Ventus Therapeutics Highlights Caspase-4/5 as Promising Therapeutic Targets in Nature Reviews Immunology
Ventus Therapeutics, a clinical-stage biopharmaceutical company focused on developing novel small-molecule therapies for immunological, inflammatory, and neurological disorders, has recently announced the publication of an article in the peer-reviewed journal Nature Reviews Immunology. The article, titled “New insights into the noncanonical inflammasome point to caspase-4 as a druggable target,” presents new findings regarding the therapeutic potential of caspase-4/5 inhibitors. The full article is accessible through the journal (doi: 10.1038/s41577-025-01142-9).
Caspases, enzymes involved in the inflammatory process, have long been considered promising therapeutic targets due to their role in a variety of diseases. However, developing potent and selective inhibitors of caspases has proven difficult. Early-stage caspase inhibitors demonstrated clinical efficacy but often required high doses that led to toxicity and eventual discontinuation of the programs.
Ventus Therapeutics, leveraging its proprietary ReSOLVE® platform, has identified highly potent, selective small-molecule inhibitors of caspase-4/5. These inhibitors operate through a novel allosteric inhibitory mechanism, which offers significantly improved cellular potency over previous caspase inhibitors. This breakthrough means that these inhibitors could be developed with lower clinical doses and improved safety profiles, thus increasing their potential for successful clinical application.
“We are excited to be at the forefront of developing caspase-4/5 inhibitors,” said Michael Crackower, Ph.D., Chief Scientific Officer of Ventus. “Ventus was founded with the goal of leveraging our expertise in structural biology and the ReSOLVE® platform to target some of the most difficult challenges in innate immunity. After progressing with our oral NLRP3 and cGAS programs—both expected to enter Phase 2 clinical trials in 2025—advancing the development of caspase-4/5 inhibitors represents the next important step in our journey.”
Caspase-4 and caspase-5 are inflammatory caspases that are expressed in a variety of immune cells, including monocytes, macrophages, and neutrophils, as well as in epithelial and endothelial cells.
These caspases play crucial roles in several inflammatory processes and are particularly relevant in diseases linked to increased levels of IL-18, such as inflammatory bowel disease and hidradenitis suppurativa. The article also reveals that caspase-4/5 is the only inflammasome expressed in certain disease-relevant cells, highlighting its pivotal role in the activation of inflammation and in the pathogenesis of various conditions, such as sepsis, acute kidney injury, and acute lung injury.
The review in Nature Reviews Immunology highlights the involvement of caspase-4/5 in systemic and neural vascular leakage, with the activation of caspase-4 being associated with the disruption of vascular integrity in multiple diseases. The activation of inflammatory caspases like caspase-4/5 can lead to cellular death (pyroptosis), promoting inflammatory responses that worsen disease progression. These findings make caspase-4/5 inhibitors highly promising therapeutic candidates for a range of inflammatory disorders that currently have limited treatment options.
“We believe that caspase-4/5 are highly promising targets for treating a range of inflammatory diseases with limited treatment options,” said Elad Elkayam, Ph.D., lead author of the article and Principal Investigator, Protein Sciences at Ventus. “By advancing our caspase-4/5 inhibitors through preclinical development, we aim to demonstrate the potential these targets hold in treating conditions like inflammatory bowel disease, sepsis, and acute lung injury. We are excited to continue progressing this research and to explore the therapeutic opportunities these inhibitors may present.”
Caspase-4/5 and Their Role in Disease
Caspase-4 and caspase-5 are cysteine-dependent proteases, which belong to a subset of caspases known as inflammatory caspases. These enzymes play a critical role in immune responses, particularly in recognizing pathogens and triggering inflammation. Caspase-4 is constitutively expressed in various immune cells, including monocytes, macrophages, and neutrophils, and is also present in epithelial and endothelial cells. Caspase-5, on the other hand, has lower basal expression, with slightly higher levels found in the gut.
In diseases like sepsis, acute lung injury, acute kidney injury, and diabetic nephropathy, caspase-4/5 are responsible for disrupting vascular integrity, contributing to organ failure. Emerging evidence links caspase-4/5 activation to conditions with elevated IL-18 levels, such as inflammatory bowel disease and hidradenitis suppurativa. This suggests that inhibiting these caspases could provide a powerful therapeutic strategy for managing a range of inflammatory and immune-related conditions.
The Promise of Caspase-4/5 Inhibitors
Ventus Therapeutics’ innovative approach to caspase-4/5 inhibition holds significant promise in advancing the treatment of a variety of inflammatory diseases. By developing highly selective and potent inhibitors with improved safety profiles, Ventus is positioning itself as a leader in this emerging therapeutic area. With its ReSOLVE® platform, the company is well-equipped to continue advancing these inhibitors into clinical development and to explore their therapeutic potential in treating diseases with high unmet medical needs.
The publication in Nature Reviews Immunology marks a significant milestone for Ventus and underscores the therapeutic potential of caspase-4/5 as druggable targets. As the company continues to progress its caspase-4/5 inhibitors through preclinical development, it remains committed to improving patient outcomes by advancing novel treatments for a variety of immune-related diseases.
