Pub Date : 2019-11-20DOI: 10.5772/intechopen.86867
S. Sharad
Nucleic acids are the backbone of antisense therapy. Antisense oligonucleotide-based therapeutics involves downregulation of gene expression. RNA-based drugs that include antisense oligonucleotides bear great therapeutic potential toward treatment of various diseases by altering RNA and/or reducing, restoring, and mod-ifying protein expression through multiple molecular mechanisms. Pharmacology of targeted antisense therapy has provided the platform to translate its utility to the clinic. Over the years, chemical modifications of antisense oligonucleotides have not only enhanced the specificity and efficacy but also reduced the side effects. These have changed the whole clinical trial design and provide newer strategies for therapies. Improvement in antisense oligonucleotide therapy technology has allowed and brought research from bench to clinic. Additionally, the use of small interfering RNAs, micro RNAs, ribozymes, and other antisense compounds toward the treatment of deadly diseases like cancers have demonstrated both preclinical and clinical responses. Furthermore, antisense therapy has great potential to target specific genes of interest in the context of precision medicine. Optimization of enhanced delivery, specificity, affinity, and nuclease resistance with reduced toxic-ity is underway in different disease context. This chapter gives a complete overview of antisense therapy and highlights its potential. Here, we focused on the advances of the antisense technology, pharmacology, therapeutics, and drug discovery.
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Pub Date : 2019-06-17DOI: 10.5772/INTECHOPEN.86920
Behiye Şenel, G. Büyükköroğlu
The antisense technology that emerged with the discovery of RNA interference nearly 20 years ago has gained a significant place in gene therapy. siRNA, one of two important components of RNA interference, efficiently downregulates gene expression in human cells, so it has the potential to eradicate disease. siRNA delivery systems, which can be applied both systemically and locally in different diseases, have gained significant importance. Naked small RNAs can be delivered directly to cells, but because of their instability, exposure to enzyme degradation, and difficulties in reaching/entering the target cell or tissue in blood stream, these initiatives are failing. For this reason, the method of delivery or encapsulation of siRNA is usually required. Various nanoparticles, nanocapsules, emulsions, micelle systems, metal ion nanoparticles, and nanoconjugates have been used for siRNA delivery. In these transport systems, lipidic and polymeric systems are very attractive due to their advantages such as being biodegradable and biocompatible, safety, being able to electrostatically bind to RNA, long-term stability, well-illuminated structure and features, simple and easy production, etc. Issues such as particle size, zeta potential, and stability of siRNA-loaded system should be taken into consideration in the development of siRNA delivery systems.
{"title":"Applications of Lipidic and Polymeric Nanoparticles for siRNA Delivery","authors":"Behiye Şenel, G. Büyükköroğlu","doi":"10.5772/INTECHOPEN.86920","DOIUrl":"https://doi.org/10.5772/INTECHOPEN.86920","url":null,"abstract":"The antisense technology that emerged with the discovery of RNA interference nearly 20 years ago has gained a significant place in gene therapy. siRNA, one of two important components of RNA interference, efficiently downregulates gene expression in human cells, so it has the potential to eradicate disease. siRNA delivery systems, which can be applied both systemically and locally in different diseases, have gained significant importance. Naked small RNAs can be delivered directly to cells, but because of their instability, exposure to enzyme degradation, and difficulties in reaching/entering the target cell or tissue in blood stream, these initiatives are failing. For this reason, the method of delivery or encapsulation of siRNA is usually required. Various nanoparticles, nanocapsules, emulsions, micelle systems, metal ion nanoparticles, and nanoconjugates have been used for siRNA delivery. In these transport systems, lipidic and polymeric systems are very attractive due to their advantages such as being biodegradable and biocompatible, safety, being able to electrostatically bind to RNA, long-term stability, well-illuminated structure and features, simple and easy production, etc. Issues such as particle size, zeta potential, and stability of siRNA-loaded system should be taken into consideration in the development of siRNA delivery systems.","PeriodicalId":401328,"journal":{"name":"Antisense Therapy","volume":"24 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2019-06-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"127958013","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2019-03-15DOI: 10.5772/INTECHOPEN.82548
T. Jerzy
AFP and IGF-I oncoproteins were introduced as biomarkers for cancer diagnosis and targeted in cancer therapy on protein level, but also on transcription and translation levels. The protein level was targeted using an injection of antibodies or radiolabeled proteins. The transcription and translation levels were targeted by triple helix and antisense technologies, respectively. AFP was especially useful for diagnosis and therapy of liver cancer, IGF-I was applied in diagnosis and therapy of colon, prostate, liver, uterus, ovary and brain tumors. The most spectacular results were obtained with IGF-I anti-gene strategy. IGF-I antisense (AS)/triple helix (TH) gene therapy was successfully introduced in clinical trial in the USA and Europe. When using IGF-I anti-gene therapy, cancer cells provided from biopsies were transfected in vitro with IGF-I AS, IGF-I TH expression vectors. A decrease in IGF-I gene expression of 80 and 60% was demonstrated when using TH and AS technologies, respectively. These transfected cells expressing MHC-I molecules, while injected in vivo , induced immune antitumor response mediated by CD8 lymphocytes. The median survival of treated glioblastoma patients was 21–22 months. IGF-I AS/TH immunogene therapy constitutes one of the most promising approaches in cancer therapy, and more specifically when it comes to glioblastoma treatment.
