Junctional epidermolysis bullosa (JEB) caused by laminin-332 deficiency (JEB-LAM332) is a severe inherited skin disorder characterized by impaired dermal–epidermal adhesion, chronic wounds, and increased cancer susceptibility. The management of JEB-LAM332 is primarily symptomatic, focusing on wound care and general supportive measures; however, many therapeutic needs remain unmet. While gene and stem cell therapy has been effective in JEB-LAM332, it is not yet broadly available owing to its complexity and cost. Translational readthrough-inducing drugs (TRIDs) represent an alternative strategy for treating JEB-LAM332, given that most patients carry nonsense mutations in at least one allele of their LAMA3, LAMB3, or LAMC2 genes, with LAMB3 c.1903C>T, p.R635* (p.Arg635Ter) being the most common variant. To determine promising TRID candidates for developing readthrough therapy for JEB-LAM332 patients with LAMB3 mutations, we evaluated different classes of TRIDs and compared their efficacy against gentamicin.Erythromycin, TRID-C5 (aminoglycoside-based cocktail), artesunate and atazanavir (non-aminoglycosides, ribosomal protein RpL35 ligand) and clitocine (nucleoside analog) were tested in patient-derived keratinocytes carrying the LAMB3 nonsense variants, homozygous c.1903C>T (p.R635*) or compound heterozygous c.124C>T;c.1903C>T (p.R42*;p.R635*). We used a previously established screening platform for systematic testing of TRIDs, including immunoblotting, cell functional assays, and transcriptomics.We identified clitocine as the most potent compound for promoting translational readthrough, restoring laminin β3 chain expression and improving keratinocyte adhesion in JEB models. Clitocine treatment elicited dose- and mutation-dependent responses, while toxicity was observed at higher concentrations, particularly in normal keratinocytes. Although normal keratinocytes are not the intended therapeutic target, these findings highlight the importance of defining a therapeutic window and optimizing mutation-specific dosing. Overall, clitocine represents a potential candidate for the topical therapy of JEB-LAM332.
Transitioning from its traditional conceptualization as a static scaffold, the extracellular matrix (ECM) is now recognized as a dynamic regulatory hub that integrates biomechanical cues with biochemical signaling to dictate cellular fate and physiological stability. Central to this regulatory network is Fibromodulin (FMOD), a Class II small leucine-rich proteoglycan (SLRP) that integrates structural scaffolding with complex signaling modulation. This review synthesizes the molecular topography of FMOD, detailing how its signature horseshoe-shaped solenoid fold facilitates high-affinity docking with type I and II collagens to orchestrate fibrillogenesis. We delineate FMOD’s dual functionality as a structural architect, responsible for matrix tensile integrity, and as a biochemical supervisor that sequesters and titrates growth factor bioavailability, specifically within the transforming growth factor-beta (TGF-β) superfamily. Under physiological conditions, FMOD-mediated matrix organization is essential for musculoskeletal resilience and ocular transparency; however, its dysregulation functions as a context-dependent amplifier and modifier of tissue pathology. We analyze the mechanistic shift where FMOD promotes aberrant collagen cross-linking in fibrotic visceral organs, contrastingly drives scleral thinning in myopia, and facilitates the assembly of a desmoplastic “stromal shield” within the tumor microenvironment. Furthermore, the ectopic overexpression of FMOD in B-cell chronic lymphocytic leukemia (B-CLL) highlights its clinical utility as a highly specific diagnostic biomarker and a viable target for TCR-based immunotherapies. By linking biomechanical cues to intracellular cascades, FMOD serves as a critical rheostat of the matrisome, offering a unique molecular target to disrupt pathological stroma and restore tissue homeostasis.
Collagen IV, encoded by genes COL4A1/COL4A2, is a major component of the basement membrane, a specialised extracellular matrix (ECM) structure. Mutations in these genes cause a genetic form of cerebral small vessel disease (cSVD), a leading cause of stroke and dementia. White matter abnormalities are a hallmark of cSVD and are closely linked to cognitive decline and dementia. While white matter defects occur in patients with COL4A1/2 mutations, they remain understudied and their mechanisms are unclear. To address these knowledge gaps, we combined magnetic resonance diffusion tensor imaging, pathology, ultrastructural investigations, behaviour and proteomic analysis of white matter in an established mouse model of cSVD due to a Col4a1 mutation (Col4a1+/Svc). The studies revealed that Col4a1+/Svc mice have reduced myelinating oligodendrocyte pools, axonal myelination defects, and altered white matter structural integrity as well as cognitive impairments. Proteomic analysis of isolated white matter from Col4a1+/Svc mice identified extensive changes to ECM and basement membrane composition. Furthermore, this provided evidence for altered endoplasmic reticulum (ER) biology including ER stress. To determine if white matter defects can be attenuated by targeting protein folding in the ER by promoting collagen IV secretion, we treated mice with the FDA-approved chemical chaperone 4-phenylbutyric acid. This revealed increased myelinating oligodendrocytes and improved axon-glial integrity in Col4a1+/Svc mice. These data provide novel insight into the pathomolecular mechanisms of collagen IV mutations in white matter abnormalities in cSVD and identify a modifiable pathway as a putative therapeutic target.
Andrew Leask and Asma Fadl interviewed Neha Dinesh, recipient of the American Society for Matrix Biology (ASMB) Founders Award at the ASMB meeting at Baltimore, November 2025.
