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Cited by 82RNA Interference and Gene DeliveryNanoparticle-Based Drug DeliveryRNA and protein synthesis mechanisms

RNA delivery biomaterials for the treatment of genetic and rare diseases

Open access
Zhao, Weiyu, Hou, Xucheng, Vick, Olivia G., Dong, Yizhou·2019·Biomaterials
DOI 10.1016/j.biomaterials.2019.119291PMC PMC6635005
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Abstract

Genetic and rare diseases (GARDs) affect more than 350 million patients worldwide and remain a significant challenge in the clinic. Hence, continuous efforts have been made to bridge the significant gap between the supply and demand of effective treatments for GARDs. Recent decades have witnessed the impressive progress in the fight against GARDs, with an improved understanding of the genetic origins of rare diseases and the rapid development in gene therapy providing a new avenue for GARD therapy. RNA-based therapeutics, such as RNA interference (RNAi), messenger RNA (mRNA) and RNA-involved genome editing technologies, demonstrate great potential as a therapy tool for treating genetic associated rare diseases. In the meantime, a variety of RNA delivery vehicles were established for boosting the widespread applications of RNA therapeutics. Among all the RNA delivery platforms which enable the systemic applications of RNAs, non-viral RNA delivery biomaterials display superior properties and a few biomaterials have been successfully exploited for achieving the RNA-based gene therapies on GARDs. In this review article, we focus on recent advances in the development of novel biomaterials for delivery of RNA-based therapeutics and highlight their applications to treat GARDs.

AI snapshot

Written from the paper’s full text.

TL;DR

This review summarizes non-viral biomaterials for delivering RNA therapeutics—siRNA, mRNA, genome-editing components, miRNA, and lncRNA—to treat genetic and rare diseases (GARDs). It highlights lipid nanoparticles, ligand conjugates, and other systems across liver, lung, brain, muscle, and other organs, with many preclinical and some clinical examples.

Key findings

  • GARDs collectively affect over 350 million patients worldwide; approximately 7,000 rare diseases affect around 30 million individuals in the US.
  • Lipid and lipid-derived nanoparticles (LNPs) are the dominant non-viral platform, enabling delivery of siRNA, mRNA, and CRISPR components. Patisiran, an LNP-formulated siRNA, was FDA-approved in 2018 for hereditary transthyretin amyloidosis.
  • Representative efficacy numbers include: DLin-KC2-DMA SNALPs silenced TTR in nonhuman primates with ED50 around 0.3 mg/kg; TT3-delivered hFIX mRNA yielded plasma FIX 1740 ng/mL and activity 791 mIU/mL at 6 h; MC3-delivered hMUT mRNA reduced plasma methylmalonic acid by up to 90% at 24 h; C12-200 hGLA mRNA reduced Fabry biomarkers Gb3 and lyso-Gb3 by 92% and 88%, versus 67% and 61% for recombinant protein.
  • Genome-editing delivery examples include LP01 LNPs achieving over 90% serum TTR reduction persisting at least 12 months, and cKK-E12/e-sgRNA reducing hepatic PCSK9 by 80% and plasma cholesterol by about 40% after a single injection.

Methods

  • Narrative review of non-viral RNA delivery biomaterials for GARD therapy, covering siRNA, mRNA, RNA-containing genome editing systems, miRNA, and lncRNA.
  • The review organizes delivery systems by RNA payload and target organ (liver, lung, brain, muscle, ear, skin, eye, nasal cavity, heart) and summarizes preclinical studies, clinical trials, and tables of representative systems.
  • No systematic search strategy, inclusion criteria, or meta-analysis is reported; conclusions are synthesized from cited literature.

Limitations

  • Stated: LNPs predominantly accumulate in the liver, limiting their use mainly to liver-oriented diseases; new LNPs and ligands are needed for other organs. GalNAc conjugation is the leading ligand strategy but is largely liver-targeting, and linker chemistry plus chemical modification of large RNAs require further optimization. Targeted genome-editing delivery remains limited to topical administration except for the liver.
  • Stated: many biomaterials (cell-derived vehicles, gold nanoparticles, polymeric nanoparticles, DNA/RNA nanotechnology) have not been widely explored for GARDs, and only a small fraction of miRNA therapeutics have reached clinical development.
  • Evident: as a narrative review, it provides no primary experimental data, no systematic quality assessment, and its 2019 publication date means later clinical and preclinical developments are not captured.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1016/j.biomaterials.2019.119291

Cites

Statistics

Nothing to recompute.

Claims the paper makes

0 of 265 cited sources checked · 0 supported · 0 flagged

  • Premisecitation

    A majority of GARDs stem from genetic disorders.

