Danazol for telomerase disorders: Prolonging the end — For chromosomes (yes), for dyskeratosis congenita (perhaps)
By Warren R. Heymann, MD
May 18, 2016
Telomeres are located at the ends of chromosomes; they are repaired by telomerases. Shortening of telomeres leads to cell senescence, apoptosis, and chromosome instability. Male hormones have been used for decades to treat bone marrow failure and may have their effect by regulating telomerase. Townsley et al performed a prospective study on 12 patients who received danazol and found that 11 of the 12 patients had a gain in telomere length at 24 months compared to baseline. Known adverse effects of danazol, elevated liver function studies and muscle cramps, developed in 41% and 33% of the patients, respectively (1).
Dyskeratosis congenital (DC) is the prototypical telomerase disorder in dermatology. Garcia and Teruya-Feldstein (2) summarize the current status of DC in the following abstract:
Dyskeratosis congenita (DC) is an inherited bone marrow failure (BMF) syndrome characterized by the classic triad of abnormal skin pigmentation, nail dystrophy, and oral leukoplakia. However, patients usually develop BMF and are predisposed to cancer, with increased risk for squamous cell carcinoma and hematolymphoid neoplasms. DC is a disease of defective telomere maintenance and is heterogeneous at the genetic level. It can be inherited in X-linked, autosomal dominant, or autosomal recessive patterns. Mutations in at least ten telomere- and telomerase-associated genes have been described in DC. There are no targeted therapies for DC and patients usually die of BMF due to a deficient renewing capability of hematopoietic stem cells. Allogeneic hematopoietic stem cell transplantation is the only curative treatment for BMF.
Androgens are considered a standard therapy for bone marrow failure in patients with DC who are unable to undergo hematopoietic stem cell transplantation. Khincha et al studied 16 patients with DC who received androgens. Improvement was noted in 70%. The age-related telomere length declined in androgen treated patients (2). This contrasts with the results from Townsley’s study.
Clearly, more research needs to be performed to determine if, indeed, androgens such as danazol really prolong telomere length to a pharmacologically significant degree. Perhaps they could also have effects on other “longevity proteins” such a sirtuins (SIRT), which are involved in cellular pathways affecting aging. Sirtuins have been implicated in DC, other genodermatoses (such ataxia-telangiectasia or Cowden syndrome), inflammatory diseases (atopic dermatitis), and connective tissue diseases. In DC, SIRT6 protects telomeric chromatin from senescence and age-induced chromosomal abnormalities such as end-to-end chromosomal fusions via deacetylation of histones at replicating telomeres (3).
Although telomeres are the end of chromosomes, we are not at the end of this story. With further refinement of manipulation of telomerase, hopefully patients with DC will have a happier ending as well.
1. Townsley DM, et al. Danazol treatment for telomere diseases. N Engl J Med 2016; 374: 1922-31.
2. Khincha PP, et al. Response to androgen therapy in patients with dyskeratosis congenital. Br J Haematol 2014; 165: 349-57.
3. Serravallo M, et al. Sirtuins in dermatology: Applications for future research and therapeutics. Arch Dermatol Res 2013: 305: 269-82.
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