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Terapia génica: sistemas de entrega, mecanismos moleculares e abordagens terapêuticas aprovadas
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Abstract(s)
Desde o reconhecimento do gene como a unidade básica do DNA, da hereditariedade e da genética, a capacidade para fazer modificações específicas no genoma humano tem sido um objetivo para a comunidade científica. A terapia génica, através da adição, silenciamento, substituição ou edição de genes, pretende modificar o prognóstico de patologias, através da inserção de ácidos nucleicos, com recurso a sistemas de entrega com características distintas, nos alvos terapêuticos correspondentes.
Diversas melhorias ao nível dos sistemas de entrega (ditos vectores), quer virais, quer não virais, como métodos físicos ou químicos, têm como objetivo aumentar a eficácia e segurança, promovendo a obtenção de benefício terapêutico, com o desafio constante de evitar respostas imunes ou efeitos tóxicos indesejados.
Após a descoberta de mecanismos de transferência genética através da transdução, por Ledeberg em 1952, até à primeira transferência de genes aprovada em humanos, por Rosenberg em 1989, a terapia génica já se tornou uma realidade, com cerca de 232 ensaios clínicos aprovados só em 2018 e com terapêuticas diversas, na abordagem de doenças monogenéticas, cardiovasculares, oncológicas, infeciosas e neurológicas, entre outras.
A atual dissertação tem como propósito, apresentar uma revisão bibliográfica atualizada da evolução da terapia génica, analisando e comparando as diferentes metodologias de administração, sistemas de entrega e estratégias terapêuticas, bem como a abordagem de terapêuticas atualmente aprovadas, cuja implementação veio alterar o rumo clínico de determinadas patologias. Pretende-se também analisar perspetivas futuras e avanços que auxiliem o desenvolvimento de novas terapias génicas, que melhorem o tratamento e a qualidade de vida dos doentes.
Since the establishment of genes as the basic unit of DNA, heredity and genetics, the ability to make specific changes to the human genome has been a milestone for the scientific community. Through addition, silencing, replacement or gene edition, gene therapy aims to modify the prognosis of diseases, through the insertion of nucleic acids, using delivery systems with distinct characteristics, in the corresponding therapeutic targets. Improvements in terms of the delivery systems (called vectors), whether viral or non-viral, such as physical methods or chemical methods, aimed to increase the efficacy and safety, which are both fundamental aspects for obtaining therapeutic benefit, with the constant challenge of avoiding unwanted immune and toxic responses. After the discovery of gene transfer mechanisms through transduction, by Lederberg in 1952, until the first approved gene transfer in humans, by Rosenberg in 1989, this therapy as already become a reality, with about 232 clinical trials of gene therapy approved just in 2018 and a wide variety of therapeutic approaches for the treatment of monogenetic, cardiovascular, oncological, infectious and neurological diseases, among others. The present dissertation aims to present na updated bibliographic review of the evolution of gene therapy, analyzing and comparing different administration methodologies, delivery systems and therapeutic strategies, as well as currently approved therapeutic approach, whose implementation has changed the course of certain pathologies. It is also intended to analyze future perspectives and advances that help the development of new gene therapies, which will improve the treatment and the life quality of patients.
Since the establishment of genes as the basic unit of DNA, heredity and genetics, the ability to make specific changes to the human genome has been a milestone for the scientific community. Through addition, silencing, replacement or gene edition, gene therapy aims to modify the prognosis of diseases, through the insertion of nucleic acids, using delivery systems with distinct characteristics, in the corresponding therapeutic targets. Improvements in terms of the delivery systems (called vectors), whether viral or non-viral, such as physical methods or chemical methods, aimed to increase the efficacy and safety, which are both fundamental aspects for obtaining therapeutic benefit, with the constant challenge of avoiding unwanted immune and toxic responses. After the discovery of gene transfer mechanisms through transduction, by Lederberg in 1952, until the first approved gene transfer in humans, by Rosenberg in 1989, this therapy as already become a reality, with about 232 clinical trials of gene therapy approved just in 2018 and a wide variety of therapeutic approaches for the treatment of monogenetic, cardiovascular, oncological, infectious and neurological diseases, among others. The present dissertation aims to present na updated bibliographic review of the evolution of gene therapy, analyzing and comparing different administration methodologies, delivery systems and therapeutic strategies, as well as currently approved therapeutic approach, whose implementation has changed the course of certain pathologies. It is also intended to analyze future perspectives and advances that help the development of new gene therapies, which will improve the treatment and the life quality of patients.
Description
Keywords
Terapia génica Vectores virais Vectores não-virais CRISPR/Cas9 Strimvelis Spinraza.