    “Since a majority of GARDs stem from genetic disorders, recent progresses in gene therapies could offer more options for treating GARDs.[3, 5]”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [3] Sun, 2017, Drug discovery and development for rare genetic disorders, Am. J. Med. Genet. source

      Not checked in the free run.

    • cites [5] Ekins, 2017, Industrializing rare disease therapy discovery and development, Nat. Biotechnol. source

      Not checked in the free run.

  • Interpretationreasoning

    Recent progress in gene therapies could offer more options for treating GARDs.

    “Since a majority of GARDs stem from genetic disorders, recent progresses in gene therapies could offer more options for treating GARDs.[3, 5]”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [3] Sun, 2017, Drug discovery and development for rare genetic disorders, Am. J. Med. Genet. source

      Not checked in the free run.

    • cites [5] Ekins, 2017, Industrializing rare disease therapy discovery and development, Nat. Biotechnol. source

      Not checked in the free run.

  • Premisecitation

    RNA interference technology enables downregulation of disease-related genes and protein expression.

    “For instance, RNA interference (RNAi) technology enables the downregulation of disease related genes and protein expression; mRNA mediates the expression and supplementation of therapeutic proteins; the CRISPR gene editing system facilitates gene engineering in vivo or through cell engineering ex vivo.[6, 9, 11, 17–20]”
    Quote in the paperSubstantial claim0 of 7 sources checked
    • cites [6] Kaczmarek, 2017, Advances in the delivery of RNA therapeutics: from concept to clinical reality, Genome Med. source

      Not checked in the free run.

    • cites [9] Kole, 2012, RNA therapeutics: beyond RNA interference and antisense oligonucleotides, Nat. Rev. Drug Discov. source

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    • cites [11] Sullenger, 2016, From the RNA world to the clinic, Science source

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    • cites [17] Hu, 2016

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    • cites [18] Cullis, 2017, Lipid nanoparticle systems for enabling gene therapies, Mol. Ther. source

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    • cites [19] Dowdy, 2017, Overcoming cellular barriers for RNA therapeutics, Nat. Biotechnol. source

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    • cites [20] Yin, 2014, Non-viral vectors for gene-based therapy, Nat. Rev. Genet. source

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  • Premisecitation

    A variety of RNA therapeutics have been developed for GARD therapies based on miRNA, siRNA, mRNA, lncRNA, and genome editing systems containing RNA components.

    “To date, a variety of RNA therapeutics have been developed for GARD therapies based on the versatile family of RNA molecules, including microRNA (miRNA), small interfering RNA (siRNA), messenger RNA (mRNA), long non-coding RNA (lncRNA), and genome editing systems containing RNA components.[6, 9, 16]”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [6] Kaczmarek, 2017, Advances in the delivery of RNA therapeutics: from concept to clinical reality, Genome Med. source

      Not checked in the free run.

    • cites [9] Kole, 2012, RNA therapeutics: beyond RNA interference and antisense oligonucleotides, Nat. Rev. Drug Discov. source

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    • cites [16] Pereira, 2012, Emerging RNA-based drugs: siRNAs, microRNAs and derivates, Cent. Nerv. Syst. Agents Med. Chem. source

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  • Interpretationnone given

    RNAs can be applied as a gene therapy tool to treat GARDs, which currently lack access to effective therapeutics.

    “Another worthwhile application of RNA technology is to apply RNAs as a gene therapy tool to treat GARDs, which currently lack access to effective therapeutics.”
    Quote in the paperSubstantial claim
  • May combine two claims. 53
  • Classified as probably not a substantial claim. 23
  • The quote only partly states this claim. 1

  • May combine two claims.

    Premisecitation

    Many rare diseases still lack effective cures and call for new therapeutics.

    “Despite the great efforts that have been devoted to supporting the development of orphan drugs, many rare diseases still lack effective cures and call for new therapeutics.[3]”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [3] Sun, 2017, Drug discovery and development for rare genetic disorders, Am. J. Med. Genet. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S4 (based). May combine two claims.

    Interpretationnone given

    Among RNA delivery platforms enabling systemic applications, non-viral RNA delivery biomaterials display superior properties, and a few have been successfully exploited for RNA-based gene therapies on GARDs.

    “Among all the RNA delivery platforms which enable the systemic applications of RNAs, non-viral RNA delivery biomaterials display superior properties and a few biomaterials have been successfully exploited for achieving the RNA-based gene therapies on GARDs.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S4 (based).

    Interpretationnone given

    RNA-based therapeutics, including RNA interference, messenger RNA, and RNA-involved genome editing technologies, have great potential as a therapy tool for treating genetic associated rare diseases.

