Nucleoside Therapy in Patients With Telomere Biology Disorders

The goal of this clinical trial is to learn if a combination therapy of deoxycytidine (dC) plus deoxythymidine (dT) is safe in patients with telomere biology disorders. The main questions it aims to answer are:

• Is the therapy safe with tolerable side effects in patients with telomere biology disorders?
• Are problems with the bone marrow or blood or lungs changed after 6 months of dC+dT treatment in patients with telomere biology disorders?

Participants will:

• Take study drug by mouth three times daily for 24 weeks
• Make approximately 2 visits to Boston Children's Hospital during the 24 weeks: once at the beginning of treatment and once at the end of treatment.
• Go to a lab for a blood draw an additional 6 times during treatment.
• Have 9 phone calls with a research nurse, including one 4 weeks after treatment ends.
• Keep a diary to track doses of study drug that were taken or missed.

Study Overview

• Status: Recruiting
• Conditions: Dyskeratosis Congenita; Hoyeraal Hreidarsson Syndrome; Revesz Syndrome; Telomere Biology Disorders; Telomere Biology Disorders With Bone Marrow Failure; Interstitial Lung Disease Due to Systemic Disease (Telomere Biology Disorder); Pulmonary Fibrosis, Familial (Telomere Biology Disorder)
• Intervention / Treatment: Drug: deoxycytidine; Drug: deoxythymidine

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Estimated): 36
• Phase: Phase 1

Contacts and Locations

• Study Contact: Name: Helen Reed, MD, MPH; Phone Number: 857-218-4578; Email: helen.reed@childrens.harvard.edu
• Study Contact Backup: Name: Brichelle Pena, BS; Phone Number: 617-919-1857; Email: brichelle.pena@childrens.harvard.edu

Study Locations

• United States
  • Massachusetts
    • Boston, Massachusetts, United States, 02115
      • Recruiting
      • Boston Childrens Hospital
      • Principal Investigator: Helen Reed, MD, MPH
      • Contact: Helen Reed, MD, MPH; Phone Number: 857-218-4578; Email: helen.reed@childrens.harvard.edu
      • Contact: Brichelle Pena, BS; Phone Number: 617-919-1857; Email: elizabeth.korn@childrens.harvard.edu

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Age ≥ 1 year and ≤ 70 years
• Karnofsky performance status ≥ 50 for participants ≥16 years of age and Lansky performance status ≥ 50 for participants <16 years of age

• Diagnosis requirement. Participants must meet at least one of the following requirements for a diagnosis of a telomere biology disorder:

  1. Age-adjusted mean telomere length < 1%ile in peripheral blood lymphocytes by flow cytometry-fluorescence in situ hybridization (flow-FISH), as reported by a Clinical Laboratory Improvement Amendments (CLIA)-approved laboratory

     OR

  2. Pathogenic or likely pathogenic variant(s) in one of the follow telomere biology associated genes: DKC1, TERC, TERT, NOP10, NHP2, WRAP53/TCAB1, TINF2, CTC1, RTEL1, ACD, PARN, NAF1, STN1, ZCCHC8, POT1, RPA1, DCLRE1B, TYMS, as reported by a CLIA-approved laboratory.
• Participants must exhibit at least one active clinical manifestation associated with a telomere biology disorder, in the judgment of the PI, which includes but is not limited to the following: one or more peripheral blood cytopenias, bone marrow hypocellular for age, pulmonary abnormalities, liver abnormalities, gastrointestinal bleeding, immunodeficiency or immune dysregulation, ophthalmologic abnormalities, or neurologic abnormalities.
• Participants must be able to take enteral liquids by mouth or enteral feeding tube.
• Female participants who are sexually active and could become pregnant must use two effective methods of contraception, at least one of which must be considered a highly effective method.
• Participants (or parent/legally authorized representative for minors) must demonstrate the ability to understand and willingness to provide informed consent, which will be documented using an institutionally approved informed consent procedure.

Exclusion Criteria:

• Participants must not have very severe aplastic anemia necessitating bone marrow transplant at the time of enrollment. Very severe aplastic anemia is defined by the presence of at least 2 of the following: ANC <200 cells/microliter, platelets <20,000 cells/microliter, absolute reticulocyte count <40,000 cells/microliter. If individuals with very severe aplastic anemia are not expected to undergo bone marrow transplant either due to the lack of an acceptable donor or medical co-morbidities and otherwise meet the inclusion/exclusion criteria, then they would be eligible for enrollment in this trial.
• Participants must not otherwise be expected to undergo bone marrow transplantation within 6 months of enrollment.
• Participants must not be taking concurrent medications intended to improve hematopoiesis such as androgens or growth factors, including granulocyte colony stimulating factor, erythropoietin, or thrombopoietin mimetics. If any of these therapies were taken previously, patients must wait 30 days after cessation of the therapy before enrollment on this trial.
• Participants must not have chronic diarrhea or an average baseline stool output of more than 4 stools per day.
• Participants must not have gastrointestinal disorders that may impair enteral absorption of dC/dT, such as inflammatory bowel disease or short bowel syndrome.
• Participants must not have chronic kidney disease with an estimated glomerular filtration rate < 60 mL/min/1.73 m2.
• Participants must not be on other medications or study agents or have other uncontrolled intercurrent illness that could interfere with study interpretation, in the opinion of the study Principal Investigator (PI)
• Participants must not have high-risk myelodysplastic syndrome or leukemia or other active malignancy.
• Pregnant individuals will not be eligible for enrollment given the physiological changes in blood counts that occur during pregnancy.
• Breastfeeding mothers will not be eligible for enrollment due to the unknown risk to nursing infants.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: dC/dT; Participants will take study therapy three times daily over 24 weeks with dose escalation.	Drug: deoxycytidine; Oral administration, in combination with deoxythymidine; Other Names: dC; Drug: deoxythymidine; Oral administration, in combination with deoxycytidine; Other Names: thymidine; dT

