👤 Matilde Molteni

Mutations in INTS11, the catalytic subunit of the Integrator complex essential for RNA processing and transcriptional termination, have been linked to neurodevelopmental disorders (NDDs), yet the underlying mechanisms remain poorly understood. To address this gap, we developed and characterized a novel ints11 loss-of-function zebrafish model using CRISPR/Cas9 and morpholino-based approaches, which recapitulates key phenotypic traits observed in human patients, including motor and behavioral deficits. ints11 deficiency led to marked impairments in locomotor activity and visual motor response, consistent with the neurological manifestations reported in INTS11-mutated patients. These behavioral abnormalities were paralleled by significant dysregulation of neurodevelopmental gene expression, including decreased expression of islet1, map2, gfap, and mag, and upregulation of the progenitor marker nestin, indicating defective neuronal differentiation and glial maturation. Interestingly, the observed phenotypes are rescued not only by mRNA-mediated re-expression of ints11, but also through pharmacological administration with brain-derived neurotrophic factor (BDNF) and the GM1 ganglioside-derived oligosaccharide (OligoGM1). These findings highlight neurotrophic signaling as a potential compensatory axis counteracting RNA-processing defects. In conclusion, our work establishes the first in vivo zebrafish model of INTS11-associated neurodevelopmental dysfunction, uncovering conserved molecular mechanisms that link Integrator complex activity, neurotrophic support, and neuronal maturation and providing a valuable platform for dissecting disease mechanisms and evaluating therapeutic strategies targeting RNA processing pathways and neurotrophic support in NDDs. Show less

The development of small molecule agonists of the liver X receptors (LXRs) has been an area of interest for over a decade, given the critical role of those receptors in cholesterol metabolism, glucose homeostasis, inflammation, innate immunity and lipogenesis. Many potential indications have been characterized over time including atherosclerosis, diabetes, inflammation, Alzheimer's disease and cancer. However, concerns about the lipogenic effects of full LXRα/β agonists have required extensive efforts aimed at identifying LXRβ agonist with limited activity on the LXRα receptor to increase the safety margins. This review includes a summary of the LXR agonists that have reached the clinic and summarizes the patent applications for LXR modulators from September 2009 to December 2012 with emphasis on chemical matters, biological data associated with selected analogs and therapeutic indications. As LXR agonists have the potential to be useful for many indications, the scientific community, despite setbacks due to on-target side effects, has maintained interest and devised strategies to overcome safety hurdles. While a clinical proof of concept still remains elusive, the recent advancement of compounds into the clinic highlights that acceptable safety margins in preclinical species have been achieved. Show less

Liver X receptors (LXRs) are ligand activated transcription factors involved in cholesterol metabolism, glucose homeostasis, inflammation and lipogenesis. With the important physiological role of LXRs in reverse cholesterol transport (RCT), atherosclerosis is the best investigated therapeutic indication. While atherosclerosis is not yet clinically validated, Wyeth's LXRalpha/beta agonist LXR-623 indicated the key LXR target genes involved in RCT (ABCA1 and ABCG1) are upregulated in peripheral blood cells in a dose-dependent manner. While discontinued for CNS safety concerns, investigation of LXR-623 supports atherosclerosis as a clinical indication, and the possibility of identifying LXR agonists with profiles that avoid the strong lipogenic effects of full LXRalpha/beta agonists. Patents for LXR agonists from late 2006 up to August 2009 with emphasis on chemical matters and relationship to earlier disclosures, the biological data associated with selected analogues and therapeutic indications. An overview of the majority of LXR scaffolds with representative structure activity relationships as well as the companies that are the chief players in the field. The future application of LXR agonists depends upon the discovery of LXR agents without lipogenic effects. Limiting activation of LXRalpha is a popular strategy. Show less