Three ‘E’ challenges for siRNA drug development

Trends in Molecular Medicine, Journal Year: 2023, Volume and Issue: 30(1), P. 13 - 24

Published: Nov. 9, 2023

Theoretically, siRNA has the ability to target any gene of interest, potentially addressing disease targets that are 'undruggable' for small molecules and proteins.Currently, there six therapeutics have been approved clinical use, approximately 20 additional candidates progressed late stages investigation.Targeted accumulation cellular uptake (entry), endolysosomal escape (escape), in vivo pharmaceutical performance (efficacy) (three 'E' challenges) most critical bottlenecks drug development.Ligand-conjugated siRNAs promising platforms made a breakthrough robust extrahepatic delivery.Sophisticated appropriate chemical modification may bring astounding breakthroughs stability long-term efficacy modalities. gained extensive attention, date use. Despite being investigated treatment metabolic, cardiovascular, infectious, rare genetic diseases, cancer, central nervous system (CNS) disorders, exist several druggability challenges. Here, we provide insightful discussions concerning these challenges, comprising targeted ('entry'), ('escape'), ('efficacy') – three challenges while also shedding light on development. Moreover, propose strategies hold great potential facilitating translation therapeutics, including exploration diverse ligand-siRNA conjugates, expansion targets, excavation novel geometries, as well development combination therapies. Viewed through prism history, enjoyed over century use earliest developed applied therapeutic modality, proteins antibodies emerged relatively almost half century. Although nucleic acid molecules, approach, had shorter developmental timeline (20–30 years), they already captured significant global attention from industry, emerging third prominent modality [1.Opalinska J.B. Gewirtz A.M. Nucleic-acid therapeutics: basic principles recent applications.Nat. Rev. Drug Discov. 2002; 1: 503-514Crossref PubMed Scopus (504) Google Scholar]. Nucleic drugs still undergoing rapid development, particularly realm RNAi, where their broad profound is increasingly manifest. With this mind, believe coming period will be pivotal era acids, both expanding scope options offering new possibilities field. Compared with traditional antibodies, (see Glossary) advantage abundant high success rate, short time, long-lasting efficacy, outstanding attributes platform-based modalities [2.Hopkins A.L. Groom C.R. The druggable genome.Nat. 727-730Crossref (2776) Scholar, 3.Wu S.Y. et al.RNAi therapies: drugging undruggable.Sci. Transl. 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Sci. 23: 2736Crossref (65) Scholar,9.Forgham al.Keeping up COVID's could siRNA-based antivirals part answer?.Exploration. 220220012Crossref (4) As August 2023, globally 15 investigational Phase 2 or later (Table 1), covering wide range areas diseases extending common diseases. Leading companies expanded focus encompass popular disorders such metabolic cardiovascular disease, hepatitis B, cancer. For instance, ALN-AGT (NCT04936035i, NCT05103332ii, randomized) currently hypertension trials [10.Huang S.A. al.Safety tolerability ALN-AGT, an interference targeting hepatic angiotensinogen synthesis, hypertensive patients during sodium depletion irbesartan coadministration.Circulation. 144A11276Google Olpasiran (NCT05581303iii, intended treat atherosclerotic plaques 3 study [11.Malick W.A. al.Clinical trial design lipoprotein(a)-lowering JACC Focus Seminar 2/3.J. Am. Coll. Cardiol. 2023; 81: 1633-1645Crossref (9) SLN360 (NCT05537571iv, randomized), lipid-lowering siRNA, investigation. RBD1016 (NCT05961098v, N-acetylgalactosamine (GalNAc)-conjugated start Europe. STP705 STP707 two transforming growth factor beta 1 (TGF-β1) cyclooxygenase (COX-2) formulated peptide nanoparticles (PNPs). was locally administered diseased tissue situ squamous cell carcinoma (isSCC) (NCT04844983vi, 2, basal (BCC) (NCT04669808vii, non-randomized), (NCT05037149viii, 1, non-randomized) intravenously injected into body solid tumors fibrotic liver primary sclerosing cholangitis (PSC).Table 1Selected late-stage therapeuticsDrug nameTarget geneDelivery technologyIndicationSponsorPhase NCT numberAdministration routeaAbbreviations: i.d., intradermal injection; i.t., intratracheal administration; ita, intratumoral i.v., intravenous o.a., ophthalmic s.c., subcutaneous injection.PatisiranTransthyretin (TTR)L NPsPolyneuropathy hereditary TTR-mediated amyloidosis (hATTR)AlnylamApprovedi.v.GivosiranAminolevulinate synthase (ALAS1)GalNAc-siRNA conjugateAcute porphyria (AHP)AlnylamApproveds.c.LumasiranHydroxyacid oxidase (HAO1)GalNAc-siRNA conjugatePrimary hyperoxaluria type (PH1)AlnylamApproveds.c.InclisiranProprotein convertase subtilisin/kexin 9 (PCSK9)GalNAc-siRNA conjugateHypercholesterolemiaAlnylam, Medicine Company, NovartisApproveds.c.VutrisiranTTRGalNAc-siRNA conjugatePolyneuropathy hATTR amyloidosisAlnylamApproveds.c.RivflozaLactate dehydrogenase A (LDHA)GalXC™ RNAi platformPH1Novo NordiskApproveds.c.Olpasiran, AMG 890, ARO-LPAApolipoprotein (APO) A1 (APOA1), Lp(a)GalNAc-siRNA conjugateCardiovascular diseaseAmgen, ArrowheadPhase NCT04270760xviiiPhase 3, NCT05581303iiis.c.ARO-APOC3APOC3GalNAc-siRNA conjugateType I hyperlipoproteinemia, hypertriglyceridemia, congenital metabolism disordersArrowheadPhase NCT05089084xixs.c.Tivanisiran, SYL1001Transient receptor cation channel subfamily V member (TRPV1)None (unmodified, carrier-free)Dry eye Sjögren's syndromeSylentisPhase NCT03108664xii NCT04819269xiiio.a.AOC 1020Double homeobox 4 (DUX4)Antibody-siRNA conjugateFSHDAvidity BiosciencesPhase NCT05747924xxi.v.SLN360APOA1, atherosclerosis, Lp(a)SilencePhase NCT05537571ivs.c.SLN-124Transmembrane serine protease 6 (TMPRSS6)GalNAc-siRNA conjugatePolycythemia veraSilencePhase 1/2, NCT05499013xxis.c.Zilebesiran, ALN-AGTAngiotensinogen (AGT)GalNAc-siRNA conjugateHypertensionAlnylamPhase NCT04936035i, NCT05103332iis.c.ALN-HSDHydroxysteroid 17-beta 13 (HSD17B13)GalNAc-siRNA conjugateNASHAlnylam, RegeneronPhase NCT05519475xxiis.c.OLX10010Connective (CTGF)Cell-penetrating asymmetric (cp-asiRNA)Hypertrophic scarringOlix, Alira HealthPhase NCT04877756xxiiii.d.XalnesiranHBV geneGalNAc-siRNA conjugateHepatitis B virus (HBV)Dicerna, Novo NordiskPhase NCT04225715xxivs.c.RBD1016HBV conjugateHBVRibo Life Science LtdPhase NCT05961098vs.c.SYL1801NOTCH regulated ankyrin repeat protein (NRARP)NoneWet macular degeneration, neovascular age-related degenerationSylentisPhase NCT05637255xxvo.a.SYL040012Adrenoceptor (ADRB2)NoneOpen-angle glaucomaSylentisPhase NCT02250612xxvi, NCT01739244 xxviio.a.STP705COX-2, TGF-β1PNPsBCC, intraepidermal SCC, skin SCC (isSCC, keloid), keloidSirnaomicsPhase NCT04669808vii, NCT04844983vi, NCT04844840xxviiis.c., itasiG12D-LODERKRAS proto-oncogene, GTPase (KRAS)LODER®Pancreatic ductal adenocarcinomaSilenseedPhase NCT01676259xxixitaa Abbreviations: injection. 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Language: Английский