{"title":"Oncoproteins Targeting: Antibodies, Antisense, Triple-helix. Case of Anti IGF-I Cancer Immunogene Therapy","authors":"T. Jerzy","doi":"10.5772/INTECHOPEN.82548","DOIUrl":"https://doi.org/10.5772/INTECHOPEN.82548","url":null,"abstract":"AFP and IGF-I oncoproteins were introduced as biomarkers for cancer diagnosis and targeted in cancer therapy on protein level, but also on transcription and translation levels. The protein level was targeted using an injection of antibodies or radiolabeled proteins. The transcription and translation levels were targeted by triple helix and antisense technologies, respectively. AFP was especially useful for diagnosis and therapy of liver cancer, IGF-I was applied in diagnosis and therapy of colon, prostate, liver, uterus, ovary and brain tumors. The most spectacular results were obtained with IGF-I anti-gene strategy. IGF-I antisense (AS)/triple helix (TH) gene therapy was successfully introduced in clinical trial in the USA and Europe. When using IGF-I anti-gene therapy, cancer cells provided from biopsies were transfected in vitro with IGF-I AS, IGF-I TH expression vectors. A decrease in IGF-I gene expression of 80 and 60% was demonstrated when using TH and AS technologies, respectively. These transfected cells expressing MHC-I molecules, while injected in vivo , induced immune antitumor response mediated by CD8 lymphocytes. The median survival of treated glioblastoma patients was 21–22 months. IGF-I AS/TH immunogene therapy constitutes one of the most promising approaches in cancer therapy, and more specifically when it comes to glioblastoma treatment.","PeriodicalId":401328,"journal":{"name":"Antisense Therapy","volume":"43 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2019-03-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"129930321","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2019-02-21DOI: 10.5772/INTECHOPEN.82105
Sara Karaki, Clément Paris, P. Rocchi
Antisense oligonucleotides (ASOs) have been validated as therapeutic agents and an important tool in molecular biology. Indeed, ASOs are used either in vitro or in vivo to generate mRNA selective knockouts. They can be used for human therapy since ASOs can inhibit specifically target genes especially whose are difficult to target with small molecules inhibitors or neutralizing antibodies. However, despite their specificity and broadness of use, some practical obstacles remain unsolved in antisense pharmacology, such as insufficient stability due to nucleases degradation activity, and poor cellular delivery as a result of low cellular uptake difficult biological membrane crossing. Moreover, in many cases, potential off-target effects and immunostimulation are also part of the problems derived from their use. In this review, we will discuss ASOs, their chemistry, limitation of use, some solutions to increase stability, and finally some of their therapeutical application.
{"title":"Antisense Oligonucleotides, A Novel Developing Targeting Therapy","authors":"Sara Karaki, Clément Paris, P. Rocchi","doi":"10.5772/INTECHOPEN.82105","DOIUrl":"https://doi.org/10.5772/INTECHOPEN.82105","url":null,"abstract":"Antisense oligonucleotides (ASOs) have been validated as therapeutic agents and an important tool in molecular biology. Indeed, ASOs are used either in vitro or in vivo to generate mRNA selective knockouts. They can be used for human therapy since ASOs can inhibit specifically target genes especially whose are difficult to target with small molecules inhibitors or neutralizing antibodies. However, despite their specificity and broadness of use, some practical obstacles remain unsolved in antisense pharmacology, such as insufficient stability due to nucleases degradation activity, and poor cellular delivery as a result of low cellular uptake difficult biological membrane crossing. Moreover, in many cases, potential off-target effects and immunostimulation are also part of the problems derived from their use. In this review, we will discuss ASOs, their chemistry, limitation of use, some solutions to increase stability, and finally some of their therapeutical application.","PeriodicalId":401328,"journal":{"name":"Antisense Therapy","volume":"9 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2019-02-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"125388744","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2018-12-24DOI: 10.5772/INTECHOPEN.82738
Andrew Walayat, Meizi Yang, D. Xiao
MicroRNAs (miRNAs) are a class of short non-coding RNA molecules that are involved in development and diseases. Early studies are focusing on the miRNA profile as a biomarker in disease. As discovery of human miRNAs increased in the setting of disease, the research focus was gradually shifted towards miRNA therapeutic strategy for diagnostic and treatment of disease. Increasing evidences suggest that miRNAs are the next important class of antisense therapeutic molecules, which have significant advantage over antisense such as siRNAs because miRNAs are naturally occurring endogenous molecules. Aberrant alteration of the endogenous miRNAs has been linked to the development of certain diseases. Correcting these altered miRNAs by their mimics or inhibitors has been developed as potential therapeutic approaches. Some of the miRNA-based therapeutics are processed in preclinical and clinical trial for treatment hepatitis C, liver cancer, and other diseases. Currently, the major focus in the development of miRNA-based therapeutics is how to increase the miRNA stability and optimize delivery systems for specific disease with minimal off-target effect. This chapter will first overview the miRNA biogenesis, patho- and physiologic function, and regulation of miRNA molecules. Then, we discuss the miRNA-based potential therapeutic approaches and implication in disease.