    “RNA-based therapeutics, such as RNA interference (RNAi), messenger RNA (mRNA) and RNA-involved genome editing technologies, demonstrate great potential as a therapy tool for treating genetic associated rare diseases.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    RNA vaccines have exhibited encouraging results in both infection therapy and cancer immunotherapy.

    “RNA vaccines, for example, have exhibited encouraging results in both infection therapy and cancer immunotherapy.[6, 7, 11–15]”
    Quote in the paperNot a substantial claim0 of 7 sources checked
    • cites [6] Kaczmarek, 2017, Advances in the delivery of RNA therapeutics: from concept to clinical reality, Genome Med. source

      Not checked in the free run.

    • cites [7] Pastor, 2018, An RNA toolbox for cancer immunotherapy, Nat. Rev. Drug Discov. source

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    • cites [11] Sullenger, 2016, From the RNA world to the clinic, Science source

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    • cites [12] Pardi, 2018, mRNA vaccines - a new era in vaccinology, Nat. Rev. Drug Discov. source

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    • cites [13] Bryant, 2019, Dendritic cells as cancer therapeutics, Semin. Cell Dev. Biol. source

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    • cites [14] Garg, 2017, Integrating next-generation dendritic cell vaccines into the current cancer immunotherapy landscape, Trends Immunol. source

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    • cites [15] Kramps, 2016

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  • May combine two claims.

    Premisecitation

    The CRISPR gene editing system facilitates gene engineering in vivo or through cell engineering ex vivo.

    “For instance, RNA interference (RNAi) technology enables the downregulation of disease related genes and protein expression; mRNA mediates the expression and supplementation of therapeutic proteins; the CRISPR gene editing system facilitates gene engineering in vivo or through cell engineering ex vivo.[6, 9, 11, 17–20]”
    Quote in the paperNot a substantial claim0 of 7 sources checked
    • cites [6] Kaczmarek, 2017, Advances in the delivery of RNA therapeutics: from concept to clinical reality, Genome Med. source

      Not checked in the free run.

    • cites [9] Kole, 2012, RNA therapeutics: beyond RNA interference and antisense oligonucleotides, Nat. Rev. Drug Discov. source

      Not checked in the free run.

    • cites [11] Sullenger, 2016, From the RNA world to the clinic, Science source

      Not checked in the free run.

    • cites [17] Hu, 2016

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    • cites [18] Cullis, 2017, Lipid nanoparticle systems for enabling gene therapies, Mol. Ther. source

      Not checked in the free run.

    • cites [19] Dowdy, 2017, Overcoming cellular barriers for RNA therapeutics, Nat. Biotechnol. source

      Not checked in the free run.

    • cites [20] Yin, 2014, Non-viral vectors for gene-based therapy, Nat. Rev. Genet. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    RNA molecules alone have difficulty penetrating target cells, are vulnerable to degradation in biological fluids, and are incapable of accumulating in target organs following systemic administration.

    “In terms of RNA therapeutics, RNA molecules alone have difficulty penetrating target cells, are vulnerable to degradations in biological fluids, and are incapable of accumulating in target organs following systemic administration.[18]”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [18] Cullis, 2017, Lipid nanoparticle systems for enabling gene therapies, Mol. Ther. source

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  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    DNA and RNA nanotechnologies have been applied to deliver RNA therapeutics such as siRNA and miRNA, mainly for cancer therapy.

    “In addition to viral vectors, DNA and RNA nanotechnologies have also been applied to deliver RNA therapeutics such as siRNA and miRNA, which are mainly used for cancer therapy.[24, 29–33]”
    Quote in the paperNot a substantial claim0 of 6 sources checked
    • cites [24] Jasinski, 2017, Advancement of the emerging field of RNA nanotechnology, ACS Nano source

      Not checked in the free run.

    • cites [29] Jones, 2015, Nanomaterials. Programmable materials and the nature of the DNA bond, Science source

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    • cites [30] Seeman, 2010, Nanomaterials based on DNA, Annu. Rev. Biochem. source

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    • cites [31] Mirkin, 2018, Spherical nucleic acids: adding a new dimension to nucleic acids and clinical chemistry, Clin. Chem. source

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    • cites [32] Jiang, 2018, Rationally designed DNA-origami nanomaterials for drug delivery in vivo, Adv. Mater.

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    • cites [33] Liu, 2019, Targeted delivery of Rab26 siRNA with precisely tailored DNA prism for lung cancer therapy, Chembiochem source

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  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Viral vectors are an efficient tool for gene transfection and account for many gene-therapy clinical trials.

    “Viral vectors are a type of efficient tool for gene transfection and account for many gene-therapy clinical trials.[20, 25, 26]”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [20] Yin, 2014, Non-viral vectors for gene-based therapy, Nat. Rev. Genet. source

      Not checked in the free run.

