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Potential drug target identified for eosinophilic esophagitis
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Researchers have identified calpain 14 as an interleukin-13–induced protease that contributes to impairment of the esophageal epithelial barrier in patients with eosinophilic esophagitis. These findings suggest that controlling calpain 14 activity could prevent the development of eosinophilic esophagitis, and may represent a potential drug target, according to a press release.
“We recently interrogated [more than] 1.5 million genetic variants in EoE and identified the strongest genome-wide association at 2p23 spanning the calpain 14 (CAPN14) gene, ... a finding that has already been replicated by an independent group,” Marc E. Rothenberg, MD, director of the Center for Eosinophilic Disorders at Cincinnati Children’s Hospital Medical Center, and colleagues wrote. In this prior study, they found that CAPN14 was primarily expressed in the esophageal epithelium, and was upregulated after exposure to IL-13, which has been previously linked to the EoE allergic process.
Marc E. Rothenberg
However, the causal mechanism of CAPN14 in EoE had not yet been described.
“We now show that recombinant CAPN14 cleaves a calpain-specific substrate and is inhibited by four classical calpain inhibitors,” the researchers wrote.
In their NIH-supported study, Rothenberg and colleagues collected esophageal biopsies from patients with EoE and exposed the epithelial cells to IL-13, which induced CAPN14 production more than 100-fold. Moreover, these cells with CAPN14 overexpression had impaired epithelial architecture (acantholysis, epidermal clefting and epidermolysis), impaired barrier function (P < .0001) and increased FITC-dextran flux (P < .0001).
They also tested whether CAPN14 might play a role in the IL-13–induced impaired barrier function pathway using a gene-silencing approach, and found that gene silencing increased the disorder of IL-13–mediated changes. Following IL-13 exposure, dilated interceullar spaces increased 5.5-fold (P < .001), and basal cell layering became 1.5-fold less organized (P < .05) in epithelium with gene-silenced CAPN14.
Finally, they found that CAPN14 overexpression also disrupts desmoglein 1 expression, “a critical component of tissue in the esophagus,” according to the press release.
“Collectively, we are reporting that CAPN14 is a functional enzyme that induces disruptive effects on esophageal epithelium,” the researchers concluded. “These findings, along with the potent induction of CAPN14 by IL-13 and genetic linkage of EoE to the CAPN14 gene locus, demonstrate a molecular and cellular pathway that contributes to T helper type 2 responses in mucosal epithelium.” – by Adam Leitenberger
Disclosure: Rothenberg reports he is a consultant for Celgene (formerly Receptos) and Akari Therapeutics (formerly Celsus Therapeutics), has received speaking honorarium from Merck, has equity interest in Immune Pharmaceuticals and NKT Therapeutics, has royalty rights from reslizumab (Teva Pharmaceuticals), and is an inventor on patents owned by CCHMC.
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