Advances in oligonucleotide drug delivery

Nature Reviews Drug Discovery, Journal Year: 2020, Volume and Issue: 19(10), P. 673 - 694

Published: Aug. 11, 2020

Language: Английский

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Non-coding RNAs as drug targets

Nature Reviews Drug Discovery, Journal Year: 2016, Volume and Issue: 16(3), P. 167 - 179

Published: July 22, 2016

Language: Английский

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Therapeutic miRNA and siRNA: Moving from Bench to Clinic as Next Generation Medicine

Molecular Therapy — Nucleic Acids, Journal Year: 2017, Volume and Issue: 8, P. 132 - 143

Published: June 13, 2017

In the past few years, therapeutic microRNA (miRNA) and small interfering RNA (siRNA) are some of most important biopharmaceuticals that in commercial space as future medicines. This review summarizes patents miRNA- siRNA-based new drugs, also provides a snapshot about significant biopharmaceutical companies investing for development miRNA siRNA molecules. An insightful view individual drugs has been depicted with their present status, which is gaining attention landscape. The efforts discussed status preclinical and/or clinical trials. Here, setbacks have highlighted during therapeutics. Finally, illustrated pharmacokinetics, pharmacodynamics absorption, distribution, metabolism, excretion (ADME), fundamental process these therapeutics, well delivery system drugs.

Language: Английский

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Renal tubule injury: a driving force toward chronic kidney disease

Kidney International, Journal Year: 2018, Volume and Issue: 93(3), P. 568 - 579

Published: Jan. 17, 2018

Language: Английский

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Chemistry, mechanism and clinical status of antisense oligonucleotides and duplex RNAs

Nucleic Acids Research, Journal Year: 2017, Volume and Issue: 46(4), P. 1584 - 1600

Published: Nov. 29, 2017

RNA plays a central role in the expression of all genes. Because any sequence within can be recognized by complementary base pairing, synthetic oligonucleotides and oligonucleotide mimics offer general strategy for controlling processes that affect disease. The two primary antisense approaches regulating through recognition cellular RNAs are single-stranded duplex RNAs. This review will discuss chemical modifications molecular mechanisms make nucleic acid drugs possible. Lessons learned from recent clinical trials summarized. Ongoing likely to decisively test adequacy our current generation technologies highlight areas where more basic research is needed.

Language: Английский

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Emerging concepts of miRNA therapeutics: from cells to clinic

