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Abordagem farmacológica da doença de huntington
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A Doença de Huntington é uma doença neurodegenerativa autossómica dominante que resulta da expansão da repetição trinucleotídica CAG no gene huntingtina. Esta mutação conduz à produção da proteína huntingtina mutada cujo processo de folding é anómalo. A proteína acumula-se nos neurónios desencadeando processos de disfunção mitocondrial, excitotoxicidade, alterações na reparação do DNA, desregulação transcricional, comprometimento da autofagia e do sistema do proteossoma.
Esta patologia manifesta-se clinicamente através de sintomas motores, cognitivos e psiquiátricos que vão piorando progressivamente. O diagnóstico baseia-se no histórico familiar, em testes genéticos e exames de imagem cerebral que permitem a deteção de alterações estruturais e funcionais anteriores ao desenvolvimento dos sintomas.
Apesar de não existir um tratamento curativo, existe uma grande diversidade farmacológica que permite um controlo sintomático através de, por exemplo, inibidores do transportador vesicular de monoamina 2 (ex.: tetrabenazina), antipsicóticos, antidepressivos e moduladores dos recetores de glutamato. A abordagem farmacológica deve ser complementada com medidas não farmacológicas como, fisioterapia, terapia ocupacional e terapia da fala para promover a qualidade de vida do doente. Nos últimos anos, têm sido estudadas novas estratégias terapêuticas como oligonucleótidos antissentido, RNA de interferência, edição genética, terapia celular e anticorpos monoclonais que demonstraram potencial no atraso da progressão da doença e, possivelmente, na modificação do seu curso natural. Esta dissertação apresenta uma revisão abrangente da fisiopatologia, diagnóstico, terapêutica atual e perspetivas terapêuticas futuras, salientando a importância da investigação e dos ensaios clínicos em curso para o desenvolvimento de tratamentos modificadores da doença.
Huntington’s disease is an autosomal dominant neurodegenerative condition that results from the expansion of the CAG trinucleotide repeat in the huntingtin gene. This mutation leads to the production of the mutated huntingtin protein, whose folding process is abnormal. The protein accumulates in neurons, triggering mitochondrial dysfunction, excitotoxicity, changes in DNA repair, transcriptional dysregulation, and impairment of autophagy and proteosome system. This condition manifests clinically through progressively worsening motor, cognitive and psychiatric symptoms. Diagnosis is based on family history, genetic testing and brain imaging, which allow the detection of structural and functional changes prior to the development of symptoms. Although there is no curative treatment, a wide range of pharmacological options allows for symptomatic control, including vesicular monoamine transporter 2 inhibitors (e.g. tetrabenazine), antipsychotics, antidepressants and glutamate receptor modulators. The pharmacological approach should be complemented by non-pharmacological measures such as physical therapy, occupational therapy and speech therapy to improve the patient’s quality of life. In past few years, new strategies such as antisense oligonucleotides, RNA interference, gene editing, cell therapies and monoclonal antibodies have been studied, which have demonstrated potential in delaying disease progression and, possibly, modifying its natural course. This dissertation presents a comprehensive review of pathophysiology, diagnosis, current therapy and future therapy perspectives, highlighting the importance of ongoing research and clinical trials for development of disease-modifying treatments.
Huntington’s disease is an autosomal dominant neurodegenerative condition that results from the expansion of the CAG trinucleotide repeat in the huntingtin gene. This mutation leads to the production of the mutated huntingtin protein, whose folding process is abnormal. The protein accumulates in neurons, triggering mitochondrial dysfunction, excitotoxicity, changes in DNA repair, transcriptional dysregulation, and impairment of autophagy and proteosome system. This condition manifests clinically through progressively worsening motor, cognitive and psychiatric symptoms. Diagnosis is based on family history, genetic testing and brain imaging, which allow the detection of structural and functional changes prior to the development of symptoms. Although there is no curative treatment, a wide range of pharmacological options allows for symptomatic control, including vesicular monoamine transporter 2 inhibitors (e.g. tetrabenazine), antipsychotics, antidepressants and glutamate receptor modulators. The pharmacological approach should be complemented by non-pharmacological measures such as physical therapy, occupational therapy and speech therapy to improve the patient’s quality of life. In past few years, new strategies such as antisense oligonucleotides, RNA interference, gene editing, cell therapies and monoclonal antibodies have been studied, which have demonstrated potential in delaying disease progression and, possibly, modifying its natural course. This dissertation presents a comprehensive review of pathophysiology, diagnosis, current therapy and future therapy perspectives, highlighting the importance of ongoing research and clinical trials for development of disease-modifying treatments.
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Doença de Huntington Huntingtina Neurodegeneração Tratamento farmacológico.