|Dr Haloom Rafehi|
Developing new drugs is an expensive, time-consuming and labour-intensive process.
As costs skyrocket, drug repurposing or repositioning – a process by which existing, clinically approved drugs are repurposed for different conditions – is attracting increasing interest.
A new study by Monash University scientists from the Department of Diabetes investigated the approach and found a group of such drugs that could potentially be used to help counter diabetic complications.
The researchers, led by Professor Sam El-Osta, explored potential candidates for drug repurposing called histone deacetylase (HDAC) inhibitors; potent enzymes that can switch genes on or off by changing the way DNA is structured inside the cell.
First author Dr Haloom Rafehi says the scientists conducted a meta-analysis of available online data that allowed them to study thousands of genes from multiple datasets at the same time. “We wanted to investigated whether HDAC inhibitors had similar effects on gene expression in different cell types,” Dr Rafehi said.
HDAC inhibitors have been used predominantly for cancer treatment meaning most of the studies conducted on them previously were on different types of cancer cells with some on normal cells. The researchers combined the data and were able to find common changes in gene expression that were affected by the inhibitors in both cancer and healthy cells.
They then tested whether the effect the HDAC inhibitors had on the ways genes were expressed applied to other diseases.
“Our meta-analysis of predominantly cancer cells supported the idea that HDAC inhibitors can potentially be used to treat cardiovascular disease, which has already been identified in animal models,” she said. “We could predict this from a completely different cell type.”
Having validated the approach, the researchers went on to show that it could potentially be used on diabetic complications. In a follow-up study testing vascular endothelial cells from both a healthy individual and one with diabetes, they showed the inhibitors could reverse the effects of diabetes in the cells.
“The pharmaceutical industry is faced with economic barriers related to the skyrocketing costs to develop new drugs coupled with longer development times for clinical trials, therefore, we are examining repositioning to shorten the timescale of drugs that have already passed development and clinical testing.
“HDAC inhibitors have a proven track record of safe clinical use. That, combined with their potential broad applicability, makes them good candidates for drug repurposing,” Dr Rafehi said.
The study builds on a paper that appeared in the high-impact journal Genome Research in 2014 in which the researchers showed that vorinostat – an HDAC inhibitor currently used to treat some forms of cancer – could control inflammation. “Inflammation plays a major role in many diseases, so that’s something we want to try to control,” Dr Rafehi said.
Rafehi H, Kaspi A, Ziemann M, Okabe J, Karagiannis TC, El-Osta A. Systems approach to the pharmacological actions of HDAC inhibitors reveals EP300 activities and convergent mechanisms of regulation in diabetes. Epigenetics. 2017 Sep 8:0. doi: 10.1080/15592294.2017.1371892. [Epub ahead of print]
Rafehi H, Balcerczyk A, Lunke S, Kaspi A, Ziemann M, Kn H, Okabe J, Khurana I, Ooi J, Khan AW, Du XJ, Chang L, Haviv I, Keating ST, Karagiannis TC, El-Osta A. Vascular histone deacetylation by pharmacological HDAC inhibition. Genome Res. 2014 Aug;24(8):1271-84.