The era of RNA interference medicines: the clinical landscape of synthetic gene silencing drugs

Detalhes bibliográficos
Autor(a) principal: Godinho, Bruno M. D. C.
Data de Publicação: 2022
Outros Autores: Khvorova, Anastasia
Tipo de documento: Artigo
Idioma: por
Título da fonte: Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)
Texto Completo: https://doi.org/10.25758/set.2227
Resumo: Therapeutic oligonucleotides, such as small interfering RNAs (siRNAs), provide a simple and effective tool to modulate the expression of any gene. siRNAs harness the RNA interference (RNAi) pathway to degrade disease-associated messenger RNAs (mRNAs). The inherent sequence specificity and potency of siRNAs make them ideal drug candidates that are expected to transform drug development and our approach to human health. However, the first wave of clinical trials was not immediately successful and temporarily dampened the excitement over this newly discovered technology. Most studies did not meet desired efficacy and failed to achieve clinically-relevant endpoints. Poor chemical design, lack of enzymatic stability, and inadequate delivery strategies were found to be the main issues stifling success. Recent advancements in RNA chemistry, biology, and mechanistic understanding of factors that define oligonucleotide pharmacokinetic/pharmacodynamic behavior have resulted in a fundamental shift in the clinical landscape of this novel class of therapeutic modalities. As a result, there has been a dramatic increase in both the number of clinical trials and, more importantly, the level of observed clinical efficacy. In 2018, we witnessed a major landmark for the field with the first formulation-based RNAi therapeutic, Patisiran (OnpattroTM), being approved by the Food and Drug Administration and the European Medicines Agency. Approximately a year later, another breakthrough was achieved with the approval of Givosiran (GIVLAARITM), the first siRNA using the conjugate-mediated approach for targeted delivery to hepatocytes. Both these approvals brought revitalized hope and enthusiasm to the field, and have restored the interest in RNAi, as a powerful disease-modifying therapeutic strategy for a variety of genetically-defined disorders. This review gives an overview of the clinical landscape of synthetic RNAi drugs, contextualizing how advances in RNAi chemistry and formulation strategies have helped define the clinical utility of this promising class of drugs.
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spelling The era of RNA interference medicines: the clinical landscape of synthetic gene silencing drugsA era dos medicamentos de ARN interferência: o panorama clínico dos fármacos para silenciamento génicoARN interferênciasiRNAmiRNAOligonucleotídios para terapêuticaDesenvolvimento de novos fármacosRNA interferencesiRNAmiRNATherapeutic oligonucleotidesGene knockdownDrug developmentTherapeutic oligonucleotides, such as small interfering RNAs (siRNAs), provide a simple and effective tool to modulate the expression of any gene. siRNAs harness the RNA interference (RNAi) pathway to degrade disease-associated messenger RNAs (mRNAs). The inherent sequence specificity and potency of siRNAs make them ideal drug candidates that are expected to transform drug development and our approach to human health. However, the first wave of clinical trials was not immediately successful and temporarily dampened the excitement over this newly discovered technology. Most studies did not meet desired efficacy and failed to achieve clinically-relevant endpoints. Poor chemical design, lack of enzymatic stability, and inadequate delivery strategies were found to be the main issues stifling success. Recent advancements in RNA chemistry, biology, and mechanistic understanding of factors that define oligonucleotide pharmacokinetic/pharmacodynamic behavior have resulted in a fundamental shift in the clinical landscape of this novel class of therapeutic modalities. As a result, there has been a dramatic increase in both the number of clinical trials and, more importantly, the level of observed clinical efficacy. In 2018, we witnessed a major landmark for the field with the first formulation-based RNAi therapeutic, Patisiran (OnpattroTM), being approved by the Food and Drug Administration and the European Medicines Agency. Approximately a year later, another breakthrough was achieved with the approval of Givosiran (GIVLAARITM), the first siRNA using the conjugate-mediated approach for targeted delivery to hepatocytes. Both these approvals brought revitalized hope and enthusiasm to the field, and have restored the interest in RNAi, as a powerful disease-modifying therapeutic strategy for a variety of genetically-defined disorders. This review