Aplastic Anemia Clinical Trial
Official title:
Male Hormones for Telomere Related Diseases
Background:
- Some people have bone marrow and lung disorders that are caused by genetic problems. These
problems often involve damage to the ends of the chromosomes that pass down genes. One of
these disorders is aplastic anemia. This is a disorder in which the bone marrow does not make
enough blood cells. Currently, doctors use a male hormone-based drug called Danazol to
improve bone marrow function and treat aplastic anemia. More information is needed on whether
Danazol can help repair the damaged chromosomes that cause aplastic anemia and similar
disorders that cause low blood cell counts or lung problems.
Objectives:
- To study the safety and effectiveness of Danazol for bone marrow and lung disorders caused
by damaged genes.
Eligibility:
- Individuals at least 2 years of age who have low blood cell counts or lung fibrosis caused
by damaged genes.
Design:
- Participants will be screened with a physical exam and medical history. Then they will
have blood and urine tests, imaging studies, and a lung function test. They will also
take a 6-minute walking test and have a bone marrow biopsy.
- Participants will receive Danazol to take twice a day for the duration of the study.
- Participants will have regular study visits at 6, 12, and 24 months, with blood tests,
imaging studies, a lung function test, and a 6-minute walking test. A bone marrow sample
will be collected at the 12-month visit.
- Participants will remain on the study for up to 2 years. Researchers will follow up with
them for 2 years after the end of the study.
Severe aplastic anemia (SAA) is a life-threatening bone marrow failure disorder characterized
by pancytopenia and a hypocellular bone marrow. Telomeres were reported to be short in up to
one-third of patients with SAA.Initially this occurrence was presumed to be secondary to
hematopoietic stress. However, the discovery of loss-of-function mutations in genes of the
telomerase complex (TERC, TERT) established a genetic etiology for telomere attrition in some
patients with marrow failure who did not have the stigmata associated to an inherited bone
marrow failure syndrome. These findings implicated telomerase dysfunction in failed
hematopoiesis. In family members of probands with SAA, telomerase mutations have been
observed which were associated to varying degrees of cytopenias, idiopathic pulmonary
fibrosis (IPF) and/or cirrhosis.
Telomere length has been associated with human cancer. Telomere attrition has been implicated
in a variety of solid organ malignancies including esophageal and colon adenocarcinoma. In a
longitudinal population based study, shorter telomere length associated to a higher cancer
mortality risk overtime. It is plausible that a shorter telomere length is not just a
biomarker associated to development of cancer, but involved in its pathogenesis. Ample
experimental data supports an important role of critically short telomere length in genomic
instability. Furthermore, our laboratory data (unpublished) shows that similar chromosome
instability occurs in bone marrow cells of mutant patients, confirming the experimental data.
Thus, a common molecular mechanism appears to underlie risk for cancer and a range of
clinical entities.
In vitro studies suggest that telomere length could, in theory, be modulated with sex
hormones.15 Exposure of normal peripheral blood lymphocytes and human bone marrow derived
CD34+ cells to androgens increased telomerase activity in vitro and androgens increased low
baseline telomerase activity in individuals carrying a loss-of-function TERT mutation to
normal levels. In retrospect, the beneficial effects of sex hormones on telomerase activity
may be the mechanism by which SAA patients treated over 40 years ago with male hormones
showed hematologic improvement in some cases.
In recent years we have seen patients referred to our clinic with varying degree of
cytopenia(s) who had significant family history for cytopenia(s), IPF and/or cirrhosis. We
have identified very short telomeres in these patients and in some mutations in TERC and
TERT. We hypothesize that male hormone therapy might modulate telomere attrition in vivo and
ameliorate progression or reverse the clinical consequences of accelerated telomere
attrition. Therefore, we propose male hormone therapy in patients with cytopenia(s) and/or
IPF who show evidence of telomere dysfunction by a short age adjusted telomere length
associated to telomerase gene mutations. The primary biologic endpoint will be delay 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. The main clinical
endpoint will be tolerability of oral danazol over two years. Secondary endpoints will be
improvement in blood counts and/or pulmonary function. The small sample size, lack of control
groups, and variable clinical course among those with marrow failure and IPF, will not allow
for definitive assessment of clinical benefit. Nevertheless, we believe this protocol will
provide insight into the possible effects of androgen therapy on telomere attrition in humans
and of possible clinical benefit in telomere related disorders, and serve as hypothesis
generating for further larger controlled studies.
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