Targeting ‘overlooked’ gene could lead to new treatments for IPF: Study
ACVRL1 and LTBP1 gene activity may help predict patients' survival
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Mutations in the ACVRL1 gene may play a role in the development of idiopathic pulmonary fibrosis (IPF), and targeting the gene — until now, little noted, according to researchers — could potentially lead to new treatments for the respiratory disease, a study suggests.
Additionally, according to the scientists, the study results show that the expression, or activity, of ACVRL1 and another gene called LTBP1 may help predict survival outcomes in people with IPF. Specifically, low activity of one and high expression of the other were significantly associated with worse survival odds for patients.
Further study into both genes is needed for a better understanding of IPF lung disease, the team noted.
“These findings highlight ACVRL1 as a compelling and previously overlooked therapeutic target,” the researchers wrote. “Future drug development efforts could focus on strategies aimed at restoring or enhancing ACVRL1 function.”
The study, “Multi-omics Analysis Reveals the Prognostic and Therapeutic Value of TGF-β Signaling-related Genes in Idiopathic Pulmonary Fibrosis,” was published in the journal Biochemical Genetics.Â
IPF is a chronic disorder marked by fibrosis, or scarring, in the lungs. A signaling molecule called transforming growth factor beta (TGF-beta) is known to play a key role in driving fibrosis in IPF — implying that inhibiting this molecule could help slow disease progression.
But TGF-beta is also vital for regulating a host of normal bodily functions, so it’s difficult to target the signaling molecule itself without causing substantial side effects.
An alternative approach would be to specifically target genes or proteins that are part of the specific TGF-beta signaling pathways that drive fibrosis in the lungs. Theoretically, this could help limit lung fibrosis while minimizing side effects elsewhere in the body. Identifying such genes could also help shed light on the underlying biology of IPF, the cause of which, as its name notes, remains unknown.
Scientists look for overlooked genes tied to IPF progression
Seeking to find such genes, scientists in China conducted detailed computational analyses using gene expression data. Gene expression refers to the extent to which individual genes are turned on or off.
“A comprehensive understanding of the functions of TGF-[beta] signaling pathway-related genes in IPF is vital for elucidating the mechanisms underlying disease onset and progression,” the scientists wrote.
The researchers’ analyses zeroed in on two TGF-beta-related genes, ACVRL1 and LTBP1, that appear to play central roles in IPF lung disease. Specifically, data suggested that people with IPF tend to have abnormally low expression of ACVRL1 and abnormally high expression of LTBP1.
“Our study identified ACVRL1 and LTBP1 as core genes within the TGF-[beta[ signaling pathway that possess significant potential for clinical translation,” the scientists wrote.
These results underscore the prognostic potential of ACVRL1 and LTBP1 in IPF, as their [activity] levels are significantly associated with disease severity and patient survival outcomes.
Analyses indicated that both low ACVRL1 expression and high LTBP1 expression were significantly associated with worse survival odds for IPF patients. The expression of these genes also correlated with measures of lung function.
“These results underscore the prognostic potential of ACVRL1 and LTBP1 in IPF, as their expression levels are significantly associated with disease severity and patient survival outcomes,” the researchers wrote.
The team added that data suggest that looking at the expression of these genes “could enhance the accuracy of prognostic models and help identify patients at high risk of rapid disease progression.”
ACVRL1 identified as treatment target to explore
The researchers also conducted a Mendelian randomization (MR) analysis, a type of genetic examination that aims to identify potential cause-and-effect relationships between genetic mutations and diseases. This work suggested that certain mutations in the ACVRL1 gene may directly contribute to causing IPF and that higher ACVRL1 activity was associated with a reduced risk of IPF.
Additional analyses using single-cell gene expression data indicated that endothelial cells — those lining blood vessels — lacking ACVRL1 undergo major shifts in their metabolism.
Collectively, these data support further investigation of the ACVRL1 gene in particular as a potential treatment target for IPF, the scientists said. The team called for future study into the biological activity of ACVRL1 and LTBP1 in IPF, as well as efforts to explore potential treatment strategies.
“Our study highlights the crucial role of TGF-[beta] signaling dysregulation in IPF and provides potential therapeutic targets for future research,” the researchers concluded, adding that “these findings may enhance our understanding of IPF and could potentially contribute to its treatment.”