{"title":"Therapeutic Implication of miRNA in Human Disease","authors":"Andrew Walayat, Meizi Yang, D. Xiao","doi":"10.5772/INTECHOPEN.82738","DOIUrl":"https://doi.org/10.5772/INTECHOPEN.82738","url":null,"abstract":"MicroRNAs (miRNAs) are a class of short non-coding RNA molecules that are involved in development and diseases. Early studies are focusing on the miRNA profile as a biomarker in disease. As discovery of human miRNAs increased in the setting of disease, the research focus was gradually shifted towards miRNA therapeutic strategy for diagnostic and treatment of disease. Increasing evidences suggest that miRNAs are the next important class of antisense therapeutic molecules, which have significant advantage over antisense such as siRNAs because miRNAs are naturally occurring endogenous molecules. Aberrant alteration of the endogenous miRNAs has been linked to the development of certain diseases. Correcting these altered miRNAs by their mimics or inhibitors has been developed as potential therapeutic approaches. Some of the miRNA-based therapeutics are processed in preclinical and clinical trial for treatment hepatitis C, liver cancer, and other diseases. Currently, the major focus in the development of miRNA-based therapeutics is how to increase the miRNA stability and optimize delivery systems for specific disease with minimal off-target effect. This chapter will first overview the miRNA biogenesis, patho- and physiologic function, and regulation of miRNA molecules. Then, we discuss the miRNA-based potential therapeutic approaches and implication in disease.","PeriodicalId":401328,"journal":{"name":"Antisense Therapy","volume":"7 6 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2018-12-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"116868332","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2018-11-14DOI: 10.5772/INTECHOPEN.81847
O. Bălăcescu, Simona Vișan, Oana Baldasici, L. Balacescu, C. Vlad, P. Achimas-Cadariu
As master modulators of the human genome, miRNAs are involved in all cancer hallmarks, disrupting the normal function of their targets. By gaining or losing the function, miRNAs lead to the validation of tumor phenotype, its progression, and metastasis as well as to drug resistance. Increasing the evidence suggests that the modulation of miRNAs in cancer cells, by suppressing the oncogenic miRNAs (oncomiRs) and substituting the deficient tumor suppressive miRNAs (TS-miRNAs), could become a reliable tool for improving the cancer therapy. In this chapter, we will present an up-to-date overview of the role of miRNA-based therapeutics in oncology, highlighting their role in cancer management, how these therapies can be used, and which would be the future challenges related to miRNA-based therapies. invasion and metastases (e.g. miR-10b, miR-31, miR-200 family, miR-21, miR-15b), reprogramming energy metabolism
{"title":"MiRNA-Based Therapeutics in Oncology, Realities, and Challenges","authors":"O. Bălăcescu, Simona Vișan, Oana Baldasici, L. Balacescu, C. Vlad, P. Achimas-Cadariu","doi":"10.5772/INTECHOPEN.81847","DOIUrl":"https://doi.org/10.5772/INTECHOPEN.81847","url":null,"abstract":"As master modulators of the human genome, miRNAs are involved in all cancer hallmarks, disrupting the normal function of their targets. By gaining or losing the function, miRNAs lead to the validation of tumor phenotype, its progression, and metastasis as well as to drug resistance. Increasing the evidence suggests that the modulation of miRNAs in cancer cells, by suppressing the oncogenic miRNAs (oncomiRs) and substituting the deficient tumor suppressive miRNAs (TS-miRNAs), could become a reliable tool for improving the cancer therapy. In this chapter, we will present an up-to-date overview of the role of miRNA-based therapeutics in oncology, highlighting their role in cancer management, how these therapies can be used, and which would be the future challenges related to miRNA-based therapies. invasion and metastases (e.g. miR-10b, miR-31, miR-200 family, miR-21, miR-15b), reprogramming energy metabolism","PeriodicalId":401328,"journal":{"name":"Antisense Therapy","volume":"47 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2018-11-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"128293400","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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