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Dissolvable hybrid microneedle patch for efficient delivery of curcumin to reduce intraocular inflammation

International Journal of Pharmaceutics, Journal Year: 2023, Volume and Issue: 643, P. 123205 - 123205

Published: July 6, 2023

Language: Английский

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Research progress of VEGFR small molecule inhibitors in ocular neovascular diseases

European Journal of Medicinal Chemistry, Journal Year: 2023, Volume and Issue: 257, P. 115535 - 115535

Published: May 29, 2023

Language: Английский

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Nanoparticle-hydrogel composite as dual-drug delivery system for the potential application of corneal graft rejection

European Journal of Pharmaceutics and Biopharmaceutics, Journal Year: 2024, Volume and Issue: 201, P. 114351 - 114351

Published: June 7, 2024

Language: Английский

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Platelet-derived extracellular vesicle drug delivery system loaded with kaempferol for treating corneal neovascularization

Biomaterials, Journal Year: 2025, Volume and Issue: 319, P. 123205 - 123205

Published: Feb. 24, 2025

Language: Английский

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Microglia-targeting nanosystems that cooperatively deliver Chinese herbal ingredients alleviate behavioral and cognitive deficits in Alzheimer’s disease model mice

Journal of Nanobiotechnology, Journal Year: 2025, Volume and Issue: 23(1)

Published: April 24, 2025

The effective treatment of Alzheimer's disease (AD) is challenging because its complex and controversial pathological mechanisms. Moreover, multiple barriers, such as the blood-brain barrier (BBB), reduce drug delivery efficiency. Microglia-related neuroinflammation has recently attracted increasing attention a possible cause AD become novel therapeutic target. Therefore, overcoming BBB targeted anti-inflammatory agents to microglia seem be practical strategies for treating AD. A large proportion natural active extracts possess exceptional immunomodulating capabilities. In this study, cooperative berberine (Ber) palmatine (Pal) by transferrin-decorated extracellular vesicles (Tf-hEVs-Ber/Pal), which can cross precisely target microglia, was performed. This nanosystem effectively cleared amyloid β-protein (Aβ) aggregates, significantly regulated neuroinflammatory environment both in vitro vivo markedly altered behavior improved cognitive learning abilities model mice. efficacy microglia-targeting combined approach demonstrated, broadens potential application Chinese herbal ingredients.

