De Smet, G. | bioRxiv Science

bioRxiv2026

A photoswitchable cannabinoid for precision treatment of refractory seizures in a mouse epilepsy model

Temporal lobe epilepsy (TLE) has an unmet need for precision treatments targeting the seizure focus while avoiding effects on other body parts to minimise side effects. Photopharmacology could enable precision treatment by combining systemic administration of a photoswitchable drug with implantation of an optic fibre in the epileptic focus to induce light-dependent drug conversion from an inactive to an active configuration that interacts with its target receptor to suppress seizures. The photoswitchable {Delta}9-tetrahydrocannabinol ({Delta}9-THC) derivative, azo-THC-3, transitions from an inactive trans to an active cis configuration upon UV irradiation. We demonstrate that local or systemic administration of azo-THC-3 and local UV irradiation in the hippocampus supresses difficult-to-treat seizures in the intrahippocampal kainic acid mouse model of TLE. Furthermore, our findings illustrate that the photoswitch strategy avoids hypolocomotion, a common side effect of systemic {Delta}9-THC administration. As such, we provide the first demonstration of seizure suppression with the systemic administration of a photoswitchable compound and its local photoactivation in the seizure focus. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=133 SRC="FIGDIR/small/720358v1_ufig1.gif" ALT="Figure 1"> View larger version (41K): org.highwire.dtl.DTLVardef@1e42794org.highwire.dtl.DTLVardef@1e26891org.highwire.dtl.DTLVardef@13f2b6forg.highwire.dtl.DTLVardef@3c8e48_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗

bioRxiv2025

Systematic disruption of zebrafish fibrillin genes identifies a translational zebrafish model for Marfan syndrome

BackgroundFibrillins are essential components of the extracellular matrix. Marfan syndrome (MFS), the most common fibrillinopathy, is characterized by severe cardiovascular complications, including cardiac valve abnormalities, myocardial dysfunction, arrhythmias, and, most commonly, thoracic aortic disease. Unfortunately, no definitive medical cure is available. ObjectivesTo establish a zebrafish model of MFS, to enhance understanding of the cardiovascular consequences of fibrillin impairment and identify novel therapeutic targets. MethodsCRISPR/Cas9 technology was used to systematically target all zebrafish fibrillin genes. The cardiovascular phenotype was investigated using fluorescent microscopy at embryonic stages and cardiac ultrasound, histology, and synchrotron X-ray imaging in adults. RNA sequencing and drug testing were performed during early development. ResultsFibrillin-2b mutant (fbn2b-/-) zebrafish had a reproducible phenotype, with a subset of embryos showing endocardial detachment leading to early mortality. Interestingly, the remaining fbn2b-/- zebrafish developed dilation of the bulbus arteriosus, a structure analogous to the aortic root in humans, and survived normally to adulthood. Adult fbn2b-/- zebrafish displayed cardiac valve abnormalities. Transcriptomic analysis of fbn2b-/-embryos suggested the involvement of extracellular matrix remodeling and immune-related pathways. Administration of nebivolol and losartan did not improve the phenotype of fbn2b-/- larvae. Zebrafish lacking fibrillin-1 and/or fibrillin-2a did not show any phenotype. ConclusionOur fbn2b-/- zebrafish model recapitulates key aspects of human cardiovascular manifestations of MFS and can therefore be considered a novel relevant animal model for MFS. Studying this model allows us to broaden the knowledge of the underlying mechanisms of the disease and discover much-needed disease-specific treatment options. CONDENSED ABSTRACTFibrillin defects lead to severe cardiovascular complications in Marfan syndrome (MFS), including aortic dilation, dissection, and rupture. To model MFS, we generated zebrafish mutants lacking various fibrillin genes. Among these mutant lines, only fibrillin-2b-deficient zebrafish exhibited cardiovascular phenotypes mimicking human disease. Multimodal imaging revealed early cardiac defects, bulbus arteriosus dilation, and valve abnormalities. Transcriptomic analysis identified altered regulation of pathways related to extracellular matrix homeostasis and immune system activation. Compound testing demonstrated the models potential for drug discovery. This zebrafish model, recapitulating key cardiovascular features of MFS, provides a valuable platform to investigate disease mechanisms and identify novel treatment strategies.

genetics↗