RESUMEN
Gaucher Disease (GD) is an inherited metabolic disorder caused by mutations in the GBA1 gene. It can manifest with severe neurodegeneration and visceral pathology. The most acute neuronopathic form (nGD), for which there are no curative therapeutic options, is characterised by devastating neuropathology and death during infancy. In this study, we investigated the therapeutic benefit of systemically delivered AAV9 vectors expressing the human GBA1 gene at two different doses comparing a neuronal-selective promoter with ubiquitous promoters. Our results highlight the importance of a careful evaluation of the promoter sequence used in gene delivery vectors, suggesting a neuron-targeted therapy leading to high levels of enzymatic activity in the brain but lower GCase expression in the viscera, might be the optimal therapeutic strategy for nGD.
Asunto(s)
Dependovirus , Enfermedad de Gaucher , Terapia Genética , Vectores Genéticos , Glucosilceramidasa , Regiones Promotoras Genéticas , Enfermedad de Gaucher/genética , Enfermedad de Gaucher/terapia , Enfermedad de Gaucher/patología , Vectores Genéticos/genética , Terapia Genética/métodos , Humanos , Regiones Promotoras Genéticas/genética , Dependovirus/genética , Glucosilceramidasa/genética , Glucosilceramidasa/metabolismo , Animales , Ratones , Encéfalo/metabolismo , Encéfalo/patología , Neuronas/metabolismo , Neuronas/patología , Técnicas de Transferencia de GenRESUMEN
Hypoxic-ischaemic encephalopathy (HIE) arises from diminished blood flow and oxygen to the neonatal brain during labor, leading to infant mortality or severe brain damage, with a global incidence of 1.5 per 1000 live births. Glucagon-like Peptide 1 Receptor (GLP1-R) agonists, used in type 2 diabetes treatment, exhibit neuroprotective effects in various brain injury models, including HIE. In this study, we observed enhanced neurological outcomes in post-natal day 10 mice with surgically induced hypoxic-ischaemic (HI) brain injury after immediate systemic administration of exendin-4 or semaglutide. Short- and long-term assessments revealed improved neuropathology, survival rates, and locomotor function. We explored the mechanisms by which GLP1-R agonists trigger neuroprotection and reduce inflammation following oxygen-glucose deprivation and HI in neonatal mice, highlighting the upregulation of the PI3/AKT signalling pathway and increased cAMP levels. These findings shed light on the neuroprotective and anti-inflammatory effects of GLP1-R agonists in HIE, potentially extending to other neurological conditions, supporting their potential clinical use in treating infants with HIE.