    • cites [25] Gao, 2009, Nonviral methods for siRNA delivery, Mol. Pharm. source

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    • cites [26] Finer, 2017, A brief account of viral vectors and their promise for gene therapy, Gene Ther. source

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  • May combine two claims.

    Interpretationreasoning

    Appropriate delivery methods are essential for enabling systemic applications of RNA therapeutics and maximizing their therapeutic window.

    “Although some naked RNAs and chemically modified RNAs were applied for therapies based on local administration or ex vivo applications, appropriate delivery methods are still essential for both enabling systemic applications of RNA therapeutics and further maximizing their therapeutic window.[22]”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [22] Tam, 2013, Advances in lipid nanoparticles for siRNA delivery, Pharmaceutics source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Many viral vectors have been employed for treating GARDs, such as hemophilia, cystic fibrosis, or rare inherited retinal diseases.

    “Also, many viral vectors have been employed for treating GARDs, such as hemophilia, cystic fibrosis, or rare inherited retinal diseases, etc.[23, 28]”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [23] Lundstrom, 2018, Viral vectors in gene therapy, Diseases source

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    • cites [28] Spencer, 2016, State of the art: gene therapy of haemophilia, Haemophilia source

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  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Several viral vector mediated cellular and gene-therapy products, such as Kymriah for CAR-T immunotherapy on lymphoblastic leukemia, have gained FDA approval.

    “Several viral vector mediated cellular and gene-therapy products, such as Kymriah for CAR-T immunotherapy on lymphoblastic leukemia, have already gained FDA approval.[27]”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [27] Prasad, 2017, Tisagenlecleucel — the first approved CAR-T-cell therapy: implications for payers and policy makers, Nat. Rev. Clin. Oncol. source

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    Premisecitation

    In 2018, Patisiran gained US FDA approval and became the first marketed RNAi-based therapy.

    “In 2018, Patisiran (ONPATTRO™) gained its approval by the US FDA and became the first marketed RNAi-based therapy.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [53] Ledford, 2018, Gene-silencing technology gets first drug approval after 20-year wait, Nature source

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    • cites [58] Wood, 2018, FDA approves patisiran to treat hereditary transthyretin amyloidosis, Nat. Rev. Neurol. source

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  • May combine two claims.

    Premisecitation

    LNPs encapsulate and protect RNAs from degradation during circulation and deliver RNA payloads to target organs following systemic administration.

    “The exceptional properties of LNPs for RNA delivery include, but are not limited to, the encapsulation and protection of RNAs from degradation during circulation, as well as the delivery of RNA payloads to the target organ following systemic administration.[18, 54, 61]”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [18] Cullis, 2017, Lipid nanoparticle systems for enabling gene therapies, Mol. Ther. source

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    • cites [54] Zatsepin, 2016, Lipid nanoparticles for targeted siRNA delivery - going from bench to bedside, Int. J. Nanomed. source

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    • cites [61] Huang, 2011, In vivo delivery of RNAi with lipid-based nanoparticles, Annu. Rev. Biomed. Eng. source

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  • May combine two claims.

    Interpretationreasoning

    The combined functionality of Patisiran's RNAi technique and LNPs enables robust reduction in expression of the hATTR disease-linked gene, providing a therapeutic treatment for the genetic disease.

    “The combined functionality of Patisiran’s RNAi technique coupled with the use of LNPs as a delivery vehicle enables a robust reduction in the expression of the hATTR disease-linked gene, ultimately providing a therapeutic treatment for the genetic disease.[56, 57]”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [56] Suhr, 2015, Efficacy and safety of patisiran for familial amyloidotic polyneuropathy: a phase II multi-dose study, Orphanet J. Rare Dis. source

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    • cites [57] Coelho, 2013, Safety and efficacy of RNAi therapy for transthyretin amyloidosis, N. Engl. J. Med. source

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    Premisecitation

    Semple et al. reported that DLin-KC2-DMA containing SNALPs exhibited in vivo activity at siRNA doses of 0.01 mg/kg in mouse and silenced TTR gene in nonhuman primates with ED50 around 0.3 mg/kg.

    “Semple et al. reported that DLin-KC2-DMA containing stable nucleic acid lipid particles (SNALPs) exhibited in vivo activity at siRNA doses of 0.01 mg/kg in the mouse model and was capable of silencing the TTR gene in nonhuman primates with ED50 around 0.3 mg/kg.[63]”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [63] Semple, 2010, Rational design of cationic lipids for siRNA delivery, Nat. Biotechnol. source

      Not checked in the free run.

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    Premisecitation

    Modified siRNA remain intact for long durations under circulation, providing the possibility of delivering siRNA without nanoparticle shielding.

