SBMA Mice Answer Some Questions, Raise Others

Researchers coordinated by Andrew Lieberman, an MDA grantee at the University of Michigan in Ann Arbor, have developed a new mouse model of spinal-bulbar muscular atrophy (SBMA, or Kennedy’s disease) that they say will improve understanding of the human disease.

Their method was distinct from one employed by MDA grantee Albert La Spada at the University of Washington-Seattle and colleagues, although both groups used established technologies.

Publishing their results in the October issue of the Journal of Clinical Investigation, they report that, contrary to previous assumptions, SBMA is not only a disease of the muscle-controlling nerve cells known as motor neurons, but that it also results from direct damage to muscle fibers.

“Understanding the muscle disease that occurs in SBMA patients and in our mice may help us define the processes that lead to this disease and may point toward new therapeutic strategies,” Lieberman said.

The researchers bred mice with an expanded section of DNA in the gene for the androgen (male hormone) receptor on the X chromosome, the defect known to cause human SBMA. Like men with SBMA, the mice developed shrunken testicles, decreased fertility and weakness.

Castrating the mice (thereby removing all androgen activity) improved their grip strength, and implanting androgen pellets reversed the improvement, which the researchers say means the weakness is dependent on androgen levels.

La Spada’s experiments showed that SBMA-affected mice that retained some androgen receptor function fared better than those without any, which suggested to him that blocking all androgen activity might not be a good idea. In addition, he noted, blocking male hormones is a “very unappealing therapeutic intervention,” not only for the more obvious reasons but because sudden reduction in androgen levels adversely affects brain function.

La Spada says SBMA results from two problems: expanded DNA in the androgen receptor gene, which requires androgens to become toxic; and a lack of normal androgen receptor function, which would help motor neurons withstand stressful conditions.

His mice, which have expanded androgen receptor DNA inserted on an artificial chromosome, show muscle shrinkage resulting from motor neuron damage and have a disease course that’s slowly progressive, like human SBMA.

Lieberman’s mice, which have expanded androgen receptor DNA inserted into one of their own chromosomes, show motor neuron damage, as do SBMA patients, as well as direct muscle damage (until now, not suspected in patients), yet they have a more rapid disease course than humans do, die early (unlike patients), and show disease in muscles of the urinary tract that’s not seen in patients.

“It’s good to have different models, because they can provide you with different windows into what’s going on in different aspects of the disease process, and because they will be useful in different ways for testing new treatments,” La Spada said.