Overactive function of normal androgen receptor protein and its interaction with disease-modifying "partner proteins" has been implicated as the specific underlying cause of motor neuron (nerve cell) degeneration and death in spinal-bulbar muscular atrophy (SBMA, or Kennedy disease).
|MDA grantee J. Paul Taylor currently is working to identify drugs that may be used in the development of selective AR-based treatments in SBMA.|
It's long been known that the molecular basis of SBMA is an abnormally expanded section of DNA in the androgen receptor (AR) gene. What had remained unclear, until now, was the specific mechanism underlying the loss of neurons in the brain stem and spinal cord that result in the disease's primary symptoms — progressive weakness in the muscles of the mouth, throat, face and limbs.
A multinational team of scientists and physicians from the United States and Italy collaborated on the project to solve the mechanism mystery. MDA funded team members Maria Pennuto at the Italian Institute of Technology in Genova, Italy, and J. Paul Taylor at St. Jude Children's Research Hospital in Memphis, Tenn.
If the findings are borne out in further testing, they may point the way to development of SBMA therapies based on the selective inhibition of particular AR protein functions.
About the new findings
The new findings, reported online Sept. 23, 2010, in the journal Neuron, represent a departure from the standard model of neurodegenerative disease, in which the "usual suspect" in motor neuron degeneration is a toxic buildup of misfolded proteins inside cells.
Instead, the researchers concluded, the SBMA disease process is caused at least in part by increased activity of normal AR protein and its interactions with a number of disease-modifying partner proteins, known as "coregulators" for their shared role in regulating gene activity.
In experiments conducted both in cultured human cells and in a fruit fly research model, the investigators identified a number of coregulator proteins that interact with the AR protein. Some (but not all) of the coregulators' interactions with the AR protein contributed to nerve cell degeneration.
Using a variety of techniques, the study team showed that inhibition of these particular interactions stops degeneration and rescues the cell.
Current AR therapies
Although therapies don't yet exist for treatment of SBMA, several medications designed to block AR protein activity already have been approved by the U.S. Food and Drug Administration (FDA) for treatment of other AR-related disorders, including prostate cancer and hair loss in men, and endometriosis in women.
The downside to the current treatments, which completely block AR protein function, are unwanted side effects in adult males that can include infertility, decreased sex drive, muscle and bone thinning, and breast enlargement. Suppression of the immune system, depression and cognitive deficits can occur as well.
It's preferable to target specific functions or interactions of a protein (as opposed to blocking it completely), Taylor said, but this requires knowing the precise aspect of normal protein function one wishes to modify.
"The advantage we've had with the androgen receptor," Taylor noted, "is that we know a lot about its normal functions, and in this paper we've identified the precise region that is desirable to target."
The region upon which Taylor's team is focusing also is being targeted by other drug programs attempting to generate drugs called "selective androgen receptor modifiers" (SARMs). The goal is to develop compounds that inhibit androgen receptor function in a highly specific way, targeting SBMA disease-modifying interactions between AR and relevant coregulator proteins and avoiding the serious side effects that result from complete blockage of AR protein function.
Taylor's laboratory team has obtained candidate SARMs and related compounds, and currently is working to identify those able to disrupt interactions between AR and the disease-modifying proteins implicated in neurodegeneration in SBMA.
Meaning for people with SBMA
Long-term implications of these findings include the potential for development of precision-targeted therapies for SBMA. The fact that the FDA has approved medications for other AR-related conditions may help speed development, testing and approval of selective AR protein-based treatments for SBMA.
The findings also suggest that achieving the greatest impact with selective AR-based treatments in SBMA may require early treatment (prior to the onset of puberty) in order to prevent motor neuron damage.
"It's possible that the damage in SBMA takes place over a long period of time, maybe beginning as early as puberty," Taylor said. "So a less toxic, less life-altering therapy that could be given to young men and taken over a lifetime is preferable."
Further studies are needed to replicate the results in an animal model, after which drug candidates for therapy may be identified, developed and tested.