Nandrolone Decanoate in the Treatment of Telomeropathies
Condition: Aplastic Anemia; Bone Marrow Failure Syndromes; Idiopathic Pulmonary Fibrosis; Telomere Shortening
MeSH terms: Pulmonary Fibrosis; Idiopathic Pulmonary Fibrosis; Anemia, Aplastic; Bone Marrow Failure Disorders; Pancytopenia; Fibrosis
Study type: Interventional
Phase: Phase 1/Phase 2

Summary: 
      Decrease in blood cell counts due to deficient bone marrow function, called bone marrow
      failure, as well as some lung diseases, called idiopathic pulmonary fibrosis, can be caused
      by genetic defects in telomere biology genes, eventually causing telomere erosion. These
      disorders are collectively termed "telomeropathies".

      There is evidence that male hormones may improve blood cell counts in marrow failure, and
      these hormones are able to stimulate telomerase function in hematopoietic cells in vitro. We
      propose this study to the use of male hormone in patients with aplastic anemia and pulmonary
      fibrosis associated with defects in telomeres.
    

Detailed description: 
      Telomeres are repeated nucleotide sequences of non-coding DNA at the ends of chromosomes that
      have protective functions and avoid chromosomes recombinations and fusions.

      Loss-of-function mutations in genes of the telomerase complex, a enzyme responsible for
      maintaining telomere length, has been associated with bone marrow failures, notedly mutations
      in DKC1 gene, detected in a rare inherited form of marrow aplasia, called dyskeratosis
      congenita. These findings implicated telomerase dysfunction and shortening telomere length in
      failed hematopoiesis.

      In family members of probands with aplastic anemia, marrow aplasia and telomerase mutations
      also have been observed and associated to varying degrees of cytopenias, IPF and/or
      cirrhosis. Moreover, patients with varying degrees of cytopenias, with significant family
      history for cytopenias, IPF and/or cirrhosis, have been identified with very short telomeres
      and some mutations in telomerase complex genes. Additionally, telomere length has been
      associated with human cancer.

      In vitro studies suggest that telomere length could be modulated with sex hormones. Normal
      lymphocytes and human bone marrow progenitor cells exposed to androgens increased telomerase
      activity in vitro, and in individuals with telomerase mutations (TERT) androgens increased
      telomerase activity.This could be the explanation for the hematologic improvement observed in
      some aplastic anemia patients treated over 40 years ago with male hormones.

      Therefore, we hypothesize that androgens therapy might modulate telomere attrition in vivo
      and ameliorate progression or reverse the clinical consequences of shortening telomere
      length, and we propose androgens therapy in patients with cytopenias and/or IPF with a short
      age adjusted telomere length, with or without telomerase gene mutations.

      The primary biologic endpoint will be the reduction of telomere attrition over time compared
      to known rates of telomere erosion in normal individuals and in those who carry mutation in
      the telomerase genes. Secondary endpoints will be tolerability of nandrolone decanoate over
      two years, improvement in blood counts and/or pulmonary function.
    

Intervention name(s): Nandrolone Decanoate
Intervention type(s): Drug
Intervention MeSH terms: Nandrolone Decanoate; Nandrolone; Nandrolone phenpropionate
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Hormones; Androgens; Aplastic Anemia; Bone Marrow Failure Syndromes; Idiopathic Pulmonary Fibrosis; Telomere; Telomere Shortening