gives an overview of the clinical landscape of synthetic RNAi drugs, contextualizing how advances in RNAi chemistry and formulation strategies have helped define the clinical utility of this promising class of drugs.Oligonucleotídeos sintéticos, como os small interfering RNAs (siRNAs), providenciam uma forma simples e eficiente de modular a expressão de qualquer gene. siRNAs utilizam um mecanismo endógeno, chamado ARN interferência, para degradar ARN mensageiros que estejam associados a condições patológicas. A capacidade de silenciar genes com elevada especificidade e potência faz dos siRNAs fármacos ideais com um elevado potencial para transformar o ramo da medicina e a forma como se faz desenvolvimento farmacêutico. Contudo, os primeiros ensaios clínicos com esta tecnologia não tiveram sucesso imediato, o que reduziu temporariamente o entusiasmo da comunidade científica. A maioria destes estudos iniciais não atingiram a eficácia clínica desejada. A introdução prematura de fármacos que não se encontravam devidamente estabilizados e a utilização de estratégias de administração inadequadas foram as principais causas dos primeiros fracassos. Avanços recentes na síntese química de oligonucleotídeos, como a melhor compreensão dos processos biológicos que definem a farmacocinética/farmacodinâmica destes fármacos, resultou numa mudança drástica no panorama clínico desta nova modalidade terapêutica. O número de ensaios clínicos tem aumentado significativamente ao longo dos últimos anos, em paralelo com o aumento da eficácia terapêutica destes medicamentos. Em 2018 foi testemunhado um marco importante para o ramo de desenvolvimento destes fármacos, com a aprovação do primeiro produto baseado em liposomas, Patisiran (OnpattroTM), pela Food and Drug Administration e pela European Medicines Agency. Aproximadamente um ano mais tarde foi aprovado o primeiro fármaco que utiliza a estratégia de conjugados que possibilita a internalização específica em hepatócitos, Givosiran (GIVLAARITM). A recente aprovação destes dois fármacos trouxe uma esperança renovada ao ramo de ARN interferência, alimentando o interesse nesta estratégia como poderosa ferramenta terapêutica para doenças do foro genético. Este artigo de revisão pretende providenciar uma perspetiva geral sobre o panorama clínico dos fármacos para silenciamento génico, contextualizando o papel dos avanços tecnológicos que permitiram a definição desta modalidade como uma nova classe farmacêutica.Escola Superior de Tecnologia da Saúde de Lisboa (Instituto Politécnico de Lisboa)2022-07-29info:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/articleapplication/pdfhttps://doi.org/10.25758/set.2227oai:journals.ipl.pt:article/536Saúde e Tecnologia; No. 21 (2019): Maio 2019; 05-17Saúde & Tecnologia; N.º 21 (2019): Maio 2019; 05-171646-9704reponame:Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)instname:Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informaçãoinstacron:RCAAPporhttps://journals.ipl.pt/stecnologia/article/view/536https://doi.org/10.25758/set.2227https://journals.ipl.pt/stecnologia/article/view/536/462Direitos de Autor (c) 2022 Saúde & Tecnologiainfo:eu-repo/semantics/openAccessGodinho, Bruno M. D. C.Khvorova, Anastasia2022-12-20T10:58:44Zoai:journals.ipl.pt:article/536Portal AgregadorONGhttps://www.rcaap.pt/oai/openaireopendoar:71602024-03-19T16:21:21.473891Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) - Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informaçãofalse
dc.title.none.fl_str_mv The era of RNA interference medicines: the clinical landscape of synthetic gene silencing drugs
A era dos medicamentos de ARN interferência: o panorama clínico dos fármacos para silenciamento génico
title The era of RNA interference medicines: the clinical landscape of synthetic gene silencing drugs
spellingShingle The era of RNA interference medicines: the clinical landscape of synthetic gene silencing drugs
Godinho, Bruno M. D. C.
ARN interferência
siRNA
miRNA
Oligonucleotídios para terapêutica
Desenvolvimento de novos fármacos
RNA interference
siRNA
miRNA
Therapeutic oligonucleotides
Gene knockdown
Drug development
title_short The era of RNA interference medicines: the clinical landscape of synthetic gene silencing drugs
title_full The era of RNA interference medicines: the clinical landscape of synthetic gene silencing drugs
title_fullStr The era of RNA interference medicines: the clinical landscape of synthetic gene silencing drugs
title_full_unstemmed The era of RNA interference medicines: the clinical landscape of synthetic gene silencing drugs
title_sort The era of RNA interference medicines: the clinical landscape of synthetic gene silencing drugs
author Godinho, Bruno M. D. C.
author_facet Godinho, Bruno M. D. C.
