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Preprint WatchMildSeptember 17th, 2026

LNA043 and ANGPTL3 Interactions with Integrin α5β1 and Fibronectin Drive Distinct Stromal and Immune Responses

Grosso, A.; Cucuzza, S.; Gambs, E.; Lapointe, T.; Huynh, T.; Kuzu, G.; King, F.; Ng, K.; Shi, J.; Vogel, M.; Gerwin, N.; Halleux, C.; Fornaro, M.

Full-length ANGPTL3 and its C-terminal fibrinogen-like domain bind integrin alpha-5 beta-1 and fibronectin, supporting mesenchymal stromal cell adhesion and integrin beta-1 dependent monocyte migration, which assigns ANGPTL3 a matrix and immune signalling role distinct from its lipid function.

Mild contradiction

1 prior failure

One documented clinical failure (Phase 1 or 2) overlaps with the claimed mechanism.

ANGPTL3 is developed almost entirely as a lipid target, and this preprint describes a separate role in which the full-length protein and its C-terminal fibrinogen-like domain engage integrin alpha-5 beta-1 and fibronectin to drive stromal adhesion and monocyte migration in an osteoarthritis context. The single ANGPTL3 entry in the Claidex graph is an RNA interference program in homozygous familial hypercholesterolemia stopped on a sponsor decision rather than on biology (aro-ang3-zodasiran-hofh-phase2-strategic-shutdown). Severity is mild because nothing here contradicts the lipid hypothesis. What it adds is that systemic ANGPTL3 knockdown removes a matrix and immune signalling ligand as well as a lipid regulator, which is an on-target consideration that silencing approaches should track rather than assume away.

Abstract excerpt

Osteoarthritis (OA) is characterized by cartilage breakdown, extracellular matrix remodeling, and synovial inflammation. Dysregulated integrin 5{beta}1 signaling and fibronectin fragmentation are key drivers of OA progression. We found that in ihMSC, LNA043, Full length ANGPTL3 (FL-ANGPTL3, and C-terminal fibronogen-tlike domain of ANGPTL3 (C-ANGPTL3) interacted with both integrin 5{beta}1 and fibronectin, consistent with a multivalent binding mode supported by AlphaFold based structural predictions. FL-ANGPTL3 supported ihMSC adhesion and induced human monocyte migration, with both effects being dependent on integrin {beta}1. C-ANGPTL3 alone was sufficient to mediate these effects, although with reduced efficacy compared to the full-length protein. In contrast, LNA043 did not support ihMSC adhesion but retained integrin {beta}1-dependent monocyte migratory activity, defining a more selective functional profile and indicating that further truncation modulates downstream responses without abolishing integrin engagement. To further explore the biology of ANGPTL3 and the mechanism of action of LNA043 we employed a targeted RASL Seq profiling. We found that both FL- and C-ANGPTL3, but not LNA043, induced broad transcriptional reprogramming and counter regulated fibronectin fragment-driven inflammatory signaling in monocytes. We uncovered a role for ANGPTL3 in fibronectin-integrin 5

Matching Claidex post-mortems

1 of 1 indexed

This is an automated contradiction flag, not an editorial judgment on the preprint's quality. Flags identify where the preclinical literature and the clinical failure record diverge.