Targeting 2 specific proteins shows promise for SBMA in early models

Gene-silencing therapy was able to improve muscle strength and coordination

Lindsey Shapiro, PhD avatar

by Lindsey Shapiro, PhD |

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A gene-silencing therapy designed to lower the levels of two proteins was found to improve muscle strength and coordination in a mouse model of spinal and bulbar muscular atrophy (SBMA), a new study shows.

The therapy, which targets the protein lysine-specific demethylase 1 (LSD1) and the protein arginine methyltransferase 6 (PRMT6), also partially normalized the activity of genes involved in muscle development and function.

Of note, both LSD1 and PRMT6 are elevated in SBMA muscle tissue and these proteins work together to increase the activation of an abnormal version of the androgen receptor (AR) protein that drives SBMA symptoms.

Overall, the study offers “proof-of-principle that selectively targeting AR co-regulators that are aberrantly expressed in tissues that primarily degenerate in SBMA is a valuable therapeutic strategy,” researchers wrote.

The study, “LSD1/PRMT6-targeting gene therapy to attenuate androgen receptor toxic gain-of-function ameliorates spinobulbar muscular atrophy phenotypes in flies and mice,” was published in Nature Communications

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SBMA is a rare, adult-onset form of spinal muscular atrophy caused by mutations in the AR gene. These mutations involve the abnormal repetition of a section of DNA in the AR gene, ultimately leading to an abnormal and elongated version of the AR protein — dubbed polyQ-AR.

Androgen receptors are normally responsible for mediating the effects of androgens, sex hormones such as testosterone that are produced at higher quantities in men and determine sex-related characteristics. When androgens bind to ARs, these receptors set off signaling pathways that influence activity of a wide range of genes.

The cellular consequences of SBMA mutations are complex and not fully understood, but in part involve a toxic overactivity (gain-of-function) of polyQ-ARs when androgens bind to them.

On the other hand, SBMA patients exhibit signs of AR loss-of-function, in which androgen receptors respond poorly upon binding of androgens, which can lead to androgen insensitivity and symptoms like sexual or metabolic problems.

No therapies currently available to cure or delay SBMA progression

There are currently no therapies to cure or delay SBMA progression. An ideal therapy would target this toxic gain-of-function of polyQ ARs while avoiding potentially harmful consequences of AR loss-of-function, according to researchers.

In the study, the researchers were interested in identifying whether targeting LSD1 and PRMT6 might be a good therapeutic approach for SBMA. These proteins are known co-activators of ARs, meaning they boost AR activity in response to androgens. Still, their potential interactions with the abnormal polyQ-ARs hasn’t been fully established.

A team led by researchers in Italy set out to study these proteins in models of SBMA.

In skeletal muscle tissue from multiple mouse models and SBMA patient cells, the genes encoding both PRMT6 and LSD1 were found to have high expression, or activity, compared with healthy tissue. This elevated expression appeared to be dependent on the presence of androgens.

Each of the proteins individually worked to boost AR activation, but their interaction amplified these effects, with both proteins needed for ARs to be fully activated by androgens. Moreover, the effects of LSD1 and PRMT6 on ARs was even more pronounced in polyQ-ARs compared with normal ARs.

“These observations highlight an intimate relationship in normal and polyQ-expanded AR co-regulation by LSD1 and PRMT6,” the researchers wrote.

In a fly model of SBMA, cellular toxicity can be easily monitored because it is reflected by a degeneration of tissue in the eye. When the genes encoding LSD1 and PRMT6 were silenced in this fly model, this toxicity was “strongly suppressed,” the researchers noted.

This finding prompted the researchers to develop a therapeutic strategy that would reduce the activity of these AR co-regulators in a mouse model.

The approach involves the use of molecules called microRNAs that work to silence the genes encoding LSD1 and PRMT6 and reduce the production of these two proteins. It’s packed into a viral carrier called an adeno-associated virus, which helps it to be taken up by the body’s cells.

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Therapy led to improvements in muscle strength and motor coordination

Findings in cell cultures and mice revealed that the therapy could significantly reduce activity of the genes, with particular effects in skeletal muscles.

In an SBMA mouse model, the therapy led to small, but significant increases in body weight, indicative of better health, and significant improvements in muscle strength and motor coordination. Other signs of muscle abnormalities were also reduced with treatment.

Moreover, the treatment led to a partial normalization of gene expression changes that are observed in the SBMA model. Genes with complete or partially normalized activity were often involved in energy metabolism or muscle structure, development, and function.

In a final experiment, the team demonstrated that their microRNA approach could be used to silence LSD1 and PRMT6 in human cells, “suggesting a potential translation of this strategy to SBMA patients and possibly other AR-associated … diseases,” the researchers wrote.

While LSD1 and PRMT6 appear to be key players, other co-regulators may also play a role, the team noted. “There is a need for further investigation of the impact of dysregulated co-regulators in vulnerable SBMA tissues,” they wrote.