Ventus Therapeutics Showcases Caspase-4/5 as Key Therapeutic Targets in Nature Reviews Immunology
Ventus Therapeutics, a clinical-stage biopharmaceutical company focused on advancing innovative small-molecule therapies for immunological, inflammatory, and neurological disorders, has announced a significant publication in the prestigious peer-reviewed journal Nature Reviews Immunology. The article, titled “New insights into the noncanonical inflammasome point to caspase-4 as a druggable target,” provides an in-depth review of the therapeutic potential of targeting caspase-4/5 and outlines the scientific advancements that could pave the way for next-generation treatments in inflammatory diseases. The full publication is accessible online (doi: 10.1038/s41577-025-01142-9).
The Challenge of Developing Caspase Inhibitors
Despite the promise of caspase inhibitors in treating a variety of inflammatory and immune-related diseases, past efforts to develop potent and selective inhibitors have been met with significant hurdles. Historically, caspase inhibitors showed efficacy in clinical trials but required high doses, leading to toxicity concerns and ultimately resulting in the discontinuation of several development programs. This has left a crucial gap in the field of immunology, as caspases play a fundamental role in inflammatory responses, apoptosis, and immune system regulation.
Ventus Therapeutics’ Breakthrough with the ReSOLVE® Platform
Ventus has made significant progress in overcoming these historical challenges through its proprietary ReSOLVE® drug discovery platform. Using cutting-edge structural biology and computational chemistry, Ventus has successfully identified highly selective and potent small-molecule inhibitors of caspase-4/5. These inhibitors function through a novel allosteric mechanism, distinguishing them from previous generations of caspase inhibitors. The newly discovered compounds demonstrate superior cellular potency, potentially allowing for lower clinical doses, thereby improving both efficacy and safety.
“We founded Ventus to leverage the ReSOLVE® platform and our deep expertise in structural biology to address the most difficult drug targets in innate immunity,” said Michael Crackower, Ph.D., Chief Scientific Officer at Ventus Therapeutics. “Following our oral NLRP3 and cGAS programs, both of which are expected to advance into Phase 2 clinical trials in 2025, caspase-4/5 inhibition represents the next frontier in our research journey.”
The Role of Caspase-4 and Caspase-5 in Disease
Caspase-4 and caspase-5 belong to the family of inflammatory caspases, enzymes that play a pivotal role in the body’s immune response. These caspases are expressed in various immune cells, including macrophages and monocytes, as well as epithelial and endothelial cells that line organs and blood vessels. They are central components of the noncanonical inflammasome pathway, which detects intracellular bacterial infections and triggers inflammatory responses by processing inflammatory cytokines like interleukin-18 (IL-18).
Recent findings highlighted in Nature Reviews Immunology shed light on how modulating caspase-4/5 activity could have profound therapeutic benefits. The publication discusses several key areas, including:
- The regulation of caspase-4/5 expression and their involvement in immune response mechanisms.
- The discovery of a novel inflammatory substrate, pro-IL-18, which is directly cleaved by caspase-4/5 to drive inflammation.
- Structural insights into how caspase-4 interacts with pro-IL-18, providing new avenues for targeted drug development.
Clinical and Therapeutic Implications
The involvement of caspase-4/5 in various disease pathways makes them particularly attractive therapeutic targets. In some disease-relevant cells, caspase-4/5 is the only inflammasome expressed, suggesting that selectively inhibiting these caspases could provide targeted relief for conditions driven by excessive inflammation. Elevated IL-18 levels, for instance, have been implicated in inflammatory bowel disease (IBD) and hidradenitis suppurativa, two conditions where effective treatments remain limited.
Additionally, caspase-4 activation has been associated with systemic and neural vascular leakage, further linking its activity to conditions such as sepsis, acute kidney injury, and acute lung injury. These findings underscore the broad therapeutic potential of caspase-4/5 inhibitors in addressing diseases characterized by excessive inflammation and immune dysregulation.
Ventus’ Commitment to Advancing Caspase-4/5 Inhibitors
Dr. Elad Elkayam, Ph.D., lead author of the Nature Reviews Immunology publication and Principal Investigator in Protein Sciences at Ventus, expressed excitement about the future of caspase-4/5 inhibitors: “Inflammatory caspases, including caspase-4/5, respond to dysbiosis by inducing disruptions in epithelial and endothelial barriers, triggering inflammatory responses. Given their critical role in multiple inflammatory diseases with high unmet medical needs, we believe caspase-4/5 inhibitors have immense therapeutic potential. We are eager to advance our compounds through preclinical development and ultimately into clinical trials.”
Ventus’ work on caspase-4/5 inhibitors represents a significant step forward in the field of innate immunity. With a strong foundation in structural biology, a cutting-edge drug discovery platform, and a commitment to tackling complex immunological targets, Ventus Therapeutics is poised to lead the charge in developing novel treatments that could transform patient care for inflammatory diseases.
