A naturally occurring form of the androgen receptor protein — which scientists have named AR45 because of its size — may be useful for treating spinal and bulbar muscular atrophy (SBMA), a rare form of adult-onset spinal muscular atrophy, a new study suggests.

In the lab, a treatment using AR45 was found to delay disease onset in a mouse model of SBMA, also called Kennedy’s disease, and to extend the animals’ survival.

“A study published in Science Advances shows very promising results for gene therapy treatment of neuromuscular conditions — and beyond,” the researchers said in a press release.

Their study is titled “Gene therapy with AR isoform 2 rescues spinal and bulbar muscular atrophy phenotype by modulating AR transcriptional activity.”  

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SBMA is caused by mutations in the gene that codes for the androgen receptor protein, or AR. This protein helps to coordinate many biological activities by regulating transcription, or how genes are “read” by the cell.

Under the right circumstances, AR can prompt cells to “read” specific genes. However, researchers are still working to understand the details of this protein’s functions.

Now, a team led by scientists at the University of Oxford, in the U.K., conducted an analysis to identify isoforms of AR. An isoform is a version of the protein that is very similar, but has slight modifications that may influence its activity. 

The researchers found nine different isoforms of AR. One of these — named AR45, because this version of the protein is 45 kilodaltons in size — attracted the team’s attention because it was widely expressed by cells in the body. A kilodalton is a unit of mass that’s used to express molecular mass, especially for large molecules.

“By performing deep transcriptomic analysis of human tissues, we have identified several naturally occurring isoforms of the transcription factor androgen receptor (AR),” said Carlo Rinaldi, MD, PhD, of the MDUK Oxford Neuromuscular Centre and a study co-author.

“One of these, AR isoform 2, attracted our interest because it is the most highly expressed, particularly in AR-responsive cell populations, such as motor neurons and skeletal muscle,” he said.

Rinaldi noted the “critical importance of AR transcriptional control” in a number of disorders in addition to muscular atrophies.

“Intriguingly, we found that this isoform, which encodes a truncated AR 45 kilodaltons in size (hence the name AR45), plays a fundamental role in biology by acting as a transcriptional decoy, fine-tuning AR activity,” Rinaldi said.

To understand the function of AR45, the team then conducted a battery of biochemical and cellular experiments.

The findings showed that increasing levels of AR45 led to a decrease in the expression of AR target genes in cells, and vice versa. Further testing confirmed that AR45 worked essentially by blocking the interaction between AR protein and its target genes, thereby lessening the activity of AR.

That led the team to wonder if AR45 might be useful in SBMA, given the fact that AR binding to its target genes has been shown to be “critical” for the development of the rare disorder, they said.

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To test this, the researchers used a mouse model of SBMA. They developed a viral vector — specifically using a virus called adeno-associated virus 9, or AAV9 — that could carry the genetic code for making AR45 to the mice’s cells.

The results showed that this treatment delayed disease onset by 12 days, and extended the animals’ survival from a median of 87 to 102 days.

Treated mice also showed improvements on measures of motor function and grip strength, and cellular analyses suggested that the treatment normalized transcription activity. The treatment did not cause any notable toxicity in the mice. 

“This strategy restored the altered transcriptional profile in affected tissues and strongly ameliorated the disease phenotype in mice, laying the ground[work] for an innovative gene therapy approach,” Rinaldi said.

Overall, the team concluded that their study provides “proof-of-principle evidence of efficacy and safety of a gene therapy strategy based on AAV9-mediated delivery of the AR variant AR45 in SBMA mice, with high potential to be translated into a treatment for patients,” they wrote.

According to the team, given the key role AR plays in various diseases, this AR45 variant could potentially be a therapeutic target not only for SBMA but also for other AR-related disorders.

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