Trends in Genetics, Journal Year: 2022, Volume and Issue: 38(6), P. 613 - 626

Published: March 15, 2022

Single microRNAs (miRNAs) regulate large subsets of mRNA targets. Although this property makes miRNAs potentially a powerful therapeutic tool, it also represents major challenge in terms controlling adverse effects that have been observed clinical trials.Besides systemic applications via injection and infusion, advanced strategies emerge for miRNA-based drug administration implantable 3D matrices, inhalation schemes, intake food.A combination miRNA therapeutics with chemical modifications, biomolecule conjugation, or the use carriers improves site-directed efficient cell targeting.A comprehensive risk assessment is required before any vivo targeting to minimize off-target avoid overdosing miRNAs. MicroRNAs are very genetic regulators, as evidenced by fact single can direct entire cellular pathways interacting broad spectrum target genes. This renders highly interesting tools restore functions altered part disease phenotype. However, strength weakness because their so numerous hardly be avoided. In review, we point out main challenges specifically address problems need surmounted push toward application Particular emphasis given approaches already found way into studies. What promises therapeutics?miRNAs (see Glossary) small, noncoding RNAs serve post-transcriptional regulators protein encoding There more than 2300 different human cells time- tissue-dependent expression patterns [1.Alles J. et al.An estimate total number true miRNAs.Nucleic Acids Res. 2019; 47: 3353-3364Crossref PubMed Scopus (207) Google Scholar, 2.Kozomara A. al.miRBase: From microRNA sequences function.Nucleic D155-D162Crossref (1326) 3.Ludwig N. al.Distribution across tissues.Nucleic 2016; 44: 3865-3877Crossref (529) Scholar]. Essential aspects biogenesis its functionality provided Box 1. Criteria fidelity addressed below.Box 1Cellular biogenesismiRNA located exons introns protein-encoding genes intergenic regions. They coregulated together host under control own promoters [103.Olena A.F. Patton J.G. Genomic organization microRNAs.J. Cell. Physiol. 2010; 222: 540-545PubMed During (thoroughly reviewed elsewhere, e.g., 104.Ha M. Kim V.N. Regulation biogenesis.Nat. Rev. Mol. Cell Biol. 2014; 15: 509-524Crossref (3208) 105.Winter al.Many roads maturity: MicroRNA regulation.Nat. 2009; 11: 228-234Crossref (1970) Scholar]), transcribed RNA polymerase II III form primary (pri-miRNAs), which up several thousand nucleotides length shaped hairpin structure. pri-miRNAs further processed Drosha-DGCR8 microprocessor complex nucleus generate an precursor (pre-miRNA) approximately 70 length. noncanonical biogenesis, intron-encoded pre-miRNAs (mirtrons) directly along coencoded transcripts through spliceosomes. The pre-miRNA exported exportin-5 cytoplasm, where cleaved duplex 22 RNase Dicer double-stranded binding enzyme TRBP. strands subsequently incorporated RISC, allowing ribonucleoprotein bind usually within 3′ untranslated regions mRNAs. Reverse complementary takes place seed region, situated at 2 7 miRNA's 5′ end. results inhibition abrogation translation process. It estimated 60% all subject regulation [106.Friedman R.C. al.Most mammalian mRNAs conserved targets microRNAs.Genome 19: 92-105Crossref (6022) Scholar], making central signaling widespread impact on almost every biological process [6.Gebert L.F.R. MacRae I.J. function animals.Nat. 20: 21-37Crossref (893) Besides level, there recent evidence translocate transcription efficiency specific genes, enhancing networks [107.Liu H. al.Nuclear gene regulation, immunity cancer.Mol. Cancer. 2018; 17: 64Crossref (167) Scholar].Physiological changes pivotal consequence cascades. many scenarios, plays likewise role modifying pathological [4.Subramanian S. Steer C.J. Special issue: health disease.Genes (Basel). 10Crossref (10) diagnostic potential levels, these small offer themselves purposes targeted manipulation crucial phenotype [5.Huang W. MicroRNAs: Biomarkers, diagnostics, therapeutics.Methods 2017; 1617: 57-67Crossref (100) intervention most efficient, consequently especially attractive, regulated Thus, spite relatively moderate effect each shown miR-34a-5p has identified hub T Scholar,7.Hart al.miR-34a networks.J. Immunother. 7: 187Crossref (19) Vice versa, one pathway typically miRNAs, resulting regulatory network, addressing majority molecular pathomechanisms humans.Against background, not surprising that, according records, since 2015, 600 articles published heading 'miRNA-based therapeutics'. future undoubtedly appealing, still great practical difficulties overcome, including identification proper routes, in-body stability, tissues types, attaining intended intracellular effects. Hence, only few drugs have, now, entered test phase (Table 1). following sections, effective nonhazardous therapeutics. We particularly emphasize preclinical studies developed associated using therapeutics.Table 1Clinical trials therapeuticsaNCT numbered registered ClinicalTrials.gov; EudraCT EU Clinical Trials Register (clinicaltrialsregister.eu).miRNA nameTargeted miRNAMode actionBackground diseaseBody application/permission uptakeClinical trial number(s)RefsAMT-130bPhase I ongoing.Artificial miRNAamiRNA expressionHuntington diseaseStereotaxic infusion/viral transfer (adeno-associated vector)NCT04120493[23.Keskin al.AAV5-miHTT lowers huntingtin without patient-derived neuronal cultures astrocytes.Mol. Ther. Methods Clin. Dev. 275-284Abstract Full Text PDF (20) 24.Miniarikova al.Design, characterization, lead selection development therapy Huntington's disease.Mol. Nucleic Acids. 