Rumi, X-Chem partner to develop BRD9 inhibitor for Huntington’s
Targeting protein helping to regulate gene activity may be disease modifying
Rumi Scientific has joined with X-Chem to advance in early development a suppressor, or inhibitor, of bromodomain-containing protein 9 (BRD9) as a possible Huntington’s disease treatment.
“BRD9 inhibition is a novel target for the treatment of HD [Huntington’s disease] identified by our proprietary high throughput [neural] organoid [feature] screening platform,” Allen Fienberg, PhD, Rumi’s CEO, said in a company press release.
Neural organoids are three-dimensional cellular structures grown in a lab that mimic the development of the human brain, allowing scientists to study a disease’s underlying mechanisms and potentially identify therapeutic targets.
“We have previously demonstrated, [in lab-grown cells], that BRD9 inhibition rescues several of the biochemical dysfunctions known to occur in HD and thus could be disease modifying,” Fienberg added.
Research into an oral therapy that might stop Huntington’s disease progression
The partnership will combine Rumi’s expertise in Huntington’s organoid models with X-Chem’s ability to develop brain-penetrable molecules related to bromodomain-containing proteins, which are involved in regulating the activity of genes.
Using Rumi’s high-throughput screening platform, which is reported to rapidly tests a variety of compounds in organoids, scientists at Rumi identified BRD9 as a potential target for Huntington’s.
BRD9 is an epigenetic reader, meaning the molecule “reads” chemical marks left on DNA to control a gene’s activity by regulating how tightly DNA is packaged and how accessible it is for providing instructions that can be translated into a protein.
Researchers at Rumi found that small molecules known to broadly suppress BRDs or specifically block BRD9 could revert Huntington’s features in neural organoids and other cell disease models without major toxic effects.
Notably, some of these oral small molecules significantly reduced nerve cell death in lab-grown cells from Huntington’s patients.
In addition, experiments in a mouse model of Huntington’s showed that blocking BRD9 through an RNA-based approach ultimately prevented BRD9 production, reduced toxic huntingtin protein clumps in the brain, and improved the animals’ mobility.
Huntington’s is caused by mutations in the HTT gene, which provides instructions for producing the huntingtin protein. The mutations result in an abnormally long version of the protein that builds into toxic clumps in the brain, killing nerve cells.
Disease symptoms include uncontrolled movements and cognitive impairment, which worsen over time. While approved medications for Huntington’s help to manage symptoms, no current treatments can slow disease progression.
To narrow down the search for an oral BRD9 inhibitor that can reach the brain, the companies will design a screening protocol able to quickly and accurately predict which candidate has the greatest clinical potential.
“We are particularly excited about the unique promise of the Rumi platform and its potential to discover additional novel targets that we can take to the next level,” said Matt Clark, PhD, X-Chem’s CEO.
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