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Updated: Jun 8, 2026
Delivery of Therapeutic Agents Through Intracerebroventricular (ICV) and Intravenous (IV) Injection in Mice
Published on: October 3, 2011
Therapeutic approaches to spinal and bulbar muscular atrophy
Srikanth Ranganathan1, Kenneth H Fischbeck
1Neuronal Survival Unit, Wallenberg Neuroscience Center, Lund University, BMC A10, 221 84 Lund, Sweden.
Abstract:
Spinal and bulbar muscular atrophy is a hereditary motor neuron disease caused by trinucleotide repeat expansion in the androgen receptor gene. The disease mechanism probably involves a toxic gain of function in the mutant protein, because other mutations that cause a loss of androgen receptor function result in a different phenotype and the mutant protein is toxic in mouse models. In these models, the toxicity is ligand-dependent and is associated with protein aggregation, as well as altered transcriptional regulation, axonal transport and mitochondrial function. Various therapeutic approaches have shown efficacy in mouse models, including androgen reduction, heat shock protein 90 (HSP90) inhibition and insulin-like growth factor (IGF)-1 overexpression. Clinical trials of androgen-reducing agents have had mixed results, with indications of efficacy but no proof of clinically meaningful benefit to date. These clinical studies have established outcome measures for future trials of other agents that have been beneficial in animal studies.
Insights
Spinal and bulbar muscular atrophy (SBMA) is a motor neuron disease caused by a toxic androgen receptor gene expansion. Therapies effective in mouse models show mixed results in human trials, highlighting the need for better treatments.
Area of Science:
- Neuroscience
- Genetics
- Molecular Biology
Background:
- Spinal and bulbar muscular atrophy (SBMA) is a hereditary motor neuron disease.
- It is caused by trinucleotide repeat expansion in the androgen receptor (AR) gene.
- The disease mechanism involves a toxic gain of function in the mutant AR protein.
Purpose of the Study:
- To review the disease mechanisms of SBMA.
- To discuss therapeutic approaches evaluated in SBMA mouse models.
- To assess the clinical trial outcomes of SBMA treatments.
Main Methods:
- Review of preclinical studies in SBMA mouse models.
- Analysis of clinical trial data for SBMA therapeutics.
- Evaluation of disease mechanisms including protein aggregation and transcriptional dysregulation.
Main Results:
- SBMA mouse models demonstrate ligand-dependent toxicity, protein aggregation, and altered cellular functions.
- Therapeutic strategies like androgen reduction, HSP90 inhibition, and IGF-1 overexpression show promise in preclinical studies.
- Clinical trials of androgen-reducing agents have yielded mixed results, with no definitive clinical benefit established.
Conclusions:
- SBMA pathogenesis involves toxic gain of function of the mutant androgen receptor.
- Preclinical therapeutic strategies show potential but require further validation.
- Established clinical outcome measures will guide future SBMA treatment trials.
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