CVN293, an Investigational Inhibitor of KCNK13 Targeting NLRP3‐Mediated Neuroinflammation in Neurodegenerative Disease: A Phase 1 Study to Investigate the Safety, Tolerability, and Pharmacokinetics.

Alzheimer s & Dementia · 2025-12-01

BACKGROUND: CVN293 is a novel, investigational, small molecule inhibitor of the two-pore domain potassium channel KCNK13. KCNK13 is selectively expressed in microglia and mediates the potassium efflux required for activation of the NLRP3 inflammasome complex. NLRP3-mediated inflammation has been identified as a central mediator of neuroinflammation in neurodegenerative diseases. Through inhibition of KCNK13 and microglial proinflammatory processes, CVN293 has the potential to dampen neuroinflammation across neurodegenerative diseases. METHOD: This Phase 1 single/multiple ascending dose (SAD/MAD) study investigated the safety, tolerability and pharmacokinetics of orally administered CVN293 in healthy subjects. Following a randomized, double-blind and placebo-controlled design, subjects received either CVN293 or placebo with SAD cohorts receiving single doses up to 1000mg (all fasted; 150mg was also tested under fed conditions). MAD cohorts received repeated doses over 14 days, up to 750mg (375mg twice daily). CSF sampling was conducted in both SAD and MAD cohorts. RESULT: CVN293 was generally well-tolerated following single and 14-day multiple dosing and all subjects completed the treatment period. There were no severe or dose-limiting adverse events (AEs), treatment-related discontinuations, or clinically meaningful changes in vital signs or laboratory parameters. All related AEs were considered mild. In both the SAD and MAD phases, CVN293 plasma exposure increased in a generally dose proportional manner. Penetrance of CVN293 into the cerebrospinal fluid (CSF) was demonstrated in both the SAD (150mg) and MAD (150mg, 75mg twice daily) studies. CONCLUSION: This Phase 1 study demonstrated a favourable tolerability profile for CVN293 in healthy adults and supports the continued development of this novel KCNK13 inhibitor for neurodegenerative diseases driven by neuroinflammation.

Supplementary Figure 4 from Hypoxia Potentiates the Inflammatory Fibroblast Phenotype Promoted by Pancreatic Cancer Cell–Derived Cytokines

2025-11-24

<p>Supplementary Figure 4, related to Figures 4 and 6</p>

Supplementary Figure 2 from Hypoxia Potentiates the Inflammatory Fibroblast Phenotype Promoted by Pancreatic Cancer Cell–Derived Cytokines

2025-11-24

<p>Supplementary Figure 2, related to Figure 2</p>

Corrigendum to Autophagy inhibition enhances therapy-induced apoptosis in a Myc-induced model of lymphoma

Journal of Clinical Investigation · 2025-07-14

VDAC2 and Bak scarcity in liver mitochondria enables targeting hepatocarcinoma while sparing hepatocytes

Nature Communications · 2025-03-11 · 10 citations

Differences between normal tissues and invading tumors that allow tumor targeting while saving normal tissue are much sought after. Here we show that scarcity of VDAC2, and the consequent lack of Bak recruitment to mitochondria, renders hepatocyte mitochondria resistant to permeabilization by truncated Bid (tBid), a Bcl-2 Homology 3 (BH3)-only, Bcl-2 family protein. Increased VDAC2 and Bak is found in most human liver cancers and mitochondria from tumors and hepatic cancer cell lines exhibit VDAC2- and Bak-dependent tBid sensitivity. Exploring potential therapeutic targeting, we find that combinations of activators of the tBid pathway with inhibitors of the Bcl-2 family proteins that suppress Bak activation enhance VDAC2-dependent death of hepatocarcinoma cells with little effect on normal hepatocytes. Furthermore, in vivo, combination of S63845, a selective Mcl-1 inhibitor, with tumor-nectrosis factor-related, apoptosis-induncing ligand (TRAIL) peptide reduces tumor growth, but only in tumors expressing VDAC2. Thus, we describe mitochondrial molecular fingerprint that discriminates liver from hepatocarcinoma and allows sparing normal tissue while targeting tumors. In this study, the authors show that low levels of VDAC2 and Bak in hepatocyte mitochondria make them resistant to cell death induced by truncated Bid (tBid), while increased VDAC2 and Bak in liver cancer cells allow specific targeting by combinations of tBid activators and Mcl-1 inhibitors.

Supplementary Figure 1 from Hypoxia Potentiates the Inflammatory Fibroblast Phenotype Promoted by Pancreatic Cancer Cell–Derived Cytokines

2025-11-24

<p>Supplementary Figure 1, related to Figure 1</p>

Collapse and restoration of mature forest habitat in California

Biological Conservation · 2025-05-14 · 2 citations

Metabolic engineering to facilitate anti-tumor immunity

Cancer Cell · 2025-02-27 · 21 citations

Metabolic adaptations direct cell fate during tissue regeneration

Nature · 2025-06-11 · 22 citations

Abstract Although cell-fate specification is generally attributed to transcriptional regulation, emerging data also indicate a role for molecules linked with intermediary metabolism. For example, α-ketoglutarate (αKG), which fuels energy production and biosynthetic pathways in the tricarboxylic acid (TCA) cycle, is also a co-factor for chromatin-modifying enzymes 1–3 . Nevertheless, whether TCA-cycle metabolites regulate cell fate during tissue homeostasis and regeneration remains unclear. Here we show that TCA-cycle enzymes are expressed in the intestine in a heterogeneous manner, with components of the αKG dehydrogenase complex 4–6 upregulated in the absorptive lineage and downregulated in the secretory lineage. Using genetically modified mouse models and organoids, we reveal that 2-oxoglutarate dehydrogenase (OGDH), the enzymatic subunit of the αKG dehydrogenase complex, has a dual, lineage-specific role. In the absorptive lineage, OGDH is upregulated by HNF4 transcription factors to maintain the bioenergetic and biosynthetic needs of enterocytes. In the secretory lineage, OGDH is downregulated through a process that, when modelled, increases the levels of αKG and stimulates the differentiation of secretory cells. Consistent with this, in mouse models of colitis with impaired differentiation and maturation of secretory cells, inhibition of OGDH or supplementation with αKG reversed these impairments and promoted tissue healing. Hence, OGDH dependency is lineage-specific, and its regulation helps to direct cell fate, offering insights for targeted therapies in regenerative medicine.

Fuels management mitigates megafires to the benefit of old forest species

Forest Ecology and Management · 2025-12-04 · 4 citations