RESUMO
Antisense oligonucleotides (ASOs) represent a new and highly promising class of drugs for personalized medicine. In the last decade, major chemical developments and improvements of the backbone structure of ASOs have transformed them into true approved and commercialized drugs. ASOs target both DNA and RNA, including pre-mRNA, mRNA, and ncRDA, based on sequence complementary. They are designed to be specific for each identified molecular and genetic alteration to restore a normal, physiological situation. Thus, the characterization of the underpinning mechanisms and alterations that sustain pathology is critical for accurate ASO-design. ASOs can be used to cure both rare and common diseases, such as orphan genetic alterations and cancer. Through pioneering examples, this review shows the versatility of the mechanisms of action that provide ASOs with the potential capacity to achieve custom treatment, revolutionizing personalized medicine. This article is categorized under: RNA in Disease and Development > RNA in Disease RNA Interactions with Proteins and Other Molecules > Small Molecule-RNA Interactions.
Assuntos
Terapia Genética , Oligonucleotídeos Antissenso/genética , Oligonucleotídeos Antissenso/farmacologia , Medicina de Precisão , Animais , Desenvolvimento de Medicamentos , Regulação da Expressão Gênica , Inativação Gênica , Terapia Genética/métodos , Humanos , Oligonucleotídeos Antissenso/química , Medicina de Precisão/métodos , Biossíntese de Proteínas , Interferência de RNA , Estabilidade de RNA , Elementos de Resposta , Reparo Gênico Alvo-Dirigido , Pesquisa Translacional BiomédicaRESUMO
Competition among RNAs to bind miRNA is proposed to influence biological systems. However, the role of this competition in disease onset is unclear. Here, we report that TYRP1 mRNA, in addition to encoding tyrosinase-related protein 1 (TYRP1), indirectly promotes cell proliferation by sequestering miR-16 on non-canonical miRNA response elements. Consequently, the sequestered miR-16 is no longer able to repress its mRNA targets, such as RAB17, which is involved in melanoma cell proliferation and tumour growth. Restoration of miR-16 tumour-suppressor function can be achieved in vitro by silencing TYRP1 or increasing miR-16 expression. Importantly, TYRP1-dependent miR-16 sequestration can also be overcome in vivo by using small oligonucleotides that mask miR-16-binding sites on TYRP1 mRNA. Together, our findings assign a pathogenic non-coding function to TYRP1 mRNA and highlight miRNA displacement as a promising targeted therapeutic approach for melanoma.
Assuntos
Proliferação de Células/genética , Melanoma/genética , Melanoma/patologia , Glicoproteínas de Membrana/genética , Oxirredutases/genética , RNA Mensageiro/genética , Animais , Sítios de Ligação/genética , Linhagem Celular Tumoral , Feminino , Humanos , Camundongos , MicroRNAs/genéticaRESUMO
Targeting RNAs appears as an important opportunity to modulate biological processes. Here, we overviewed critical parameters implied in RNAs competition to bind small RNAs. These competitions influence small RNA availability and thereby gene expression and cell fate. We focused on the ability of RNAs to sequester small RNA, mainly the microRNAs (miRNAs) and proposed experimental workflows to demonstrate the existence and activity of RNA-sponge. From this basic science, we detailed tailored oligonucleotides, developed to challenge the binding of small RNA. In vitro and in vivo, these tailored oligonucleotides efficiently restore small RNA activity by preventing their sequestration on RNA-sponges.