    “With the development of chemical modifications on RNA molecules, modified siRNA are reported to remain intact for long durations under circulation, which provides the possibility of delivering siRNA without the shielding of nanoparticles.[19, 75, 76]”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [19] Dowdy, 2017, Overcoming cellular barriers for RNA therapeutics, Nat. Biotechnol. source

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    • cites [75] Janas, 2019

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    • cites [76] Sun, 2017, Enhancing the therapeutic delivery of oligonucleotides by chemical modification and nanoparticle encapsulation, Molecules source

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  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    The most commonly reported siRNA LNP formulation contains five key components: lipid or lipid derivatives, phospholipid, cholesterol, PEG, and payload siRNA.

    “The most commonly reported siRNA LNP formulation contains five key components, which are the lipid or lipid derivatives, phospholipid, cholesterol, polyethylene glycol (PEG), and the payload siRNA.[59]”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [59] Kulkarni, 2018, Lipid nanoparticles enabling gene therapies: from concepts to clinical utility, Nucleic Acid Therapeut. source

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    Premisecitation

    GalNAc-siRNA conjugates achieve systemic stability against nucleases, improving pharmacokinetics.

    “Results showed that by conjugating the engineered ASGPR ligand to the chemically modified siRNA molecule, GalNAc-siRNA conjugates could achieve systemic stability against nucleases, which would in turn improve pharmacokinetics.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [51] Huang, 2017, Preclinical and clinical advances of GalNAc-decorated nucleic acid therapeutics, molecular therapy, Nucl. Acid.

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    • cites [77] Nair, 2014, Multivalent N-Acetylgalactosamine-Conjugated siRNA localizes in hepatocytes and elicits robust RNAi-mediated gene silencing, J. Am. Chem. Soc. source

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    • cites [78] Springer, 2018, GalNAc-siRNA conjugates: leading the way for delivery of RNAi therapeutics, Nucleic Acid Therapeut. source

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    Premisecitation

    ARO-AAT was developed as a therapy for alpha-1 antitrypsin deficiency (AATD) and has completed a Phase 1 clinical study.

    “ARO-AAT, one of the candidates built on the TRiM™ platform, was developed as a therapy for alpha-1 antitrypsin deficiency (AATD) and has completed a Phase 1 clinical study (NCT03362242).”
    Quote in the paperNot a substantial claim

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    Premisecitation

    Arrowhead's TRiM platform uses ligand-mediated delivery and stringent bioinformatics to design tissue-specific targeting conjugates.

    “The TRiM™ platform utilizes ligand-mediated delivery and stringent bioinformatics to design tissue-specific targeting conjugates.[89]”
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    • cites [89] Pharmaceuticals

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    Premisecitation

    ARO-ENaC mediated targeted silencing of αENaC mRNA in rat lungs and dose-dependently improved mucociliary clearance in sheep after inhaled aerosol exposure.

    “ARO-ENaC thus mediated targeted silencing of αENaC mRNA in the lungs of rats, and dose-dependently improved mucociliary clearance in sheep after inhaled aerosol exposure.[98]”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [98] Bush, 2018

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    Premisecitation

    ASGPR is highly expressed on hepatocytes and GalNAc facilitates uptake of its payload into hepatocytes through ASGPR via clathrin-mediated endocytosis.

    “The ASGPR is highly expressed on hepatocytes and GalNAc facilitates the uptake of its payload into hepatocytes through ASGPR via clathrin-mediated endocytosis.[77]”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [77] Nair, 2014, Multivalent N-Acetylgalactosamine-Conjugated siRNA localizes in hepatocytes and elicits robust RNAi-mediated gene silencing, J. Am. Chem. Soc. source

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    Premisecitation

    The ESC platform features higher 2'-OMe content and four additional terminal PS linkages compared with first generation STC-based GalNAc-siRNA.

    “As compared with their first generation ‘Standard Template Chemistry’ (STC)-based GalNAc-siRNA, in which RNA molecules were 2’-OMe and 2’-F modified and contained two terminal phosphorothioate (PS) linkages, the newly developed ESC platform features higher 2’-OMe content and four additional terminal PS linkages.[81]”
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    • cites [81] Janas, 2019

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    Premisecitation

    Inclisiran significantly decreases production of PCSK9 in liver and reduces LDL-C level, enabling management of autosomal dominant hypercholesterolemia (ADH).

    “Inclisiran was reported to be able to significantly decrease the production of PCSK9 in liver and thus reduce the LDL-C level, which enables it to be used for the management of autosomal dominant hypercholesterolemia (ADH).[85, 86]”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [85] Kosmas, 2018, Inclisiran: a new promising agent in the management of hypercholesterolemia, Diseases source

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    • cites [86] Ogura, 2018, PCSK9 inhibition in the management of familial hypercholesterolemia, J. Cardiol. source

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    Premisecitation

    LPR nanocomplexes facilitated translocation of siRNA through mucus, mediated efficient ENaCsiRNA transfections in primary CF epithelial cells, and reduced 30% of αENaC and βENaC mRNA.

