Percorrer por autor "Vaz, Adriana Afonso"
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- Gene therapy for Cockayne syndrome: in vivo studiesPublication . Vaz, Adriana Afonso; Nóbrega, ClévioCockayne Syndrome (CS) is a rare, severe, multi-systemic disorder inherited in an autosomal recessive pattern, with an incidence of 2.77 cases per million births. First documented by Dr. Edward Cockayne in 1936, this syndrome presents a variety of clinical features, primarily impacting the vision, hearing, growth, and motor and cognitive functions. Neuropathologically, it involves white matter loss, microcephaly, and brain calcifications. CS can be categorized into three severity groups: CS type II (most severe), CS type I (moderate), and CS type III (least severe). It can also be classified according to the underlying genetic mutation: ERCC8 mutation causes CS type A (CS-A) and ERCC6 mutation leads to CS type B (CS-B), with 65% of cases being CS-B. This study focuses on CS-B, due to its therapeutic relevance. The ERCC6 gene, which translates the CSB protein, is crucial in several cellular mechanisms, such as DNA damage repair (induced by ultraviolet radiation or oxidative stress), transcription regulation, and mitochondrial function. Mutations in ERCC6 lead to DNA damage accumulation, transcriptional arrest, and mitochondrial dysfunction. Currently, treatments are limited to symptom management, highlighting the need for gene-based therapies. Gene therapy aims to treat genetic disorders by delivering genetic material to human cells, through vectors. There are several gene therapy strategies and more than a dozen have been approved for clinical use. As a monogenic disorder with recessive inheritance, CS-B poses a strong candidate for a gene therapy-based treatment. Therefore, the aim of this work is to determine the therapeutic potential of a gene therapy for CS-B in vivo. This strategy is based on delivering a functional ERCC6 gene through an AAV9 vector. The first step in this study was to test eight therapeutic strategies in vitro, with the objective of narrowing it down to one (Cure1) for further in vivo testing in a CS-B mouse model, CSB m/m. Following, we injected a CS-B mouse model with Cure1 and these preliminary results showed promising CSB expression in the injected brain hemisphere. Lastly, given the success of preliminary tests, this strategy was injected CSB m/m mice for further behavioural assessment. However, these tests showed no significant improvements, suggesting Cure1’s limited effectiveness. Additionally, histological analysis of these brains showed no expression of CSB in mice injected with Cure1, further supporting the inference that Cure1 has limited therapeutic potential. In conclusion, the findings indicate that Cure1 gene therapy does not significantly enhance CSB expression or improve the phenotype in CS-B mice. Further studies are required to confirm the reliability of these results and assess Cure1's therapeutic potential comprehensively.