May 5, 2020

BIOLOGICAL MECHANISMS DRIVING HDAC INHIBITOR TREATMENT EFFECTS IN RP

Valproic acid (VA), belongs to a family of drugs called HDAC inhibitors (HDACi) and has been tested as a potential treatment for retinitis pigmentosa (RP) with mixed results. In some clinical trials, participants who took VA had improved vision and in other trials VA treatment led to worse vision. What could cause such dramatically different results? There is some evidence that the results may be dependent on the specific gene mutation that caused RP. However, this leads to the questions of why would this happen and is there a way to predict who will benefit from VA or other HDACi treatments? These questions get to the heart of Dr. Orson Moritz’s FBC funded project on understanding the biological mechanisms driving HDACi treatment effects in RP.

Researchers know that many genetic mutations that cause RP lead to a build-up in damaged proteins or “garbage” in light sensing photoreceptor cells. It’s as if the city stopped picking up the garbage, and piles slowly collected and eventually overwhelmed the city or in this case the photoreceptor cell. Dr. Moritz’s research asks if HDACis help the photoreceptor cells clear this “garbage” by increasing a process called autophagy. Doing experiments in photoreceptor cells, his team found that HDACis did protect photoreceptor cells with the RHO P23H mutation, the most common cause of autosomal dominant RP, but had no effect on photoreceptor cells with three other RP mutations. HDACis also increased autophagy in these photoreceptors with the RHO P23H mutation, but interestingly, this was not why cells survived better, since another drug that also increased autophagy didn’t have the same effect. With this information in hand, the team is now looking at new strategies to increase the cell’s ability to clear “garbage.”

Dr. Moritz’s work, provides evidence that drug treatments can have vastly different effects depending on the underlying genetic mutation. As he explains, “This is a cautionary tale that suggests clinical trials should be designed to target forms of RP with well-characterized disease mechanisms and not applied indiscriminately, otherwise, the trial may fail to discover an effect, even if the treatment works in some people. Our studies help to define these underlying mechanisms, and to group RP into genetic subsets with similar underlying mechanisms that presumably would require similar treatments.”