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Selective modulation of the androgen receptor AF2 domain rescues degeneration in spinal bulbar muscular atrophy
- Source :
- Nature Medicine. April, 2018, Vol. 24 Issue 4, p427, 11 p.
- Publication Year :
- 2018
-
Abstract
- Spinal bulbar muscular atrophy (SBMA) is a motor neuron disease caused by toxic gain of function of the androgen receptor (AR). Previously, we found that co-regulator binding through the activation function-2 (AF2) domain of AR is essential for pathogenesis, suggesting that AF2 may be a potential drug target for selective modulation of toxic AR activity. We screened previously identified AF2 modulators for their ability to rescue toxicity in a Drosophila model of SBMA. We identified two compounds, tolfenamic acid (TA) and 1-[2-(4-methylphenoxy)ethyl]-2-[(2-phenoxyethyl)sulfanyl]-1H-benzimidazole (MEPB), as top candidates for rescuing lethality, locomotor function and neuromuscular junction defects in SBMA flies. Pharmacokinetic analyses in mice revealed a more favorable bioavailability and tissue retention of MEPB compared with TA in muscle, brain and spinal cord. In a preclinical trial in a new mouse model of SBMA, MEPB treatment yielded a dose-dependent rescue from loss of body weight, rotarod activity and grip strength. In addition, MEPB ameliorated neuronal loss, neurogenic atrophy and testicular atrophy, validating AF2 modulation as a potent androgen-sparing strategy for SBMA therapy.<br />Author(s): Nisha M Badders [1]; Ane Korff [1, 2]; Helen C Miranda [3]; Pradeep K Vuppala [4]; Rebecca B Smith [1]; Brett J Winborn [1]; Emmanuelle R Quemin [1]; Bryce [...]
- Subjects :
- Biological response modifiers -- Physiological aspects -- Health aspects
Kennedy disease -- Development and progression -- Genetic aspects -- Care and treatment
Hormone receptors -- Genetic aspects -- Health aspects
Muscular atrophy -- Analysis -- Physiological aspects -- Care and treatment
Androgens -- Physiological aspects -- Health aspects
Biological sciences
Health
Subjects
Details
- Language :
- English
- ISSN :
- 10788956
- Volume :
- 24
- Issue :
- 4
- Database :
- Gale General OneFile
- Journal :
- Nature Medicine
- Publication Type :
- Academic Journal
- Accession number :
- edsgcl.534048722
- Full Text :
- https://doi.org/10.1038/nm.4500