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 peripheral blood counts improved in patients with telomere biology disorders who have cytopenias?

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.

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. Other therapeutic approaches used for bone marrow failure are not effective 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 peripheral blood counts, lymphocyte telomere lengths, bone marrow cellularity, and variant allele frequencies of hematopoietic clones may be explored pre- and post-treatment.

Eligibility Criteria:
Inclusion Criteria:

* Age \> 1 year and ≤ 60 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 mutation(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 psychological or social conditions that would limit adherence with study requirements, in the opinion of the study 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.