    “Results showed that the established LPR nanocomplexes facilitated the translocation of siRNA through mucus, mediated efficient ENaCsiRNA transfections in primary CF epithelial cells, and reduced 30% of the αENaC and βENaC mRNA.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [95] Manunta, 2017, Delivery of ENaC siRNA to epithelial cells mediated by a targeted nanocomplex: a therapeutic strategy for cystic fibrosis, Sci. Rep. source

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    • cites [96] Tagalakis, 2018, Effective silencing of ENaC by siRNA delivered with epithelial-targeted nanocomplexes in human cystic fibrosis cells and in mouse lung, Thorax source

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    Premisecitation

    mRNA functions as the bridge between DNA and proteins in eukaryotic cells.

    “mRNA functions as the bridge between DNA and proteins in eukaryotic cells.[8, 12, 119]”
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    • cites [8] Hajj, 2017, Tools for translation: non-viral materials for therapeutic mRNA delivery, Nat. Rev. Mater. source

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    • cites [12] Pardi, 2018, mRNA vaccines - a new era in vaccinology, Nat. Rev. Drug Discov. source

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    • cites [119] Sahin, 2014, mRNA-based therapeutics—developing a new class of drugs, Nat. Rev. Drug Discov. source

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    Premisecitation

    Administration of hsiRNA-loaded exosomes through unilateral infusion into mouse striatum showed in vivo efficacy, with 35% of HTT mRNA silenced in the brain of mice.

    “Moreover, administration of hsiRNA-loaded exosomes through unilateral infusion into mouse striatum further showed in vivo efficacy of these established exosomes, where 35% of HTT mRNA were silenced in the brain of mice.[106]”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [106] Didiot, 2016, Exosome-mediated delivery of hydrophobically modified siRNA for huntingtin mRNA silencing, Mol. Ther. source

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    Premisecitation

    Although FIX PRT improves the outcome of hemophilia B, its short half-life, frequent intravenous administration, and cost limit broader utilization.

    “Although the FIX PRT improves the outcome of hemophilia B, its short half-life, frequent intravenous (i.v.) administration method, and cost still limit the broader utilization.[167]”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [167] Nazeef, 2016, New developments in the management of moderate-to-severe hemophilia B, J. Blood Med.

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    Premisecitation

    Ionizable lipid and lipid derived materials acquire positive charges at low pH and become neutral at physiological pH, and have been developed for decreasing toxicity and immunogenicity while retaining delivery efficiency.

    “Meanwhile, ionizable lipid and lipid derived materials, which acquire positive charges at low pH and become neutral at physiological pH, have been developed for decreasing the toxicity and immunogenicity while retaining the delivery efficiency.[8]”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [8] Hajj, 2017, Tools for translation: non-viral materials for therapeutic mRNA delivery, Nat. Rev. Mater. source

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  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Many biomaterials have been developed for mRNA delivery, including lipids and lipid derived materials, polymers, and many others.

    “Recently, many biomaterials have been developed for mRNA delivery, including lipids and lipid derived materials, polymers, and many others. [8, 39, 120, 124]”
    Quote in the paperNot a substantial claim0 of 4 sources checked
    • cites [8] Hajj, 2017, Tools for translation: non-viral materials for therapeutic mRNA delivery, Nat. Rev. Mater. source

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    • cites [39] Li, 2019, Nanoscale platforms for messenger RNA delivery, Wiley Interdiscip. Rev. Nanomed. Nanobiotechnol. source

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    • cites [120] Xiong, 2018, Biomedical applications of mRNA nanomedicine, Nano Res. source

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    • cites [124] Kowalski, 2019

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    Premisecitation

    In 2018, the nucleic acid drug Patisiran based on MC3 lipid was approved by the US FDA.

    “In 2018, the nucleic acid drug Patisiran (ONPATTRO™) based on MC3 lipid have been approved by the US FDA.[124]”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [124] Kowalski, 2019

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Relative to plasmid DNA, mRNA possesses temporary bioactivity and functions outside the nucleus, leading to more controllable protein expression and avoiding potential insertion of the genome.

    “Relative to plasmid DNA (pDNA), mRNA possesses temporary bioactivity and functions outside the nucleus, leading to a more controllable protein expression and avoiding the potential insertion of the genome.[8, 119, 120]”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [8] Hajj, 2017, Tools for translation: non-viral materials for therapeutic mRNA delivery, Nat. Rev. Mater. source

      Not checked in the free run.