Khvorova, Anastasia
author_role author
author2 Khvorova, Anastasia
author2_role author
dc.contributor.author.fl_str_mv Godinho, Bruno M. D. C.
Khvorova, Anastasia
dc.subject.por.fl_str_mv ARN interferência
siRNA
miRNA
Oligonucleotídios para terapêutica
Desenvolvimento de novos fármacos
RNA interference
siRNA
miRNA
Therapeutic oligonucleotides
Gene knockdown
Drug development
topic ARN interferência
siRNA
miRNA
Oligonucleotídios para terapêutica
Desenvolvimento de novos fármacos
RNA interference
siRNA
miRNA
Therapeutic oligonucleotides
Gene knockdown
Drug development
description Therapeutic oligonucleotides, such as small interfering RNAs (siRNAs), provide a simple and effective tool to modulate the expression of any gene. siRNAs harness the RNA interference (RNAi) pathway to degrade disease-associated messenger RNAs (mRNAs). The inherent sequence specificity and potency of siRNAs make them ideal drug candidates that are expected to transform drug development and our approach to human health. However, the first wave of clinical trials was not immediately successful and temporarily dampened the excitement over this newly discovered technology. Most studies did not meet desired efficacy and failed to achieve clinically-relevant endpoints. Poor chemical design, lack of enzymatic stability, and inadequate delivery strategies were found to be the main issues stifling success. Recent advancements in RNA chemistry, biology, and mechanistic understanding of factors that define oligonucleotide pharmacokinetic/pharmacodynamic behavior have resulted in a fundamental shift in the clinical landscape of this novel class of therapeutic modalities. As a result, there has been a dramatic increase in both the number of clinical trials and, more importantly, the level of observed clinical efficacy. In 2018, we witnessed a major landmark for the field with the first formulation-based RNAi therapeutic, Patisiran (OnpattroTM), being approved by the Food and Drug Administration and the European Medicines Agency. Approximately a year later, another breakthrough was achieved with the approval of Givosiran (GIVLAARITM), the first siRNA using the conjugate-mediated approach for targeted delivery to hepatocytes. Both these approvals brought revitalized hope and enthusiasm to the field, and have restored the interest in RNAi, as a powerful disease-modifying therapeutic strategy for a variety of genetically-defined disorders. This review gives an overview of the clinical landscape of synthetic RNAi drugs, contextualizing how advances in RNAi chemistry and formulation strategies have helped define the clinical utility of this promising class of drugs.
publishDate 2022
dc.date.none.fl_str_mv 2022-07-29
dc.type.status.fl_str_mv info:eu-repo/semantics/publishedVersion
dc.type.driver.fl_str_mv info:eu-repo/semantics/article
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dc.identifier.uri.fl_str_mv https://doi.org/10.25758/set.2227
oai:journals.ipl.pt:article/536
url https://doi.org/10.25758/set.2227
identifier_str_mv oai:journals.ipl.pt:article/536
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dc.relation.none.fl_str_mv https://journals.ipl.pt/stecnologia/article/view/536
https://doi.org/10.25758/set.2227
https://journals.ipl.pt/stecnologia/article/view/536/462
dc.rights.driver.fl_str_mv Direitos de Autor (c) 2022 Saúde & Tecnologia
info:eu-repo/semantics/openAccess
rights_invalid_str_mv Direitos de Autor (c) 2022 Saúde & Tecnologia
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
dc.publisher.none.fl_str_mv Escola Superior de Tecnologia da Saúde de Lisboa (Instituto Politécnico de Lisboa)
publisher.none.fl_str_mv Escola Superior de Tecnologia da Saúde de Lisboa (Instituto Politécnico de Lisboa)
dc.source.none.fl_str_mv Saúde e Tecnologia; No. 21 (2019): Maio 2019; 05-17
Saúde & Tecnologia; N.º 21 (2019): Maio 2019; 05-17
1646-9704
reponame:Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)
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