Dr. Colleen McClung, with a Rising Star award funded by One Mind and Johnson & Johnson, is working to improve drugs for bipolar mania by pinpointing the specific HDAC inhibitors that reverse mania among those with bipolar disorder.
The mania which can disrupt the lives of bipolar disorder sufferers is often treated with mood stabilizers. While effective for many people, these drugs can lead to many unhealthy side effects. Dr. Colleen McClung is committed to the development of better mood stabilizers with lesser side effects and has studied HDAC inhibitors in order to pinpoint specific HDACs that are connected with mania.
HDACs are vital enzymes that regulate gene expression by allowing specific genes to produce proteins. McClung’s earlier research in mice suggests that, in people with specific gene variants that appear to promote the mania, mood stabilizers work therapeutically by inhibiting HDACs. These HDAC inhibitors allow expression of gene variants that apparently reduce mania and help stabilize mood. However, current mood stabilizers, like Valproate (Depakotetm), cause several types of HDACs to be inhibited instead of just targeting the specific HDACs involved in mania. They also have effects on many other proteins that are not involved in mood regulation. This is the cause of side effects like: weight gain, liver or kidney impairment, nausea, and tremors. On the road to a better mood stabilizer with fewer side effects, Dr. McClung is conducting experiments to target only the specific HDAC inhibitors that relate directly to mania.
In order to identify effective HDAC inhibitors, Dr. McClung uses her original mouse mania model, which utilizes mutant mice with a specific genetic mutation called Clock∆19. This mutation results in bipolar behavior, including mania.
Dr. McClung’s lab has been working to differentiate whether class l HDAC inhibitors or class lla HDACs inhibitors reduce mania among mutant mice. MS-275, a drug that inhibits class l HDACs has been administered continuously to the Clock∆19 mutant mice and initial results from Dr. McClung’s lab have shown that MS-275 has effectively normalized mania-like behavior including anxiety and depression related behaviors. Other early pilot studies using ACY-957 also targeted class l HDACs and showed reduced mania among the mutant mice. In contrast, the administration of MC-1568, which is a class lla HDAC inhibitor, had no effect on mania-like behaviors among the mutant mice. McClung tell us, “these results really serve to focus our attention on the class I HDACs (HDAC1, 2, 3, and 8) for further analysis ¬ However, an even more selective compound would be preferred since it should have fewer side effects”. Most current mood stabilizers inhibit both class l and lla HDACs but with Dr. McClung’s research better and more effective drugs to treat bipolar disorder are on the near horizon.
McClung’s team has also made some exciting discoveries concerning how the suppression (i.e., the knock-down) of specific class l HDAC genes might remedy the manic behaviors. After establishing that class l HDAC inhibitors reduced mania, Dr. McClung moved on to identify which specific class l HDACs (HDAC1, HDAC2, HDAC3, HDAC 8) were most closely related to mania. Dr. McClung tells us that, “Interestingly we find that knock-down of HDAC2 in both cases leads to a reduction of manic-like behavior in the Clock∆19 mice. The knock-down of HDAC1 thus far has had no effect, suggesting that HDAC2 is the therapeutic target that we should focus on for future drug development. This is very exciting since it will allow very specific treatment development that should be more effective and produce far fewer side effects then valproate (Depakotetm) which is currently used in the clinic.” Her team still plans to investigate HDAC 3 and HDAC 8 to confirm that they are not connected with manic behavior. Incidentally, the team also found that both HDAC1 and HDAC2 inhibition reduced anxiety-related behavior in wild-type mice (mice without mutation). Dr. McClung says, “This suggests that perhaps HDAC1 inhibition might be a preferred therapeutic target for the treatment of anxiety disorders if this effect is highly specific.”
We at One Mind are impressed with Dr. McClung’s research and are inspired by her commitment to improving the lives of those suffering from bipolar disorder.