UM171-Mediated hematopoietic stem cell expansion for patients with immune aplastic anemia: clinical scale for therapy

• Grant number: 24/01325-5
• Support Opportunities: Scholarships abroad - Research Internship - Post-doctor
• Start date: June 17, 2024
• End date: June 16, 2025
• Field of knowledge: Health Sciences - Medicine - Medical Clinics
• Principal Investigator: Rodrigo do Tocantins Calado de Saloma Rodrigues
• Grantee: Alexandre Gomes de Macedo Maganin
• Supervisor: Guy Sauvageau
• 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
• Institution abroad: Université de Montréal, Canada
• Associated to the scholarship: 23/06646-1 - Scaling up for preclinical study of hematopoietic stem cells from patients with Immune Aplastic Anemia expanded with UM171, BP.PD

Abstract

In acquired immune aplastic anemia (immune AA), cytotoxic Th1 cells release cytokines that trigger changes in cell cycle and cell transcription, leading to HSC apoptosis, causing hematopoietic failure. Current treatments are limited and are hampered by the lack of compatible donors and complications. The current standard treatment is related-matched allogeneic hematopoietic stem cell transplantation, but available donors are scarce the transplant complications are of concern and increase with age. Therefore, our group has been studying a new therapeutic alternative for patients with aplastic anemia, through the development of ex vivo autologous CD34+ cell expansion processes. The UM171 molecule, a pyrimidoindole derivative, is capable of stimulating the expansion of human HSCs, in addition to inhibiting their differentiation, allowing the long-term repopulation of these cells in xenotransplants. UM171 blocks epigenetic changes in the cell through the potentiation of complexes responsible for degrading the CoREST protein complex, thus allowing the HSC self-renewal process, suggesting that UM171 is capable of promoting in vitro expansion of HSCs without causing genetic changes in the cells. In this project, we propose to optimize the culture of CD34+ cells from patients with immune AA and determine the optimal dose of UM171 for scaling the patients' HSCs. The bone marrow of seven patients with immune AA will be collected and the HSCs will be isolated and using a screening protocol, we will determine the best concentrations of cytokines and the UM171 for expansion. We will verify the phenotypic and functional expansion of CD34+ cells in open and closed systems. After determining the best culture conditions for the cells, we will begin standardizing clinical scaling in transfusion bags for CD34+ cells from patients with immune AA. The results contributed to clinical studies in patients with immune AA using UM171.