    • cites [119] Sahin, 2014, mRNA-based therapeutics—developing a new class of drugs, Nat. Rev. Drug Discov. source

      Not checked in the free run.

    • cites [120] Xiong, 2018, Biomedical applications of mRNA nanomedicine, Nano Res. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    After i.v. injection of OTC mRNA with HMT, prolonged survival was observed in OTCD mice, with no obvious changes of cytokines or significant pathological lesions in blood and liver.

    “After i.v. injection of OTC mRNA with HMT, a prolonged survival was observed in OTCD mice. Meanwhile, no obvious changes of cytokines or significant pathological lesions were detected in the blood and liver, respectively.[177]”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [177] Prieve, 2018, Targeted mRNA therapy for ornithine transcarbamylase deficiency, Mol. Ther. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Repeated administrations of hMUT mRNA improved growth and survival of MMA mice without obvious liver damage and inflammation.

    “In addition, repeated administrations improved the growth and survival of MMA mice without obvious liver damage and inflammation.[47]”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [47] An, 2017, Systemic messenger RNA therapy as a treatment for methylmalonic acidemia, Cell Rep. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    On day 3 after intranasal administration of MC3-based LNPs delivering hCFTR mRNA to Cftr knockout mice, chloride secretion reached 55% of that in healthy mice and was maintained more than 15 days.

    “On day 3 post-administration, chloride secretion reached 55% of that in healthy mice and the secretion maintained more than 15 days.[131]”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [131] Robinson, 2018, Lipid nanoparticle-delivered chemically modified mRNA restores chloride secretion in cystic fibrosis, Mol. Ther. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    PBGD expression in the liver lasted for at least 10 days, providing full protection throughout the diseased period (5 to 7 days).

    “Importantly, the PBGD expression in the liver lasted for at least 10 days, which provided a full protection throughout the diseased period (5 to 7 days).[130]”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [130] Jiang, 2018, Systemic messenger RNA as an etiological treatment for acute intermittent porphyria, Nat. Med. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    After 6 hours of i.v. injection of TT3-delivered hFIX mRNA, plasma FIX concentration was 1740 ng/mL and activity was 791 mIU/mL, within normal physiological values.

    “After 6 hours of i.v. injection, the plasma concentration of FIX was 1740 ng/mL and the activity was 791 mIU/mL, which were well within the normal physiological values.[40]”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [40] Li, 2015, An orthogonal array optimization of lipid-like nanoparticles for mRNA delivery in vivo, Nano Lett. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Small molecules that restore chloride transport function of mutant CFTR have shown promising clinical results, but their narrow application range, poor improvements in lung function, and side effects limit their utilization.

    “Some small molecules that aim to restore the chloride transport function of the mutant CFTR have shown promising clinical results. However, their narrow application range, poor improvements in lung function, and side effects limit their utilization.[188–190]”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [188] Ren, 2018, Cystic fibrosis foundation pulmonary guidelines. Use of cystic fibrosis transmembrane conductance regulator modulator therapy in patients with cystic fibrosis, Annal. Am. Thoracic Soc. source

      Not checked in the free run.

    • cites [189] Jennings, 2017, An observational study of outcomes and tolerances in patients with cystic fibrosis initiated on lumacaftor/ivacaftor, Annal. Am. Thoracic Soc. source

      Not checked in the free run.

    • cites [190] Hagemeijer, 2018, Translational research to enable personalized treatment of cystic fibrosis, J. Cyst. Fibros. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The therapeutic level of hADAMTS13 was maintained for up to five days, significantly longer than the 24-hour half-life of recombinant human ADAMTS13 protein.

    “Furthermore, therapeutic level was maintained for up to five days, which was significantly longer than the half-life (24 hours) of the recombinant human ADAMTS13 (rhADAMTS13) protein.[170]”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [170] Liu-Chen, 2018, mRNA treatment produces sustained expression of enzymatically active human ADAMTS13 in mice, Sci. Rep. source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    mRNA-based PRT is a promising alternative for liver transplant, which is currently the only option for treating OTCD.

    “mRNA-based PRT is a promising alternative for liver transplant which is currently the only option for treating OTCD.[176]”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [176] Rowe, 1986, Natural history of symptomatic partial ornithine transcarbamylase deficiency, N. Engl. J. Med. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    A phase 1/2 clinical trial (NCT03767270) on MRT5201 has been launched.

    “Recently, a phase 1/2 clinical trial (NCT03767270) on MRT5201 has been launched (Table 2).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites NCT03767270

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    After 24 h of nebulization, luciferase signal was observed in the lungs but not in the spleen and liver.

