanism, UM171 promoted the effective expansion of hematopoietic progenitors without inducing observable chromosomal, genetic, or telomeric erosion changes. In the present project, we plan to evaluate whether UM171 can efficiently and safely expand CTHs from patients with telomeropathies in vitro. We propose to establish a platform for the cultivation and expansion of CTHs from patients in the presence of UM171, to verify the phenotypic and functional expansion of CTHs, and to test their safety: chromosomal and genomic stabilities and telomeric dynamics, in addition to grafting these CTHs into a murine xenotransplantation model. The results will allow us to define whether UM171 is also able to safely expand the CTHs of patients with hereditary aplastic anemia due to telomeropathy and to establish the basis for clinical trials for its use in patients without allogeneic transplant donors.