Looking for ways to help it do its day job

I was reading an article the other day about the move that some researchers are making towards trying to reprogram genes to help them clean up waste materials in nerve cells. The article mentions Kennedy's Disease, Parkinson's Disease, Huntington's Disease, ALS, and other diseases of the motor neurons. The article was well written (i.e., I could understand it), but it is only an overview and does not really go into any detail about the current research in this area. The link to this article is Hoarding Junk is Hard on the Nerves in Neurodegenerative Diseases. Reading the article, however, made me want to write a little more about the mutated gene in Kennedy's Disease.

Since the mutation in the CAG (three pieces of DNA that are repeated and expanded in people with Kennedy's Disease) caused the Androgen Receptor to not function normally, most of the earlier research and clinical trials focused on blocking the AR from trying to "do its day job" (cleaning the cell of garbage). Since we cannot change the gene, researchers are attempting to change the process (normalize it) to remove or minimize the toxicity (trying to make the protein behave normally).

In several posts I wrote about how some researchers today are trying to find a way to make the Androgen Receptors "do their day jobs." The two recent articles on IGF-1 (Part I and Part II) are an example of this new way of thinking. Maria Pennuto explained more about the AR's role (its day job), and how IGF-1 might help it to continue to do its job if we catch the mutation early enough.

Dr. Diane Merry in a chat last fall talked about her team's approach and some researchers at Duke University working on ways to allow the AR to do its day job and still slow the progression of Kennedy's Disease. "Donald McDonald at Duke has been designing whole libraries of compounds that bind to the AR and prevent the shape change that we have found to be involved in the toxicity. So, the nice thing about the Duke compounds, called SARMs for selective AR modulators, is that they can bind to the AR, prevent its toxicity (in our initial studies), but still allow the AR to do its day job. ASC-J9 (another potential treatment) seems to prevent aggregation and promote the shredding of the protein, probably by directly affecting the shape change of the AR."

Heather Montie's chat last December also discussed how earlier and current research differs on combating the mutation. "So Leuporelin, the drug they used in Japan's clinical trial, which inhibits testosterone formation, keeps the AR out of the nucleus. To an extent, Avodart does kind of the same thing, since it inhibits the more potent androgen (DHT) from being made. My work gave us clues as to what we need to focus on … direct a therapy towards the events that occur within the nucleus when the mutant AR is there ... that leads to toxicity. My current project concerns a modification that normally occurs to the AR ... called Acetylation. It is the addition of a chemical group to the AR protein, which allows it to do various things within the nucleus. I have found that if you inhibit this 'modification' it inhibits the toxicity of the mutant AR. But, this poses a little bit of an issue, because inhibiting this 'modification' decreases the AR's ability to do its 'day job.' So, I have also found that if you just 'toggle' down this modification a little bit, it still rescues cells and motor neurons from mutant AR's toxic effects."

Personally, I like the concept of allowing the AR to do its day job. It seems more normal than trying to prohibit or inhibit the AR from functioning. I am anxious to hear more about this approach and hope to see a clinical trial soon.