5e297Abstract (64) 25.Samaranch L. al.MR-guided parenchymal delivery adeno-associated viral vector serotype 5 non-human primate brain.Gene 24: 253-261Crossref (41) Scholar]RG-012/lademirsen/SAR339375cPhase ongoing.miR-21Anti-miRAlport syndromeSubcutaneous injection/chemical modification (phosphorothioate)NCT03373786, NCT02855268[70.Gomez I.G. al.Anti-microRNA-21 oligonucleotides prevent Alport nephropathy progression stimulating metabolic pathways.J. Invest. 2015; 125: 141-156Crossref (246) Scholar,76.Kelnar K. al.Quantification mimics whole blood from nonhuman primates.Anal. Chem. 86: 1534-1542Crossref (49) Scholar,122.Kashtan C.E. Gross O. practice recommendations diagnosis management syndrome children, adolescents, young adults – update 2020.Pediatr. Nephrol. 2021; 36: 711-719Crossref (14) Scholar,123.Kashtan Correction to: adults-an 731Crossref (2) Scholar]RG-125/AZD4076dPhase completed.miR-103/107Anti-miRNonalcoholic steatohepatitis (NASH) patients type diabetes/prediabetesSubcutaneous injection/biomolecule conjugation (GalNAc)NCT02612662, NCT02826525[76.Kelnar 77.Drenth J.P.H. Schattenberg J.M. nonalcoholic graveyard: Established hurdles planning success.Expert Opin. Investig. Drugs. 2020; 29: 1365-1375Crossref (16) 78.Huang Y. Preclinical advances GalNAc-decorated nucleic acid therapeutics.Mol. 6: 116-132Abstract (171) Scholar]MRG-110dPhase completed.miR-92aAnti-miRWoundsSkin (LNA)NCT03603431[124.Gallant-Behm C.L. al.A synthetic microRNA-92a inhibitor (MRG-110) accelerates angiogenesis wound healing diabetic nondiabetic wounds.Wound Repair Regen. 26: 311-323Crossref (46) Scholar,125.Abplanalp W.T. al.Efficiency derepression anti-miR-92a: Results first study.Nucleic Acid 30: 335-345Crossref (32) Scholar]MesomiR 1dPhase completed.miR-16miRNA mimicMalignant pleural mesothelioma, non–small lung cancerIntravenously/vehicle (nonliving minicells)NCT02369198[56.Reid G. al.Clinical TargomiRs, mimic-based treatment recurrent thoracic cancer.Epigenomics. 8: 1079-1085Crossref (120) Scholar,57.van Zandwijk al.Safety activity microRNA-loaded minicells malignant mesothelioma: A first-in-man, 1, open-label, dose-escalation study.Lancet Oncol. 18: 1386-1396Abstract (316) Scholar,126.Reid al.Restoring miR-16: novel approach mesothelioma.Ann. 2013; 3128-3135Abstract (158) Scholar]CDR132LdPhase completed.miR-132Anti-miRHeart failureIntravenously/chemical (LNA)NCT04045405[127.Taubel al.Novel antisense microRNA-132 heart failure: first-in-human 1b randomized, double-blind, placebo-controlled study.Eur. Heart 42: 178-188Crossref (47) Scholar,128.Batkai al.CDR132L systolic diastolic animal model chronic failure.Eur. 192-201Crossref (22) Scholar]Remlarsen/MRG-201ePhase completed.miR-29miRNA mimicKeloid disorderSkin (cholesterol)NCT02603224, NCT03601052[73.Gallant-Behm microRNA-29 mimic (remlarsen) represses extracellular matrix fibroplasia skin.J. Dermatol. 139: 1073-1081Abstract (74) Scholar,103.Olena Scholar,104.Ha Scholar]Miravirsen/SPC3649ePhase completed., fUnknown status.miR-122Anti-miRChronic hepatitis C virusSubcutaneous (LNA)NCT02508090, NCT02452814, NCT01200420, NCT01872936, NCT01727934, NCT01646489[16.Ottosen al.In vitro antiviral resistance profile miravirsen, anti-hepatitis virus factor miR-122.Antimicrob. Agents Chemother. 59: 599-608Crossref (130) Scholar,129.Gebert L.F. al.Miravirsen (SPC3649) inhibit miR-122.Nucleic 609-621Crossref (228) 130.Elmen al.LNA-mediated silencing primates.Nature. 2008; 452: 896-899Crossref (1381) 131.Lanford R.E. al.Therapeutic microRNA-122 primates infection.Science. 327: 198-201Crossref (1427) 132.Janssen H.L. al.Treatment HCV infection microRNA.N. Engl. Med. 368: 1685-1694Crossref (1644) Scholar]MRX34gStopped/terminated.miR-34amiRNA mimicSolid tumors (e.g., hepatocellular carcinoma), melanomaIntravenously/vehicle (liposomal)NCT01829971, NCT02862145[29.Beg M.S. al.Phase study MRX34, liposomal miR-34a mimic, administered twice weekly solid tumors.Investig. New 35: 180-188Crossref (468) Scholar,32.Daige al.Systemic miR34a liver Cancer 13: 2352-2360Crossref (112) Scholar,133.Huang H.Y. al.miRTarBase 2020: Updates experimentally validated microRNA-target interaction database.Nucleic 48: D148-D154PubMed Scholar]RG-101gStopped/terminated.miR-122Anti-miRChronic (GalNAc)EudraCT numbers 2015-001535-21, 2015-004702-42, 2016-002069-77[76.Kelnar Scholar,79.van der Ree M.H. al.Safety, tolerability, RG-101 C: 1B, randomised controlled trial.Lancet. 389: 709-717Abstract (143) Scholar,80.Stelma F. al.Immune natural killer who received dose anti-microRNA-122, RG-101.Hepatology. 66: 57-68Crossref (23) Scholar]Cobomarsen/MRG-106gStopped/terminated.miR-155Anti-miRMycosis fungoidesIntravenously/chemical (LNA)NCT02580552, NCT03713320, NCT03837457[134.Seto A.G. al.Cobomarsen, oligonucleotide miR-155, co-ordinately regulates multiple survival reduce proliferation cutaneous T-cell lymphoma.Br. Haematol. 183: 428-444Crossref (126) 135.James A.M. al.SOLAR: 2, global, active comparator investigate efficacy safety cobomarsen subjects mycosis fungoides (MF) [abstract].Hematol. 37: 562-563Crossref 136.Querfeld C. al.Preliminary 1 evaluating MRG-106, antagonist (LNA antimiR) microRNA-155, CTCL.Blood. 128: 1829Crossref Scholar]a NCT (clinicaltrialsregister.eu).b Phase ongoing.c ongoing.d completed.e completed.f Unknown status.g Stopped/terminated. Open table new tab How modify expression?The general aim ideally reverse changes. includes enhancement reconstitution endogenous act suppressors expressional reduction functional blocking drivers. To acids commonly used (Figure 1), (miRNA mimics), recombinant vectors carrying sequences, oligonucleotide-based inhibitors (anti-miRs) [8.van Rooij E. Kauppinen Development coming age.EMBO 851-864Crossref (433) Scholar].One currently pursued permeable molecules. These molecules exert by, example, proteins involved miRNA-specific secondary structures [9.Fan R. al.Small big roles biology microRNA-targeted therapeutics.RNA 16: 707-718Crossref Small designed aid bioinformatics experimental screening pharmacologically compounds [10.Disney M.D. al.Inforna 2.0: platform sequence-based design structured RNAs.ACS 1720-1728Crossref (95) Scholar,11.Suresh B.M. fragment-based identify optimize bioactive ligands RNA.Proc. Natl. Acad. Sci. U. 117: 33197-33203Crossref (0) example oncogenic miR-21. was target-oriented various low-molecular-weight [11.Suresh Natural rich source interfering [12.Alnuqaydan Targeting micro-RNAs products: strategy combat cancer.Am. Transl. 12: 3531-3556PubMed Curcumin has, breast cancer growth [13.Norouzi al.Curcumin adjunct modulator cancer.Curr. Pharm. Des. 171-177Crossref (35) Scholar].A combine treatments conventional drugs. drug-based therapies improved interventions pathways, affect outcomes [14.Seo H.A. al.MicroRNA-based combinatorial therapy: Effects anti-cancer therapies.Cells. 9: 29Crossref Liver-specific miR-122 considered driver (HCV) maintenance hepatocytes [15.Panigrahi al.miR-122 affects both initiation infections.J. Virol. 96e0190321PubMed (ClinicalTrials.gov identifiers NCT01872936), against counteracted combining miravirsen/SPC3649 [16.Ottosen Combined schemas chemotherapeutics manipulators being improvement antitumor therapies, common cancers such [17.Gong al.Functional exosome-mediated co-delivery doxorubicin hydrophobically modified 159 triple-negative therapy.J. Nanobiotechnol. 93Crossref (93) Scholar,18.Saatci al.Targeting lysyl oxidase (LOX) overcomes chemotherapy triple negative cancer.Nat. Commun. 2416Crossref (62) Scholar].The combined siRNAs offers another route improve constitute group conceived [19.Lam J.K. al.siRNA versus silencing.Mol. 4e252Abstract (465) establishment siRNA [20.Zhang al.The risks therapeutics: perspective.Drug Devel. 721-733Crossref (40) achieved coexpression plasmid, recently [21.Petrek al.Bioengineering long molecule carries RNAs.Appl. Microbiol. Biotechnol. 103: 6107-6117Crossref (13) Scholar].Artificially constructs, referred 'amiRNAs,' promise advancement amiRNAs combinations scaffolds transcripts. While show high specificity, siRNA-based design, processing ensured structure [22.Kotowska-Zimmer al.Artificial tools: Challenges opportunities.Wiley Interdiscip. RNA. 12e1640Crossref (3) An amiRNA-based (AMT-130) sequence Huntingtin pri-miR-451 scaffold employed identifier NCT04120493) [23.Keskin Scholar].miRNA sponges option manipulate levels constructs harboring sites. sequestration effectiveness sponges, circular RNAs, analyzed artificially sponge, six alternating sites miR-132 miR-212, tested, mouse models cardiovascular diseases [26.Lavenniah al.Engineered attenuate pressure overload-induced cardiac hypertrophy.Mol. 28: 1506-1517Abstract (45) Additional highlight naturally occurring therapeutically usable sponges. Recently, hsa_circ_0120472, two predicted sites, sponge miR-550a [27.Meng al.Circular circCCDC85A inhibits acting miR-550a-5p enhance MOB1A expression.Breast 2022; 1Crossref yet increasing will certainly promote approaches.What severe side therapeutics?Depending chosen warrant delivery, necessarily restricted tissue but cause prominent occurrence disastrous mimic. MRX34 tumor NCT01829971), hematologic malignancies, had terminated prematurely immune-related causing death four [28.Hong D.S. tumours.Br. 122: 1630-1637Crossref (183) Scholar,29.Beg make properties suppressor [30.Saito al.microRNA-34a agent cancer.J. 4: 1951-1959Crossref systemically amphoteric (i.e., pH-dependent) strategy, supposed take low-pH environment tumorous [31.Bouchie First enters clinic.Nat. 31: 577Crossref Animal models, however, showed uptake bone marrow spleen [32.Daige Scholar,33.Kelnar Bader qRT-PCR method determining biodistribution mimic.Methods 1317: 125-133Crossref (11) known generation preservation immune cells. Accordingly, context testing, dose-dependent modulation white now evident impacts cells, regulating calcium chemokine [3

Language: Английский

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MicroRNAs in Cardiovascular Disease

Journal of the American College of Cardiology, Journal Year: 2016, Volume and Issue: 68(23), P. 2577 - 2584

Published: Dec. 1, 2016

Language: Английский

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Antisense Oligonucleotides: An Emerging Area in Drug Discovery and Development

Journal of Clinical Medicine, Journal Year: 2020, Volume and Issue: 9(6), P. 2004 - 2004

Published: June 26, 2020

Antisense oligonucleotides (ASOs) bind sequence specifically to the target RNA and modulate protein expression through several different mechanisms. The ASO field is an emerging area of drug development that targets disease source at level offers a promising alternative therapies targeting downstream processes. To translate ASO-based into clinical success, it crucial overcome challenges associated with off-target side effects insufficient biological activity. In this regard, chemical modifications diverse delivery strategies have been explored. review, we systematically discuss modifications, mechanism action, optimized classes ASOs. Further, highlight recent advances made in drugs focus on are approved by Food Drug Administration (FDA) European Medicines Agency (EMA) for applications. We also various candidates trials, outstanding opportunity microRNA as viable therapeutic future therapies.

Language: Английский

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MicroRNA-Based Diagnosis and Therapy

International Journal of Molecular Sciences, Journal Year: 2022, Volume and Issue: 23(13), P. 7167 - 7167

Published: June 28, 2022

MicroRNAs (miRNAs) are a group of endogenous non-coding RNAs that regulate gene expression. Alteration in miRNA expression results changes the profile genes involving range biological processes, contributing to numerous human disorders. With high stability fluids, miRNAs circulation considered as promising biomarkers for diagnosis, well prognosis disease. In addition, translation miRNA-based therapy from research setting clinical application has huge potential. The aim current review is to: (i) discuss how traffic intracellularly and extracellularly; (ii) emphasize role circulating attractive potential diagnosis prognosis; (iii) describe microRNA can be measured, emphasizing technical problems may influence their relative levels; (iv) highlight some panels available use; (v) could utilized novel therapeutics, finally update those therapeutics trials potentially lead breakthrough treatment different pathologies.

Language: Английский

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MicroRNAs (miRNAs) and Long Non-Coding RNAs (lncRNAs) as New Tools for Cancer Therapy: First Steps from Bench to Bedside

Targeted Oncology, Journal Year: 2020, Volume and Issue: 15(3), P. 261 - 278

Published: May 25, 2020

Non-coding RNAs represent a significant proportion of the human genome. After having been considered as 'junk' for long time, non-coding are now well established playing important roles in maintaining cellular homeostasis and functions. Some show cell- tissue-specific expression patterns specifically deregulated under pathological conditions (e.g. cancer). Therefore, have extensively studied potential biomarkers context different diseases with focus on microRNAs (miRNAs) (lncRNAs) several years. Since their discovery, miRNAs attracted more attention than lncRNAs research studies; however, both families to play an role gene control, either transcriptional or post-transcriptional regulators. Both can regulate key genes involved development cancer, thus influencing tumour growth, invasion, metastasis by increasing activation oncogenic pathways limiting suppressors. Furthermore, also emerging mediators drug-sensitivity drug-resistance mechanisms. In light these premises, number pre-clinical early clinical studies exploring new therapeutics. The aim this review is summarise latest knowledge use therapeutic tools cancer treatment.

Language: Английский

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