    “After 24 h of nebulization, luciferase signal was observed in the lungs but not in the spleen and liver.[151]”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [151] Patel, 2019, Inhaled nanoformulated mRNA polyplexes for protein production in lung epithelium, Adv. Mater.

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    The Cas9 nuclease utilizes a sgRNA to recognize the target sequence and subsequently cleaves the genome at the specific site.

    “The Cas9 nuclease utilizes a sgRNA to recognize the target sequence and subsequently cleaves the genome at the specific site.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [202] Yin, 2017, Delivery technologies for genome editing, Nat. Rev. Drug Discov. source

      Not checked in the free run.

    • cites [205] Wang, 2017, CRISPR/Cas9-based genome editing for disease modeling and therapy: challenges and opportunities for nonviral delivery, Chem. Rev. source

      Not checked in the free run.

    • cites [207] Glass, 2018, Engineering the delivery system for CRISPR-based genome editing, Trends Biotechnol. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    After subretinal injection of MC3-based mRNA LNPs in albino BALB/c mice, photoreceptor expression persisted for 96 h (began within 4 h and peaked at 24 h) and mainly distributed in the retinal pigmented epithelium.

    “After a subretinal injection, the photoreceptor expression persisted for 96 h (began within 4 h and reached peak expression at 24 h), and mainly distributed in the retinal pigmented epithelium (RPE).[132]”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [132] Patel, 2019, Lipid nanoparticles for delivery of messenger RNA to the back of the eye, J. Control. Release source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisenone given

    CRISPR-Cas9 is one of the most widely used genome editing systems for in vivo applications.

    “Among them, CRISPR-Cas9 is one of the most widely used genome editing systems for in vivo applications.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Restored lung function in CF was determined by increasing CFTR expression and improved forced expiratory volume.

    “The restored lung function was determined by increasing CFTR expression and improved forced expiratory volume (FEV).[149]”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [149] Haque, 2018, Chemically modified h CFTR mRNAs recuperate lung function in a mouse model of cystic fibrosis, Sci. Rep. source

      Not checked in the free run.

  • The quote only partly states this claim.

    Premisecitation

    Intranasal administration of polyplex nanomicelles delivering mRNA encoding neutrophilic factor promoted recovery of olfactory function in mice with olfactory dysfunction.

    “Intranasal administration of the nanomicelles promoted the recovery of their olfactory function.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [156] Baba, 2015, Treatment of neurological disorders by introducing mRNA in vivo using polyplex nanomicelles, J. Control. Release source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Relative to non-targeted LNPs, systemic administration of PECAM-1 coupled mRNA LNPs exhibited approximately 200-fold inhibition and 25-fold elevation of luciferase expression in the liver and lungs, respectively.

    “Relative to non-targeted LNPs, systemic administration of PECAM-1 coupled mRNA LNPs exhibited approximately 200-fold inhibition and 25-fold elevation of luciferase expression in the liver and the lungs, respectively.[42]”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [42] Parhiz, 2018, PECAM-1 directed re-targeting of exogenous mRNA providing two orders of magnitude enhancement of vascular delivery and expression in lungs independent of apolipoprotein E-mediated uptake, J. Control. Release source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Preclinical studies indicated LUNAR nanoparticles effectively delivered mRNA into pulmonary epithelial cells and were resistant to degradation in CF sputum during nebulization.

    “Preclinical studies indicated LUNAR nanoparticles effectively delivered mRNA into pulmonary epithelial cells and were resistant to the degradation in CF sputum during nebulization.[191]”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [191] A. Therapeutics, Pipeline. .

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    hPBAE nanoparticles were stable without lipid-PEG and withstood shearing forces from the vibrating mesh nebulizer.

    “The hPBAE nanoparticles were stable without lipid-PEG and withstood the shearing forces from the vibrating mesh nebulizer.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [151] Patel, 2019, Inhaled nanoformulated mRNA polyplexes for protein production in lung epithelium, Adv. Mater.

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Genome editing components must reach the cell nucleus to achieve therapeutic effects, requiring overcoming extracellular and intracellular barriers including enzymatic degradation in blood, RES clearance, cell membrane penetration, endosome escape, and nuclear membrane infiltration.

    “Firstly, genome editing components must reach the cell nucleus to achieve therapeutic effects. Thus, extracellular and intracellular barriers need to be overcome, including avoiding enzymatic degradation in the blood, circumventing clearance by the reticuloendothelial system (RES), penetrating cell membranes, escaping endosome entrapment, and infiltrating nuclear membranes.”
    Quote in the paperSubstantial claim0 of 4 sources checked
    • cites [205] Wang, 2017, CRISPR/Cas9-based genome editing for disease modeling and therapy: challenges and opportunities for nonviral delivery, Chem. