The ability of small nucleic acids to modulate gene expression via a range of processes has been widely explored.Compared with conventional treatments,small nucleic acid therapeutics have the potential to achieve long...The ability of small nucleic acids to modulate gene expression via a range of processes has been widely explored.Compared with conventional treatments,small nucleic acid therapeutics have the potential to achieve long-lasting or even curative effects via gene editing.As a result of recent technological advances,effcient small nucleic acid delivery for therapeutic and biomedical applications has been achieved,accelerating their clinical translation.Here,we review the increasing number of small nucleic acid therapeutic classes and the most common chemical modifications and delivery platforms.We also discuss the key advances in the design,development and therapeutic application of each delivery platform.Furthermore,this review presents comprehensive profiles of currently approved small nucleic acid drugs,including 11 antisense oligonucleotides(AsOs),2 aptamers and 6 siRNA drugs,summarizing their modifications,disease-specific mechanisms of action and delivery strategies.Other candidates whose clinical trial status has been recorded and updated are also discussed.We also consider strategic issues such as important safety considerations,novel vectors and hurdles for translating academic breakthroughs to the clinic.Small nucleic acid therapeutics have produced favorable results in clinical trials and have the potential to address previously"undruggable"targets,suggesting that they could be useful for guiding the development of additional clinical candidates.展开更多
Epigenetics refers to heritable changes in gene function that occur without alterations to the DNA sequence.Major epigenetic mechanisms include DNA methylation,histone modifications,chromatin remodeling,and the regula...Epigenetics refers to heritable changes in gene function that occur without alterations to the DNA sequence.Major epigenetic mechanisms include DNA methylation,histone modifications,chromatin remodeling,and the regulatory ac-tions of small RNAs and long noncoding RNAs(Allis and Jenuwein,2016).These layers of regulation are essential for modulating gene expression and are widely involved in the regulation of plant growth and development,as well as in responses to environmental cues(Hemenway and Gehring,2023).展开更多
In recent years,posttranscriptional cellular processes such as alternative splicing,messenger RNA(mRNA)decay and translational control have emerged as important regulatory layers required for fine-tuning the inflammat...In recent years,posttranscriptional cellular processes such as alternative splicing,messenger RNA(mRNA)decay and translational control have emerged as important regulatory layers required for fine-tuning the inflammatory response in coordination with transcriptional regulation.However,among these posttranscriptional mechanisms,very little is known regarding the role of alternative polyadenylation(APA),a process that generates transcripts with different 3'ends,in modulating gene expression during inflammation.In a paper published on this topic,Chen and coworkers provided evidence indicating that alternative polyadenylation promotes macrophage inflammatory functions by modulating the expression of genes involved in the autophagy pathway[1].展开更多
Zinc-dependent histone deacetylases(HDACs)are pivotal enzymes governing the epigenetic modulation of gene expression through chromatin remodeling.The dysregulated expression of HDACs is intricately linked to various p...Zinc-dependent histone deacetylases(HDACs)are pivotal enzymes governing the epigenetic modulation of gene expression through chromatin remodeling.The dysregulated expression of HDACs is intricately linked to various pathological conditions,including cancer and inflammation.Histone deacetylase inhibitors(HDACi)have shown therapeutic potential in certain hematologic malignancies.However,the clinical performance of HDACi in solid tumors remains unsatisfactory,and the precise mechanisms of its therapeutic effect in solid tumors has not been fully elucidated.In this study,we identified nucleus-localized PFKL(Liver-type phosphofructokinase),as a key regulator of HDACi efficacy and intracellular epigenetic dynamics.Nuclear PFKL directly binds to classⅠHDACs through interacting with zinc-binding sites,thereby inhibiting HDAC enzymatic activity and promoting intracellular histone acetylation.In addition,the Thr562 residue within PFKL enhances the chelation effect between the zinc-binding group(ZBG)of the HDACi romidepsin and the zinc within the HDACs,further promoting drug efficacy.Based on the mechanism of PFKL facilitates the efficacy of romidepsin,we developed a therapeutic peptide,PFKL-552-572-R8,which significantly enhances the antitumor effect of romidepsin both in vitro and in vivo.Our findings reveal that spatiotemporal regulation confers a moonlight function to PFKL as an endogenous HDAC inhibitor to maintain the stability of epigenetic modifications and highlight PFKL as a promising therapeutic target for enhancing the clinical utility of HDACi in solid tumors.展开更多
基金supported by the 1.3.5 Project for Disciplines of Excellence,West China Hospital,Sichuan University(No.ZYGD23008)by the Frontiers Medical Center,Tianfu Jincheng Laboratory Foundation(No.TFJC202310005)by the Scientific Research and Innovation Team Program of Sichuan University of Science and Technology(No.SUSE652B003).
