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Advisor(s)
Abstract(s)
A Atrofia Muscular Espinhal (AME) é uma doença neuromuscular hereditária caracterizada pela degeneração dos neurónios motores no corno anterior da medula espinhal, levando à fraqueza muscular progressiva e atrofia. O Nusinersen, um oligonucleótido antisense desenvolvido para aumentar os níveis da proteína SMN, demonstrou eficácia na melhoria da função motora em doentes com esta condição. No entanto, os biomarcadores moleculares específicos que preveem e monitorizam a resposta ao tratamento, particularmente na AME de início tardio, continuam pouco estudados. Esta meta-análise tem como objetivo analisar o papel de vários biomarcadores na avaliação dos resultados clínicos em doentes com AME de início tardio tratados com Nusinersen. A Creatinina demonstrou uma associação positiva significativa com melhorias nos resultados clínicos, sugerindo a sua utilidade no acompanhamento da progressão da doença e da eficácia do tratamento ao longo do tempo.
Por outro lado, o miR-206, CK e Tau apresentaram associações negativas com a resposta ao tratamento, indicando que níveis elevados destes biomarcadores podem refletir um estado de neurodegeneração mais avançado ou uma menor resposta ao tratamento. Uma limitação relevante deste estudo prende-se com o número reduzido de estudos disponíveis para cada biomarcador, o que pode ter limitado o poder estatístico e a generalização dos resultados. É necessário que seja desenvolvida mais investigação nesta área, aumentando o número de estudos para cada biomarcador, permitindo assim comparações mais robustas e conclusões mais confiáveis.
Esta meta-análise destaca o potencial de biomarcadores específicos para a monitorização da resposta ao tratamento em doentes com AME de início tardio tratados com Nusinersen. A identificação de marcadores com associações negativas aponta para a importância de estratégias de tratamento personalizadas. É essencial a condução de estudos futuros com maiores conjuntos de dados para validar estas observações e otimizar a gestão clínica destes doentes.
Spinal Muscular Atrophy (SMA) is a hereditary neuromuscular disorder characterized by the degeneration of motor neurons in the anterior horn of the spinal cord, leading to progressive muscle weakness and atrophy. Nusinersen, an antisense oligonucleotide designed to increase SMN protein levels, has shown effectiveness in improving motor function in SMA patients. However, the specific molecular biomarkers that predict and monitor treatment responses, particularly in late-onset SMA, remain insufficiently studied. This meta-analysis aimed to evaluate the role of several biomarkers in assessing clinical outcomes in late-onset SMA patients treated with Nusinersen. Creatinine demonstrated significant positive association with improved clinical outcomes, suggesting its utility in tracking disease progression and treatment efficacy over time. In contrast, miR-206, CK and Tau were negatively associated with treatment response, indicating that elevated levels of these biomarkers might reflect more advanced neurodegeneration or poor treatment responsiveness. A key limitation of the study was the relatively small number of studies available for each biomarker, which may have limited the statistical power and widening of the findings. As a result, further research is needed to increase the number of studies for each biomarker, allowing for more robust comparisons and reliable conclusions. This meta-analysis highlights the potential of specific biomarkers for monitoring treatment response in late-onset SMA patients treated with Nusinersen. Meanwhile, the identification of negative markers points to the importance of personalized treatment strategies. Future studies with larger datasets are essential to further validate these findings and refine biomarker-driven clinical management in SMA.
Spinal Muscular Atrophy (SMA) is a hereditary neuromuscular disorder characterized by the degeneration of motor neurons in the anterior horn of the spinal cord, leading to progressive muscle weakness and atrophy. Nusinersen, an antisense oligonucleotide designed to increase SMN protein levels, has shown effectiveness in improving motor function in SMA patients. However, the specific molecular biomarkers that predict and monitor treatment responses, particularly in late-onset SMA, remain insufficiently studied. This meta-analysis aimed to evaluate the role of several biomarkers in assessing clinical outcomes in late-onset SMA patients treated with Nusinersen. Creatinine demonstrated significant positive association with improved clinical outcomes, suggesting its utility in tracking disease progression and treatment efficacy over time. In contrast, miR-206, CK and Tau were negatively associated with treatment response, indicating that elevated levels of these biomarkers might reflect more advanced neurodegeneration or poor treatment responsiveness. A key limitation of the study was the relatively small number of studies available for each biomarker, which may have limited the statistical power and widening of the findings. As a result, further research is needed to increase the number of studies for each biomarker, allowing for more robust comparisons and reliable conclusions. This meta-analysis highlights the potential of specific biomarkers for monitoring treatment response in late-onset SMA patients treated with Nusinersen. Meanwhile, the identification of negative markers points to the importance of personalized treatment strategies. Future studies with larger datasets are essential to further validate these findings and refine biomarker-driven clinical management in SMA.
Description
Tese de mestrado, Ciências Biofarmacêuticas, 2024, Universidade de Lisboa, Faculdade de Farmácia.
Keywords
Spinal Muscular Atrophy Nusinersen Late-onset Biomarkers Teses de mestrado - 2024