Anti-amyloid treatment is broadly effective in neuronopathic mucopolysaccharidoses and synergizes with gene therapy in MPS-IIIA.

Mucopolysaccharidoses (MPSs) are childhood diseases caused by inherited deficiencies in glycosaminoglycan degradation. Most MPSs involve neurodegeneration, which to date is untreatable. Currently, most therapeutic strategies aim at correcting the primary genetic defect.

Genome editing without nucleases confers proliferative advantage to edited hepatocytes and corrects Wilson disease.

Application of classic liver-directed gene replacement strategies is limited in genetic diseases characterized by liver injury due to hepatocyte proliferation, resulting in decline of therapeutic transgene expression and potential genotoxic risk. Wilson disease (WD) is a life-threatening autosomal disorder of copper homeostasis caused by pathogenic variants in copper transporter ATP7B and characterized by toxic copper accumulation, resulting in severe liver and brain diseases. Genome editing holds promise for the treatment of WD; nevertheless, to rescue copper homeostasis, ATP7B function must be restored in at least 25% of the hepatocytes, which surpasses by far genome-editing correction rates.

Full-length ATP7B reconstituted through protein -splicing corrects Wilson disease in mice.

Wilson disease (WD) is a genetic disorder of copper homeostasis, caused by deficiency of the copper transporter ATP7B. Gene therapy with recombinant adeno-associated vectors (AAV) holds promises for WD treatment. However, the full-length human gene exceeds the limited AAV cargo capacity, hampering the applicability of AAV in this disease context.

Up-regulation of miR-34b/c by JNK and FOXO3 protects from liver fibrosis.

α1-Antitrypsin (AAT) deficiency is a common genetic disease presenting with lung and liver diseases. AAT deficiency results from pathogenic variants in the gene encoding AAT and the common mutant Z allele of encodes for Z α1-antitrypsin (ATZ), a protein forming hepatotoxic polymers retained in the endoplasmic reticulum of hepatocytes. PiZ mice express the human ATZ and are a valuable model to investigate the human liver disease of AAT deficiency.

Aldosterone Jeopardizes Myocardial Insulin and β-Adrenergic Receptor Signaling G Protein-Coupled Receptor Kinase 2.

Hyperaldosteronism alters cardiac function, inducing adverse left ventricle (LV) remodeling either increased fibrosis deposition, mitochondrial dysfunction, or both. These harmful effects are due, at least in part, to the activation of the G protein-coupled receptor kinase 2 (GRK2). In this context, we have previously reported that this kinase dysregulates both β-adrenergic receptor (βAR) and insulin (Ins) signaling.

Aldosterone and Mineralocorticoid Receptor System in Cardiovascular Physiology and Pathophysiology.

The mineralocorticoid hormone aldosterone (Aldo) has been intensively studied for its ability to influence both the physiology and pathophysiology of the cardiovascular system. Indeed, although research on Aldo actions for decades has mainly focused on its effects in the kidney, several lines of evidence have now demonstrated that this hormone exerts disparate extrarenal adverse effects, especially in the circulatory system. Accordingly, in the last lusters, a number of studies in preclinical models ( and ) and in humans have established that Aldo, following the interaction with its receptor-the mineralocorticoid receptor (MR)-is able to activate specific intracellular genomic and nongenomic pathways, thus regulating the homeostasis of the cardiovascular system.