文摘The ability of small nucleic acids to modulate gene expression via a range of processes has been widely explored.Compared with conventional treatments,small nucleic acid therapeutics have the potential to achieve long-lasting or even curative effects via gene editing.As a result of recent technological advances,effcient small nucleic acid delivery for therapeutic and biomedical applications has been achieved,accelerating their clinical translation.Here,we review the increasing number of small nucleic acid therapeutic classes and the most common chemical modifications and delivery platforms.We also discuss the key advances in the design,development and therapeutic application of each delivery platform.Furthermore,this review presents comprehensive profiles of currently approved small nucleic acid drugs,including 11 antisense oligonucleotides(AsOs),2 aptamers and 6 siRNA drugs,summarizing their modifications,disease-specific mechanisms of action and delivery strategies.Other candidates whose clinical trial status has been recorded and updated are also discussed.We also consider strategic issues such as important safety considerations,novel vectors and hurdles for translating academic breakthroughs to the clinic.Small nucleic acid therapeutics have produced favorable results in clinical trials and have the potential to address previously"undruggable"targets,suggesting that they could be useful for guiding the development of additional clinical candidates.
基金supported by the National Natural Science Foundation of China(32230005).
文摘Epigenetics refers to heritable changes in gene function that occur without alterations to the DNA sequence.Major epigenetic mechanisms include DNA methylation,histone modifications,chromatin remodeling,and the regulatory ac-tions of small RNAs and long noncoding RNAs(Allis and Jenuwein,2016).These layers of regulation are essential for modulating gene expression and are widely involved in the regulation of plant growth and development,as well as in responses to environmental cues(Hemenway and Gehring,2023).
文摘In recent years,posttranscriptional cellular processes such as alternative splicing,messenger RNA(mRNA)decay and translational control have emerged as important regulatory layers required for fine-tuning the inflammatory response in coordination with transcriptional regulation.However,among these posttranscriptional mechanisms,very little is known regarding the role of alternative polyadenylation(APA),a process that generates transcripts with different 3'ends,in modulating gene expression during inflammation.In a paper published on this topic,Chen and coworkers provided evidence indicating that alternative polyadenylation promotes macrophage inflammatory functions by modulating the expression of genes involved in the autophagy pathway[1].
基金supported by grants from the National Key R&D Program of China(2022YFC2503704 to L.-W.D.)the National Natural Science Foundation of China(81988101and 91859205 to H.-Y.W.,82473208 to L.-W.D.,92253306 to Y.-X.T.,and 32270814 and 92359301 to T.-Y.J.)+1 种基金Open Project of State Key Laboratory of Systems Medicine for Cancer(KF2125-93 to L.-W.D.)Shanghai Science and Technology Committee Rising-Star Program(24QA2711800 to T.-Y.J.).
文摘Zinc-dependent histone deacetylases(HDACs)are pivotal enzymes governing the epigenetic modulation of gene expression through chromatin remodeling.The dysregulated expression of HDACs is intricately linked to various pathological conditions,including cancer and inflammation.Histone deacetylase inhibitors(HDACi)have shown therapeutic potential in certain hematologic malignancies.However,the clinical performance of HDACi in solid tumors remains unsatisfactory,and the precise mechanisms of its therapeutic effect in solid tumors has not been fully elucidated.In this study,we identified nucleus-localized PFKL(Liver-type phosphofructokinase),as a key regulator of HDACi efficacy and intracellular epigenetic dynamics.Nuclear PFKL directly binds to classⅠHDACs through interacting with zinc-binding sites,thereby inhibiting HDAC enzymatic activity and promoting intracellular histone acetylation.In addition,the Thr562 residue within PFKL enhances the chelation effect between the zinc-binding group(ZBG)of the HDACi romidepsin and the zinc within the HDACs,further promoting drug efficacy.Based on the mechanism of PFKL facilitates the efficacy of romidepsin,we developed a therapeutic peptide,PFKL-552-572-R8,which significantly enhances the antitumor effect of romidepsin both in vitro and in vivo.Our findings reveal that spatiotemporal regulation confers a moonlight function to PFKL as an endogenous HDAC inhibitor to maintain the stability of epigenetic modifications and highlight PFKL as a promising therapeutic target for enhancing the clinical utility of HDACi in solid tumors.
