RESUMO
DNA-like molecules called antisense oligonucleotides have opened new treatment possibilities for genetic diseases by offering a method of regulating gene expression. Antisense oligonucleotides are often used to suppress the expression of mutated genes which may interfere with essential downstream pathways. Since antisense oligonucleotides have been introduced for clinical use, different chemistries have been developed to further improve efficacy, potency, and safety. One such chemistry is a chimeric structure of a central block of deoxyribonucleotides flanked by sequences of modified nucleotides. Referred to as a gapmer, this chemistry produced promising results in the treatment of genetic diseases. Mipomersen and inotersen are examples of recent FDA-approved antisense oligonucleotide gapmers used for the treatment of familial hypercholesterolemia and hereditary transthyretin amyloidosis, respectively. In addition, volanesorsen was conditionally approved in the EU for the treatment of adult patients with familial chylomicronemia syndrome (FCS) in 2019. Many others are being tested in clinical trials or under preclinical development. This chapter will cover the development of mipomersen and inotersen in clinical trials, along with advancement in gapmer treatments for cancer, triglyceride-elevating genetic diseases, Huntington's disease, myotonic dystrophy, and prion diseases.
Assuntos
Ensaios Clínicos como Assunto , Desenvolvimento de Medicamentos , Doenças Genéticas Inatas/terapia , Oligonucleotídeos Antissenso , Adulto , Ensaios Clínicos como Assunto/história , Ensaios Clínicos como Assunto/métodos , Desenvolvimento de Medicamentos/história , Desenvolvimento de Medicamentos/métodos , Doenças Genéticas Inatas/genética , História do Século XX , História do Século XXI , Humanos , Oligonucleotídeos/síntese química , Oligonucleotídeos/uso terapêutico , Oligonucleotídeos Antissenso/síntese química , Oligonucleotídeos Antissenso/uso terapêuticoRESUMO
The field of neuromuscular and neurodegenerative diseases has been revolutionized by the advent of genetics and molecular biology to evaluate the pathogenicity, thereby providing considerable insight to develop suitable therapies. With the successful translation of antisense oligonucleotides (AOs) from in vitro into animal models and clinical practice, modifications are being continuously made to the AOs to improve the pharmacokinetics and pharmacodynamics. In order to activate RNase H-mediated cleavage of the target mRNA, as well as to increase the binding affinity and specificity, gapmer AOs are designed to have a phosphorothioate (PS) backbone flanked with the modified AOs on both sides. Antisense-mediated knockdown of mutated huntingtin is a promising therapeutic approach for Huntington's disease (HD), a devastating disorder affecting the motor and cognitive abilities. This chapter focuses on the modified gapmer AOs for the treatment of HD.
Assuntos
Desenvolvimento de Medicamentos , Doença de Huntington/terapia , Oligonucleotídeos Antissenso/síntese química , Oligonucleotídeos Antissenso/uso terapêutico , Animais , Desenvolvimento de Medicamentos/história , Desenvolvimento de Medicamentos/métodos , História do Século XX , História do Século XXI , Humanos , Proteína Huntingtina/genética , Doença de Huntington/genética , Oligonucleotídeos Antissenso/genéticaRESUMO
The Annual Meeting of the American Academy of Neurology (AAN) is the largest conference convening neurology professionals from all over the world to share and discuss the latest breakthroughs in neurology treatment. The conference covers basic scientific research to clinical application through a wide range and interesting programs. This report covers some of the therapeutic highlights presented during the conference.