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Evolução das abordagens farmacológicas no tratamento da paramiloidose amiloidótica familiar
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A Polineuropatia Amiloidótica Familiar (PAF) é uma patologia neurodegenerativa hereditária, causada pela deposição sistémica de fibrilas amiloides constituídas por transtirretina (TTR) em múltiplos tecidos. Esta condição resulta, na maioria dos casos, de mutações pontuais no gene da TTR, que comprometem a estabilidade da sua estrutura tetramérica, promovendo a dissociação em monómeros instáveis e facilitando a agregação amiloide. As manifestações clínicas surgem habitualmente entre a terceira e a quarta décadas de vida, tornando imprescindível a compreensão aprofundada dos mecanismos fisiopatológicos envolvidos. Nos últimos anos, têm sido desenvolvidas terapêuticas inovadoras com impacto significativo no curso clínico da PAF. Os estabilizadores da TTR, como o Tafamidis, representam uma abordagem farmacológica eficaz, ao promoverem a estabilização da estrutura tetramérica da proteína, prevenindo a sua dissociação. O Tafamidis foi o primeiro fármaco aprovado para o tratamento da PAF e demonstrou eficácia na redução da progressão da neuropatia e na melhoria da qualidade de vida dos doentes. Paralelamente, surgiram terapias que visam reduzir a produção da TTR hepática, através de mecanismos de silenciamento génico. Entre estas destacam-se os fármacos baseados em RNA de interferência (RNAi), como o Patisiran e o Vutrisiran, que atuam promovendo a degradação do RNA mensageiro (RNAm) da TTR no fígado, diminuindo significativamente os níveis circulantes da proteína mutada. O Patisiran demonstrou, em ensaios clínicos, melhorias neurológicas mensuráveis. O Vutrisiran, de administração subcutânea e posologia menos frequente, surge como uma alternativa mais conveniente, mantendo níveis de eficácia semelhantes. Outra abordagem relevante é representada pelos oligonucleótidos antisense, como o Inotersen, que também atuam ao nível do RNAm da TTR, inibindo a sua tradução. Apesar da necessidade de monitorização rigorosa devido ao risco de efeitos adversos hematológicos e renais, o Inotersen mostrou resultados positivos na estabilização da doença. O transplante hepático, anteriormente considerado o tratamento de referência, tem vindo a ser progressivamente substituído por estas terapias menos invasivas e mais amplamente acessíveis. Embora eficaz na eliminação da produção hepática de TTR mutada, o transplante apresenta limitações, como a seleção restrita de candidatos e os riscos inerentes ao procedimento cirúrgico. Apesar de tradicionalmente pouco explorada, a saliva tem-se revelado um fluido biológico de interesse na investigação da PAF, devido à presença de depósitos de TTR nas glândulas salivares de doentes afetados. Alterações no proteoma salivar poderão refletir processos patológicos subjacentes. Embora preliminares, estes dados sugerem que a análise salivar poderá constituir uma ferramenta complementar na investigação de biomarcadores não invasivos, contribuindo para o diagnóstico precoce e estratificação de doentes. Em suma, os avanços recentes nas terapias direcionadas à TTR representam um marco na abordagem da PAF, possibilitando intervenções mais eficazes e adaptadas às necessidades individuais dos doentes. A sua integração com ferramentas de diagnóstico inovadoras poderá potenciar uma medicina mais personalizada e centrada no doente.
