Nucleoside Therapy in Patients With Telomere Biology Disorders

This is an investigator-initiated, single-arm, single-center phase 1 clinical trial investigating nucleoside therapy in patients telomere biology disorder (TBDs). TBDs are a group of rare, inherited conditions characterized by critically short telomeres which can limit cellular replication resulting in a wide spectrum of clinical manifestations. From a hematologic standpoint, patients with TBDs often present with bone marrow failure. Therapy options for bone marrow failure for patients with TBDs are limited to androgen therapy and hematopoietic cell transplantation, which are associated with significant challenges and toxicities. From a pulmonary standpoint, patients with TBDs can present with low oxygen levels due to hepatopulmonary syndrome or lung fibrosis, which requires organ transplantation. New therapeutic approaches are needed in patients with an underlying TBD. Recent studies emerging from multiple independent human genetic studies have established a critical role for deoxythymidine (dT) metabolism in human telomere maintenance and demonstrated that upregulation of nucleotide metabolism by dT supplementation in vitro led to telomere elongation. The goals of this trial are to (1) assess the safety and tolerability of enteral nucleoside therapy in patients with TBDs and (2) explore the clinical and biologic effects of enteral nucleoside therapy in patients with TBDs. A total of 36 pediatric and adult patients with a diagnosis of a TBD will be enrolled at Boston Children's Hospital. Patients will receive enteral nucleoside therapy for a total of 24 weeks. Drug diary reviews and safety and tolerability assessments will be conducted on a weekly basis during an initial dose-escalation phase (4 weeks) and then monthly until study treatment completion at week 24. Pharmacokinetic studies will be conducted on a subset of participants. Additionally, changes in lymphocyte telomere lengths, peripheral blood counts, bone marrow cellularity, clonal hematopoiesis, pulmonary function tests, and chest CT imaging may be explored pre- and post-treatment.