Nucleoside Therapy in Patients with Telomere Biology Disorders

About This Grant

PROJECT SUMMARY/ABSTRACT Telomere biology disorders (TBDs) are a group of rare, inherited conditions characterized by critically short telomeres resulting in a wide spectrum of clinical manifestations, including bone marrow failure and cancer predisposition. Therapy options for bone marrow failure in patients with TBDs are limited to androgen therapy and hematopoietic stem cell transplantation, which are associated with significant challenges, toxicities, and variable rates of success. Recent findings emerging from multiple independent studies have established a critical role for the pyrimidine nucleoside deoxythymidine (dT) in human telomere maintenance and have demonstrated that upregulation of nucleoside metabolism by dT supplementation in vitro leads to telomere elongation. Dr. Helen Reed has developed collaborations across Boston Children’s Hospital (BCH) with the goal of answering the following questions: 1) By targeting telomere maintenance can pyrimidine nucleosides serve as a therapy for patients with TBDs? 2) What biologic effects do pyrimidine nucleosides have in vivo among patients with TBDs? To answer these questions, she has proposed an investigator-initiated, single-center phase I clinic trial with the following objectives: 1) Assess the safety and tolerability of enteral nucleoside therapy in patients with TBDs and 2) Investigate the clinical and biologic effects of enteral nucleoside therapy. In addition to evaluating the primary and secondary endpoints of safety/tolerability and changes in peripheral blood counts, respectively, this phase I trial also proposes biologic correlative studies investigating nucleoside therapy’s effect on peripheral blood lymphocyte telomere lengths, bone marrow cellularity, and clonal hematopoiesis. The results of this research will form the basis of future investigations including efficacy trials and mechanistic studies of nucleoside therapy in patients with TBDs. Dr. Reed has completed significant preliminary work toward study activation including protocol development, FDA IND authorization (FDA IND #173750), and BCH IRB approval. Dr. Reed is an Instructor in Pediatrics at Harvard Medical School with appointments in the Division of Hematology/Oncology at Boston Children’s Hospital and Dana-Farber Cancer Institute. Dr. Reed is dedicated to improving the outcomes of patients with telomere biology disorders and other inherited bone marrow failure disorders with the goal of becoming an independent clinical investigator and clinical trialist. While she has a strong track record in clinical research, she requires further training in clinical trial design and conduct in order gain deeper expertise to support the development of future trials in a rare disease space. Her co-mentors, Dr. Akiko Shimamura and Dr. Suneet Agarwal, and her scientific advisory committee bring a considerable wealth of experience in translational research and early phase clinical trial design in hematology/oncology. This mentorship team, along with the dynamic scientific environment at Boston Children’s Hospital, will position Dr. Reed well for a successful, independent career in patient-oriented research in inherited bone marrow failure syndromes.