RESUMEN
Leukoencephalopathy with vanishing white matter (VWM) is a progressive incurable white matter disease that most commonly occurs in childhood and presents with ataxia, spasticity, neurological degeneration, seizures, and premature death. A distinctive feature is episodes of rapid neurological deterioration provoked by stressors such as infection, seizures, or trauma. VWM is caused by autosomal recessive mutations in one of five genes that encode the eukaryotic initiation factor 2B complex, which is necessary for protein translation and regulation of the integrated stress response. The majority of mutations are in EIF2B5. Astrocytic dysfunction is central to pathophysiology, thereby constituting a potential therapeutic target. Herein we characterize two VWM murine models and investigate astrocyte-targeted adeno-associated virus serotype 9 (AAV9)-mediated EIF2B5 gene supplementation therapy as a therapeutic option for VWM. Our results demonstrate significant rescue in body weight, motor function, gait normalization, life extension, and finally, evidence that gene supplementation attenuates demyelination. Last, the greatest rescue results from a vector using a modified glial fibrillary acidic protein (GFAP) promoter-AAV9-gfaABC(1)D-EIF2B5-thereby supporting that astrocytic targeting is critical for disease correction. In conclusion, we demonstrate safety and early efficacy through treatment with a translatable astrocyte-targeted gene supplementation therapy for a disease that has no cure.
Asunto(s)
Astrocitos , Dependovirus , Modelos Animales de Enfermedad , Factor 2B Eucariótico de Iniciación , Terapia Genética , Vectores Genéticos , Leucoencefalopatías , Animales , Dependovirus/genética , Ratones , Leucoencefalopatías/terapia , Leucoencefalopatías/genética , Leucoencefalopatías/etiología , Terapia Genética/métodos , Vectores Genéticos/genética , Vectores Genéticos/administración & dosificación , Astrocitos/metabolismo , Astrocitos/patología , Factor 2B Eucariótico de Iniciación/genética , Factor 2B Eucariótico de Iniciación/metabolismo , Proteína Ácida Fibrilar de la Glía/metabolismo , Proteína Ácida Fibrilar de la Glía/genética , HumanosRESUMEN
In the realm of visual working memory research, the retro-cue paradigm helps us study retro-cue effects such as retro-cue benefit (RCB) and retro-cue cost (RCC). RCB reflects better performance with cued items, while RCC indicates poorer performance with uncued items. Despite consistent evidence for RCB, it's still uncertain whether it remains when previously uncued items are cued afterward. Additionally, research findings have been inconsistent. This study combines prior experiments by controlling the proportion of cue types and the number of memory items. Besides, using a CDA index to assess the status of items after the cue appeared. Results showed better performance under the double-cue condition (involving two cues pointing inconsistently with only the second cue being valid) compared to the neutral-cue condition, and better performance under the single-cue condition compared to double-cue. EEG data revealed that after the appearance of the second cue in the double-cue condition, there was a significant increase in CDA wave amplitude compared to the single-cue condition. Behavior results suggests that RCB occurs under double-cue but to a lesser extent than the single-cue. And EEG outcomes indicates that individuals did not remove the uncued item from their visual working memory after the first cue. Instead, they kept it in a passive state and then shifted it to an active state after the appearance of the second cue.