Genetic analysis unveils 3 potentially key treatment targets for PSC
Computer models also ID existing drugs that may treat cholangitis and IBD
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Researchers have identified three proteins that may be key targets for treating primary sclerosing cholangitis (PSC), and one of these proteins may also be used to treat inflammatory bowel disease (IBD), a common co-occurring condition marked by inflammation in the intestines.
The team’s work aimed to better understand the shared mechanisms between PSC and IBD — part of an attempt to uncover new treatment strategies for patients with both conditions.
The three targets — COL7A1, ABCB9, and TRIM10 — were discovered through a detailed battery of genetic analyses. The researchers also identified six existing medications that may modulate these three proteins and could therefore be promising candidates for PSC and IBD clinical trials.
“This study bridges a critical gap in targeted therapies for PSC by identifying COL7A1, ABCB9, and TRIM10 as actionable targets and supporting six drugs’ therapeutic potential in clinical trials,” the researchers wrote in detailing their findings.
“Notably, COL7A1 emerged as a stable candidate for cotargeting PSC and IBD,” the team added.
Titled “Integrative multi-omics and causal inference unveil novel therapeutic targets for primary sclerosing cholangitis and its genetic comorbidity with inflammatory bowel disease,” the study was published in the journal npj Gut and Liver by researchers in China.
An autoimmune disease, PSC is marked by inflammation in the bile ducts, a series of tubes that normally carry bile, a digestive fluid, from the liver to the intestines. Bile duct inflammation, known as cholangitis, can disrupt the flow of bile and set the stage for liver damage.
Study aimed to bridge treatment gap for patients with PSC and IBD
Current treatment options for PSC are limited, and a key challenge is its frequent co-occurrence with IBD, which is seen in about 70% of individuals with the liver-related condition. Still, the molecular mechanisms underlying the association between the two conditions remain unknown.
Now, a team led by a quartet of scientists from Peking University First Hospital in Beijing set out to identify proteins involved in the development and progression of PSC. The goal was to identify potentially useful targets for treating the disease. The scientists also sought to glean more information about the shared mechanisms between PSC and IBD.
An analysis was first conducted to comprehensively assess genetic differences between people with and without PSC, examining differences in both the genetic code and gene expression. Gene expression refers to how active individual genes are.
This far-ranging genetic analysis zeroed in on the genes that encode the proteins COL7A1, ABCB9, and TRIM10 as likely targets for PSC treatment. The COL7A1 protein was also identified to play a role in both diseases — implying that medications to target this protein might be able to treat PSC and IBD simultaneously.
These findings advance PSC drug discovery, elucidate mechanisms underlying PSC-IBD [co-occurrence], and propose dual therapeutic strategies.
After confirming the three proteins as potential PSC and IBD treatment targets, the researchers conducted further computer analyses of their molecular structure to look for existing drugs that might be able to interact with them.
Six compounds, including ursodiol — a therapy that increases bile flow and is sometimes used to help ease symptoms in PSC — and cilofexor, an experimental therapy that’s been tested in trials of PSC and other liver diseases, were able to interact with all three targets. These medications may offer promising starting points for future PSC research, the scientists said.
Overall, the researchers concluded, “these findings advance PSC drug discovery, elucidate mechanisms underlying PSC-IBD [co-occurrence], and propose dual therapeutic strategies.” The team added that the results “underscore the power of integrative genomics in accelerating drug discovery for diseases with high unmet needs.”
A notable caveat of this study is that the analyses relied primarily on computer-based models. As such, further experiments using biological models will be needed to validate the findings.
