Danazol Treatment for Telomere Diseases

Townsley, Danielle M.; Dumitriu, Bogdan; Liu, Delong; Biancotto, Angélique; Weinstein, Barbara; Chen, Christina; Hardy, Nathan; Mihalek, Andrew; Lingala, Shilpa; Kim, Yun Ju; Yao, Jianhua; Jones, Eric T.; Gochuico, Bernadette R.; Heller, Theo; Wu, Colin O.; Calado, Rodrigo T.; Scheinberg, Phillip; Young, Neal S.

doi:10.1056/nejmoa1515319

Cited by 306 publications

(238 citation statements)

References 40 publications

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“…Our preliminary data in a cohort 18 patients with TERT or TERC mutations suggest that pirfenidone is well tolerated [49]. Very recently, danazol, a synthetic sex hormone with androgenic properties, showed promise for pulmonary fibrosis associated with telomere disease, with stabilisation of diffusing capacity of the lung for carbon monoxide (DLCO), FVC and CT scan findings during the 2-year treatment [50]. Moreover, treatment with danazol was associated with telomere elongation and haematological response in 79% of cases (19 out of 24).…”

Section: Pulmonary Involvementmentioning

confidence: 88%

Management of suspected monogenic lung fibrosis in a specialised centre

et al. 2017

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At least 10% of patients with interstitial lung disease present monogenic lung fibrosis suspected on familial aggregation of pulmonary fibrosis, specific syndromes or early age of diagnosis. Approximately 25% of families have an identified mutation in genes mostly involved in telomere homeostasis, and more rarely in surfactant homeostasis.Beyond pathophysiological knowledge, detection of these mutations has practical consequence for patients. For instance, mutations involved in telomere homeostasis are associated with haematological complications after lung transplantation and may require adapted immunosuppression. Moreover, relatives may benefit from a clinical and genetic evaluation that should be specifically managed.The field of genetics of pulmonary fibrosis has made great progress in the last 10 years, raising specific problems that should be addressed by a specialised team.

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Section: Pulmonary Involvementmentioning

confidence: 88%

Management of suspected monogenic lung fibrosis in a specialised centre

et al. 2017

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“…Patients ineligible for HSCT may benefit from androgen therapy, as some recent studies have shown improvement of the hematopoiesis in patients with TBD treated with androgen. 31,32 Interestingly, this improvement is associated with telomere elongation in peripheral blood mononuclear cells. 32 However, androgen therapy remains associated with frequent adverse effects, and its chronic administration could eventually result in stem cell exhaustion in the treated patients.…”

Section: Discussionmentioning

confidence: 99%

“…31,32 Interestingly, this improvement is associated with telomere elongation in peripheral blood mononuclear cells. 32 However, androgen therapy remains associated with frequent adverse effects, and its chronic administration could eventually result in stem cell exhaustion in the treated patients. 33 In our cohort, androgen therapy was introduced in P4, but was stopped because of the lack of biological improvement.…”

Section: Discussionmentioning

confidence: 99%

Extended clinical and genetic spectrum associated with biallelic RTEL1 mutations

et al. 2016

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Key Points• Biallelic RTEL1 mutations generate a large clinical spectrum ranging from classical Hoyeraal-Hreidarsson syndrome to isolated aplastic anemia.Telomeres are repetitive hexameric sequences located at the end of linear chromosomes.They adopt a lariat-like structure, the T-loop, to prevent them from being recognized as DNA breaks by the DNA repair machinery. RTEL1 is a DNA helicase required for proper telomere replication and stability. In particular, it has been postulated that RTEL1 is involved in the opening of the T-loop during telomere replication to avoid sudden telomere deletion and telomere circle (T-circle) formation. In humans, biallelic RTEL1 mutations cause HoyeraalHreidarsson syndrome (HH), a rare and severe telomere biology disorder characterized by intrauterine growth retardation, bone marrow failure, microcephaly and/or cerebellar hypoplasia, and immunodeficiency. To date, 18 different RTEL1 mutations have been described in 19 cases of HH with short telomeres. The impaired T-loop resolution has been proposed to be a major cause of telomere shortening in RTEL1 deficiency. However, the biological and clinical consequences of this disorder remain incompletely documented.Here, we describe 4 new patients harboring biallelic RTEL1 mutations, including 2 novel missense mutations located in the C-terminal end of RTEL1 (p.Cys1268Arg and p.Val1294Phe). Clinical characteristics from these 4 patients were collected as those from 4 other RTEL1-deficient patients previously reported. In addition, we assessed whether T-circles, the product of improper T-loop resolution, were detected in our RTEL1-deficient patients. Overall, our study broadens and refines the clinical and biological spectrum of human RTEL1 deficiency.

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“…The net effect of these opposing genetic forces likely leads to normalized telomerase activity. Evidence from a recent study demonstrating telomere elongation in response to danazol suggests pharmacologic activation of the telomerase promoter (22). Male sex hormones are known to upregulate telomerase and have been used to treat bone marrow failure, even for patients with DC (23).…”

Section: And Christine Kim Garciamentioning

confidence: 99%