Language: Английский

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A Synergistic Therapy With Antioxidant and Anti‐VEGF: Toward its Safe and Effective Elimination for Corneal Neovascularization

Advanced Healthcare Materials, Journal Year: 2023, Volume and Issue: 13(5)

Published: Nov. 29, 2023

Corneal neovascularization (CNV) is one of the leading causes blindness in world. In clinical practice; however, it remains a challenge to achieve noninvasive and safe treatment. Herein, biocompatible shell with excellent antioxidant antivascularity prepared by co-assembly epigallocatechin gallate/gallic acid Cu (II). After loading glucose oxidase (GOx) inside, modified dimeric DPA-Zn for codelivering vascular endothelial growth factor (VEGF) small interfering RNA (VEGF-siRNA). Meanwhile, Arg-Gly-Asp peptide (RGD) peptide-engineered cell membranes coating improves angiogenesis-targeting multifunctional nanomedicine (CEGs/RGD). eye drops administration, CEGs/RGD targets enrichment CEGs NPs enter cells. Then, inner GOx consumes decrease local pH, which turn leads release EGCE VEGF-siRNA. As result, nanomedicines significantly reduce angiogenesis inhibit CNV formation through synergistic effect antivascular via down-regulation cluster differentiation 31 VEGF. The represents efficient treatment combined antioxidant/gene, provides important theoretical significance.

Language: Английский

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Versatile Platforms of Microneedle Patches Loaded with Responsive Nanoparticles: Synthesis and Promising Biomedical Applications

Advanced NanoBiomed Research, Journal Year: 2024, Volume and Issue: 4(4)

Published: Feb. 15, 2024

Microneedle array systems loaded with responsive nanoparticles have received increasing attention due to the advantages of good drug stability, targeting ability, controlled release drugs, high bioavailability, painlessness, and patient compliance. Compared oral delivery, microneedle transdermal delivery eliminates need pass through gastrointestinal tract liver, reducing metabolic consumption drugs by first‐pass effect. While compared intravenous reduces discomfort does not require professional administration. However, there are few review articles on microneedles nanoparticles. Herein, current researches specific such as glucose‐responsive, pH‐responsive, enzyme‐responsive, light‐responsive, magnetic‐responsive, ultrasound‐responsive, multiresponsive, biomedical application these summarized. In addition, challenges prospects strategies briefly discussed, which will facilitate development versatile drug‐delivery strategy.

Language: Английский

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A SU6668 pure nanoparticle-based eyedrops: toward its high drug Accumulation and Long-time treatment for corneal neovascularization

Journal of Nanobiotechnology, Journal Year: 2024, Volume and Issue: 22(1)

Published: May 27, 2024

Abstract Corneal neovascularization (CNV) is one of the common blinding factors worldwide, leading to reduced vision or even blindness. However, current treatments such as surgical intervention and anti-VEGF agent therapy still have some shortcomings evoke adverse effects. Recently, SU6668, an inhibitor targeting angiogenic tyrosine kinases, has demonstrated growth inhibition neovascularization. But hydrophobicity low ocular bioavailability limit its application in cornea. Hereby, we proposed preparation SU6668 pure nanoparticles (NanoSU6668; size ~135 nm) using a super-stable pure-nanomedicine formulation technology (SPFT), which possessed uniform particle excellent aqueous dispersion at 1 mg/mL. Furthermore, mesenchymal stem cell membrane vesicle (MSCm) was coated on surface NanoSU6668, then conjugated with TAT penetrating peptide, preparing multifunctional TAT-MSCm@NanoSU6668 (T-MNS). The T-MNS concentration 200 µg/mL treated for CNV via eye drops, accumulated blood vessels high performance, resulting elimination recovery cornea transparency after 4 days treatment. Meanwhile, drug safety test confirmed that did not cause any damage cornea, retina other tissues. In conclusion, drop had potential treat effectively safely dosing frequency, broke new ground theranostics.

Language: Английский

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Small interfering RNA (siRNA) as a potential gene silencing strategy for diabetes and associated complications: challenges and future perspectives

Journal of Diabetes & Metabolic Disorders, Journal Year: 2024, Volume and Issue: 23(1), P. 365 - 383

Published: March 25, 2024

Language: Английский

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