Familial Amyloid Polyneuropathy (FAP) is a hereditary neurodegenerative disorder caused by the systemic deposition of amyloid fibrils composed of transthyretin (TTR) in multiple tissues. In most cases, this condition results from point mutations in the TTR gene, which compromise the stability of its tetrameric structure, promoting dissociation into unstable monomers and facilitating amyloid aggregation. Clinical manifestations typically arise between the third and fourth decades of life, making a comprehensive understanding of the underlying pathophysiological mechanisms essential. In recent years, innovative therapeutic strategies have been developed with significant impact on the clinical course of FAP. TTR stabilizers, such as Tafamidis, represent an effective pharmacological approach by promoting the stabilization of the protein’s tetrameric structure and preventing its dissociation. Tafamidis was the first drug approved for the treatment of FAP and has demonstrated efficacy in slowing disease progression and improving patients’ quality of life. In parallel, therapies aimed at reducing hepatic TTR production through gene-silencing mechanisms have emerged. Among these, RNA interference (RNAi)-based drugs such as Patisiran and Vutrisiran act by promoting the degradation of TTR messenger RNA (mRNA) in the liver, significantly decreasing circulating levels of the mutated protein. Patisiran has shown measurable neurological improvements in clinical trials. Vutrisiran, administered subcutaneously and with a less frequent dosing schedule, offers a more convenient alternative while maintaining similar efficacy. Another relevant therapeutic approach involves antisense oligonucleotides such as Inotersen, which also target TTR mRNA, inhibiting its translation. Despite requiring careful monitoring due to potential hematological and renal adverse effects, Inotersen has shown positive outcomes in disease stabilization. Liver transplantation, previously considered the standard treatment, has been progressively replaced by these less invasive and more widely accessible therapies. Although effective in eliminating hepatic production of mutated TTR, transplantation poses limitations such as restricted candidate eligibility and risks associated with surgery and immunosuppression. Although traditionally underexplored, saliva has emerged as a biological fluid of interest in FAP research due to the presence of TTR deposits in the salivary glands of affected patients. Changes in the salivary proteome may reflect underlying pathological processes. While preliminary, these findings suggest that salivary analysis may serve as a complementary tool in the investigation of non-invasive biomarkers, contributing to early diagnosis and patient stratification. In summary, recent advances in TTR-targeted therapies represent a milestone in the management of FAP, enabling more effective and tailored interventions. Their integration with innovative diagnostic tools may enhance the development of a more personalized and patient-centered approach to treatment.
Familial Amyloid Polyneuropathy (FAP) is a hereditary neurodegenerative disorder caused by the systemic deposition of amyloid fibrils composed of transthyretin (TTR) in multiple tissues. In most cases, this condition results from point mutations in the TTR gene, which compromise the stability of its tetrameric structure, promoting dissociation into unstable monomers and facilitating amyloid aggregation. Clinical manifestations typically arise between the third and fourth decades of life, making a comprehensive understanding of the underlying pathophysiological mechanisms essential. In recent years, innovative therapeutic strategies have been developed with significant impact on the clinical course of FAP. TTR stabilizers, such as Tafamidis, represent an effective pharmacological approach by promoting the stabilization of the protein’s tetrameric structure and preventing its dissociation. Tafamidis was the first drug approved for the treatment of FAP and has demonstrated efficacy in slowing disease progression and improving patients’ quality of life. In parallel, therapies aimed at reducing hepatic TTR production through gene-silencing mechanisms have emerged. Among these, RNA interference (RNAi)-based drugs such as Patisiran and Vutrisiran act by promoting the degradation of TTR messenger RNA (mRNA) in the liver, significantly decreasing circulating levels of the mutated protein. Patisiran has shown measurable neurological improvements in clinical trials. Vutrisiran, administered subcutaneously and with a less frequent dosing schedule, offers a more convenient alternative while maintaining similar efficacy. Another relevant therapeutic approach involves antisense oligonucleotides such as Inotersen, which also target TTR mRNA, inhibiting its translation. Despite requiring careful monitoring due to potential hematological and renal adverse effects, Inotersen has shown positive outcomes in disease stabilization. Liver transplantation, previously considered the standard treatment, has been progressively replaced by these less invasive and more widely accessible therapies. Although effective in eliminating hepatic production of mutated TTR, transplantation poses limitations such as restricted candidate eligibility and risks associated with surgery and immunosuppression. Although traditionally underexplored, saliva has emerged as a biological fluid of interest in FAP research due to the presence of TTR deposits in the salivary glands of affected patients. Changes in the salivary proteome may reflect underlying pathological processes. While preliminary, these findings suggest that salivary analysis may serve as a complementary tool in the investigation of non-invasive biomarkers, contributing to early diagnosis and patient stratification. In summary, recent advances in TTR-targeted therapies represent a milestone in the management of FAP, enabling more effective and tailored interventions. Their integration with innovative diagnostic tools may enhance the development of a more personalized and patient-centered approach to treatment.
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Palavras-chave
Paramiloidose amiloidótica familiar Amiloide Transtirretina Tratamento farmacológico Familial amyloidotic polyneuropathy Amyloid Transthyretin Pharmacological treatment