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence of treatment-related diarrhea [Tolerability]	Proportion of study participants with grade 3 or higher treatment-related diarrhea refractory to dose adjustments	8 weeks from study drug initiation
Incidence of treatment-related adverse events [Safety]	Proportion of patients with grade 3 or higher treatment-related adverse events refractory to dose adjustments	8 weeks from study drug initiation

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in hemoglobin	Change in hemoglobin (in grams per deciliter)	From pre-treatment baseline to end of treatment
Change in platelet count	Change in platelet count (in thousands of cells per microliter)	From pre-treatment baseline to end of treatment
Change in absolute neutrophil count	Change in absolute neutrophil count (in thousands of cells per microliter)	From pre-treatment baseline to end of treatment
Maximal plasma concentration [Cmax] of dC	Maximal plasma concentration [Cmax] of dC will be obtained during pharmacokinetic profiling of dC at starting dose and maximum dose in some subjects	24 weeks
Maximal plasma concentration [Cmax] of dT	Maximal plasma concentration [Cmax] of dT will be obtained during pharmacokinetic profiling of dT at starting dose and maximum dose in some subjects	24 weeks
Plasma half-life [T1/2] of dC	Plasma half-life [T1/2] of dC will be obtained during pharmacokinetic profiling of dC at starting dose and maximum dose in some subjects	24 weeks
Plasma half-life [T1/2] of dT	Plasma half-life [T1/2] of dT will be obtained during pharmacokinetic profiling of dC at starting dose and maximum dose in some subjects	24 weeks

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in forced vital capacity (FVC)	Change in forced vital capacity (percent predicted) on pulmonary function testing	Up to 24 weeks
Change in diffusing capacity of the lungs for carbon monoxide (DLCO)	Change in diffusing capacity of the lungs for carbon monoxide (percent predicted) by pulmonary function testing	Up to 24 weeks

Collaborators and Investigators

• Sponsor: Suneet Agarwal
• Investigators: Principal Investigator: Helen Reed, MD, MPH, Boston Children's Hospital

Publications and helpful links

General Publications

• Mannherz W, Agarwal S. Thymidine nucleotide metabolism controls human telomere length. Nat Genet. 2023 Apr;55(4):568-580. doi: 10.1038/s41588-023-01339-5. Epub 2023 Mar 23.

Study record dates

Study Major Dates

• Study Start (Actual): September 29, 2025
• Primary Completion (Estimated): June 1, 2028
• Study Completion (Estimated): June 1, 2029

Study Registration Dates

• First Submitted: January 30, 2025
• First Submitted That Met QC Criteria: February 4, 2025
• First Posted (Actual): February 10, 2025

Study Record Updates

• Last Update Posted (Actual): August 4, 2026
• Last Update Submitted That Met QC Criteria: August 1, 2026
• Last Verified: September 1, 2025

More Information

Terms related to this study

• Keywords: tolerability; safety; pharmacokinetics; bone marrow; phase I; bone marrow failure; pulmonary fibrosis; nucleoside; deoxycytidine; deoxythymidine; telomere biology disorders; telomere lengths; clonal hematopoiesis
• Additional Relevant MeSH Terms: Congenital Bone Marrow Failure Syndromes; Pathologic Processes; Genetic Diseases, Inborn; Respiratory Tract Diseases; Lung Diseases; Hematologic Diseases; Skin Diseases; Congenital Abnormalities; Bone Marrow Diseases; Lung Diseases, Interstitial; Skin Diseases, Genetic; Genetic Diseases, X-Linked; Skin Abnormalities; Fibrosis; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Pathological Conditions, Signs and Symptoms; Skin and Connective Tissue Diseases; Hemic and Lymphatic Diseases; Bone Marrow Failure Disorders; Pulmonary Fibrosis; Dyskeratosis Congenita; Revesz Debuse syndrome; Hoyeraal Hreidarsson syndrome; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Nucleic Acids, Nucleotides, and Nucleosides; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Nucleosides; Deoxyribonucleosides; Deoxycytidine; Thymidine
• Other Study ID Numbers: IRB-P00049530

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No