Bicalutamide and trehalose show promise in mouse model of SBMA
Treatment found to extend survival and improve motor function
Treatment with bicalutamide and trehalose extended survival and improved motor function in a mouse model of spinal and bulbar muscular atrophy (SBMA), a study has found.
Both compounds had beneficial effects on some aspects of muscle fiber structure and reduced cell death. While bicalutamide also lowered levels of toxic protein clumps, trehalose reversed impairments in cellular energy production.
Altogether, the treatments “ameliorated SBMA pathology,” the researchers wrote, adding that the compounds are “valuable candidates for future clinical trials in SBMA patients.”
The study, “Bicalutamide and Trehalose Ameliorate Spinal and Bulbar Muscular Atrophy Pathology in Mice,” was published in Neurotherapeutics.
SBMA is a slowly-progressing, adult-onset form of SMA that affects mostly men
SBMA, also called Kennedy’s disease, is a slowly-progressing, adult-onset form of SMA that mostly affects men. Like other SMA types, SBMA is marked by the degeneration of nerve cells involved in controlling voluntary movements, leading to progressive muscle weakness and wasting.
This rare form of the disease is caused by mutations in the AR gene, in particular an excess repetition of a specific trio of nucleotides — the building blocks of DNA. This abnormality, called a polyQ expansion, leads to the production of an abnormal version of the androgen receptor (AR) protein.
AR is a kind of receptor that binds to male sex hormones called androgens — the most common of which is testosterone — and this complex controls the expression of multiple genes involved in sexual characterstics.
However, the polyQ expansion that causes SBMA leads to the production of an AR protein that’s prone to misfold and accumulate inside the nucleus of nerve and muscle cells, disrupting their function.
Thus, treatment approaches that prevent this toxic version of the protein from reaching the nucleus are of significant interest.
Researchers in Italy previously found that bicalutamide, an AR blocker approved to treat prostate cancer, was able to increase the degradation of mutant forms of AR in the cytoplasm — the gelatinous liquid that fills the inside of a cell — of an SBMA nerve cell model. It did so via a cellular process called autophagy, in which unneeded and dysfunctional proteins are broken down and recycled.
These effects were further enhanced when bicalutamide was combined with trehalose, a naturally occurring pro-autophagy sugar molecule that’s being investigated as a treatment for some neurodegenerative diseases.
In the new study, the research team examined the effects of these molecules, alone and in combination, in a mouse model of SBMA. Mice were given bicalutamide injections twice per week, trehalose in their drinking water, or both medications simultaneously.
As expected, the mouse model of SBMA exhibited significantly shorter survival compared with healthy control mice, with 39% of SBMA mice surviving to one year of age.
While trehalose tended to increase median survival time, only bicalutamide significantly increased the percentage of animals surviving after a year. Specifically, 61% of mice given bicalutamide alone and 52% of those given the combination survived for one year.
The SBMA mouse model also exhibited significant motor impairments, including deficits in coordination and grip strength, which emerged at about six months of age.
When treatment was started early, at six weeks of age, motor coordination deficits were completely prevented with trehalose, but not with bicalutamide or the combination treatment. Still, grip strength was significantly improved in bicalutamide-treated mice, with or without trehalose, after 46 weeks.
However, the researchers suspected that the early start of bicalutamide treatment may have had adverse effects on muscle development. Consistently, when treatment was instead started at 12 weeks of age, after muscle development is complete, bicalutamide and the combination treatment were also able to prevent motor coordination deficits.
Treatment influenced important cellular processes involved in SBMA
Mechanistically, bicalutamide and trehalose demonstrated an ability to partially recover more normal structure of muscle fibers in the SBMA mouse model, but did not significantly counteract a loss of motor neurons in the spinal cord.
Bicalutamide alone or in combination with trehalose also reversed the formation of insoluble AR clumps in the skeletal muscles, and showed signs of promoting autophagy to clear the unwanted proteins.
All three treatment approaches were able to reduce apoptosis, a type of cell death that was increased in the muscles of SBMA mice. Abnormalities to mitochondria, the centers of energy production for cells, were also observed in the early symptomatic stages of the SBMA mouse model, but were reduced with trehalose.
Overall, the study “reveals alterations in muscle morphology and function at an early symptomatic stage of the disease in SBMA … mice, underlying the importance of developing muscle-targeted therapeutic intervention,” the researchers wrote.
Although bicalutamide and trehalose did not seem to exhibit additive effects, each treatment did influence important cellular processes involved in SBMA, they added.
“Altogether, this resulted in a partial recovery of the original muscle fiber morphology and in an improved motor behavior and extended survival of SBMA mice,” the team concluded.