INT'L GUEST: Professor Kenneith Fischbeck MD, NINDS, NIH Bethesda MD : ‘Spinal and bulbar muscular atrophy’


Spinal and bulbar muscular atrophy
Kenneth Fischbeck, M.D., National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA.
Spinal and bulbar muscular atrophy (SBMA, Kennedy’s disease) is a progressive X-linked neuromuscular disorder with bulbar and extremity muscle weakness, atrophy, and fasciculations. Affected males may also show signs of androgen insensitivity. The causative mutation is expansion of a CAG repeat in the androgen receptor gene on the X chromosome. The mutation causes expansion of a polyglutamine tract in the receptor protein, which results in loss of receptor function and makes the protein toxic to motor neurons and muscle. The toxicity of the mutant protein in SBMA is likely related to the mechanism of other polyglutamine expansion diseases; as with the others it is evident in cell culture and animal models and associated with inclusion formation and protein aggregation. The mutant receptor protein has aberrant interactions with other nuclear factors, leading to transcriptional dysregulation and adverse effects on axonal transport, signal transduction, mitochondrial function, and autophagy. Importantly, the toxicity of the mutant protein is ligand-dependent in transgenic flies and mice. Androgen reduction mitigates disease manifestations in mice, but placebo-controlled trials have not yet shown effects on primary outcome measures in patients. Thus there is a need for better therapeutic targets. Other interventions such as Hsp90 inhibition that block the toxic effects of the mutant protein or enhance cellular protective mechanisms have been effective in mice. We and others have found benefits with the synthetic curcumins ASC-J9 and ASC-JM17, which reduce toxic protein levels and activate Nrf1/Nrf2. IGF-1 over-expression and administration are also beneficial in SBMA mice, and a placebo-controlled clinical trial of an IGF-1 agonist is currently underway. Finally, targeting disease gene expression with miRNA and antisense oligonucleotides has been effective in mouse models, and a clinical oligonucleotide trial is planned. SBMA currently has tractable therapeutic targets with preclinical efficacy, biomarkers to confirm target engagement, and established outcome measures to test benefit in patients. Thus the path to safe and effective treatment is clear.