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September 25, 2006
TRICOSTATIN A (HDAC inhibitors)
This last week, Dr. Lorenzo Puri’s paper was published in Nature Medicine and for those of us on ‘google alerts’, the news came fast and furious. This paper is very interesting and opens one more door for possible therapeutic intervention in DMD. This class of drugs is known as HDAC inhibitors. These inhibitors stimulate satellite cell regeneration. In other words, they tip the scales toward regeneration. For those of us that are waiting, it is good news as several HDAC inhibitors are currently available. My head would be swimming, thinking I could ask my physician to give my son a prescription for Trichostatin A and somewhere deep inside I would hope that I had found magic – one more step forward in the quest to find the cocktail that would halt muscle degeneration. It is a very positive step forward, of course, but needs further investigation to understand if the HDAC inhibitors will work the same way in our sons. The path is clear – additional investigation and possibly pilot trials to determine if HDAC inhibitors might replace prednisone with fewer side effects and/or used in addition to prednisone. HDAC inhibitors alter the expression of many many genes in the cell, as they are acting nonspecifically, so the short and long-term effects on other organs are not well known.
WHO:
For the last several years Lorenzo Puri and collaborators have been investigating the potential benefit of HDAC inhibitors in the MDX mouse. This work has been supported by our International Partner -Duchenne Parent Project, Italy (Filippo Buccella) and the Italian Telethon.
Dr. Puri and collaborators investigated three deacetylase inhibitors (HDAC inhibitors) – Tricostatin A (TSA), Valproic Acid (VPA) and Phenylbutyrate (PhB) and found that they share the ability to promote myoblast fusion into hypernucleated myotubes with an increase in size. Among the three compounds, TSA was the best tolerated for long term treatment and did not cause noticeable side effects or signs of toxicity in the MDX mouse. Myofibers derived from TSA treated MDX mice gave rise to satellite cells that showed an increased expression of Follistatin and embryonic MyHC and formed myotubes earlier and with increased size as compared to myofibers from untreated MDX mice.
WHAT:
HDAC Inhibitors act directly on the myogenic machinery increasing the number of satellite cells. The action is similar to myostatin inhibitors although the cellular pathway is different.
WHEN:
These results will encourage additional preclinical studies to evaluate the potential beneficial effects of this group of drugs (HDAC inhibitors). It is important to further elucidate their mechanism of action in order to identify more selective strategies to counter the progression of muscle of muscle wasting. Phase I studies in children of several of the HDAC inhibitors are almost complete. These data will provide insight into dosing and toxicity and move us one step closer to clinical trials.
We will be hearing more about this approach in the coming months.
Posted by ppmd at 03:10 PM | Comments (1)