Advances in siRNA therapeutics and synergistic effect on siRNA activity using emerging dual ribose modifications
Nucleic acid-based therapeutics that control gene expression have been steadily progressing towards achieving their full clinical potential throughout the last few decades. Rapid progress has been achieved in RNAi-based therapy by optimizing high specificity and gene silencing efficiency using chemi...
| Main Authors: | , |
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| Format: | Article |
| Language: | English |
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Taylor & Francis Group
2022-12-01
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| Series: | RNA Biology |
| Subjects: | |
| Online Access: | http://dx.doi.org/10.1080/15476286.2022.2052641 |
| _version_ | 1797403950566080512 |
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| author | Sumit Gangopadhyay Kiran R Gore |
| author_facet | Sumit Gangopadhyay Kiran R Gore |
| author_sort | Sumit Gangopadhyay |
| collection | DOAJ |
| description | Nucleic acid-based therapeutics that control gene expression have been steadily progressing towards achieving their full clinical potential throughout the last few decades. Rapid progress has been achieved in RNAi-based therapy by optimizing high specificity and gene silencing efficiency using chemically modified siRNAs. Since 2018, four siRNA drugs – patisiran, givosiran, lumasiran, and inclisiran, were approved by the US FDA, providing a testament to the promise of RNAi therapeutics. Despite these promising results, safe and efficient siRNA delivery at the target site remains a major obstacle for efficient siRNA-based therapeutics. In this review, we have outlined the synergistic effects of emerging dual ribose modifications, including 2’,4’- and 2’,5’-modifications, 5’-E/Z-vinylphosphonate, and northern methanocarbacyclic (NMC) modifications that have contributed to drug-like effects in siRNA. These modifications enhance nuclease stability, prolong gene silencing efficiency, improve thermal stability, and exhibit high tissue accumulation. We also highlight the current progress in siRNA clinical trials. This review will help to understand the potential effects of dual ribose modifications and provides alternative ways to use extensive 2’-modifications in siRNA drugs. Moreover, the minimal number of these dual ribose modifications could be sufficient to achieve the desired therapeutic effect. In future, detailed in vivo studies using these dual ribose modifications could help to improve the therapeutic effects of siRNA. Rational design could further open doors for the rapid progress in siRNA therapeutics. |
| first_indexed | 2024-03-09T02:46:59Z |
| format | Article |
| id | doaj.art-1b442cb0076743a195ab1c13e6b38ea2 |
| institution | Directory Open Access Journal |
| issn | 1547-6286 1555-8584 |
| language | English |
| last_indexed | 2024-03-09T02:46:59Z |
| publishDate | 2022-12-01 |
| publisher | Taylor & Francis Group |
| record_format | Article |
| series | RNA Biology |
| spelling | doaj.art-1b442cb0076743a195ab1c13e6b38ea22023-12-05T16:09:51ZengTaylor & Francis GroupRNA Biology1547-62861555-85842022-12-0119145246710.1080/15476286.2022.20526412052641Advances in siRNA therapeutics and synergistic effect on siRNA activity using emerging dual ribose modificationsSumit Gangopadhyay0Kiran R Gore1Indian Institute of Technology KharagpurIndian Institute of Technology KharagpurNucleic acid-based therapeutics that control gene expression have been steadily progressing towards achieving their full clinical potential throughout the last few decades. Rapid progress has been achieved in RNAi-based therapy by optimizing high specificity and gene silencing efficiency using chemically modified siRNAs. Since 2018, four siRNA drugs – patisiran, givosiran, lumasiran, and inclisiran, were approved by the US FDA, providing a testament to the promise of RNAi therapeutics. Despite these promising results, safe and efficient siRNA delivery at the target site remains a major obstacle for efficient siRNA-based therapeutics. In this review, we have outlined the synergistic effects of emerging dual ribose modifications, including 2’,4’- and 2’,5’-modifications, 5’-E/Z-vinylphosphonate, and northern methanocarbacyclic (NMC) modifications that have contributed to drug-like effects in siRNA. These modifications enhance nuclease stability, prolong gene silencing efficiency, improve thermal stability, and exhibit high tissue accumulation. We also highlight the current progress in siRNA clinical trials. This review will help to understand the potential effects of dual ribose modifications and provides alternative ways to use extensive 2’-modifications in siRNA drugs. Moreover, the minimal number of these dual ribose modifications could be sufficient to achieve the desired therapeutic effect. In future, detailed in vivo studies using these dual ribose modifications could help to improve the therapeutic effects of siRNA. Rational design could further open doors for the rapid progress in siRNA therapeutics.http://dx.doi.org/10.1080/15476286.2022.2052641sirnasugar modificationvinylphosphonategene silencingrnai clinical trial |
| spellingShingle | Sumit Gangopadhyay Kiran R Gore Advances in siRNA therapeutics and synergistic effect on siRNA activity using emerging dual ribose modifications RNA Biology sirna sugar modification vinylphosphonate gene silencing rnai clinical trial |
| title | Advances in siRNA therapeutics and synergistic effect on siRNA activity using emerging dual ribose modifications |
| title_full | Advances in siRNA therapeutics and synergistic effect on siRNA activity using emerging dual ribose modifications |
| title_fullStr | Advances in siRNA therapeutics and synergistic effect on siRNA activity using emerging dual ribose modifications |
| title_full_unstemmed | Advances in siRNA therapeutics and synergistic effect on siRNA activity using emerging dual ribose modifications |
| title_short | Advances in siRNA therapeutics and synergistic effect on siRNA activity using emerging dual ribose modifications |
| title_sort | advances in sirna therapeutics and synergistic effect on sirna activity using emerging dual ribose modifications |
| topic | sirna sugar modification vinylphosphonate gene silencing rnai clinical trial |
| url | http://dx.doi.org/10.1080/15476286.2022.2052641 |
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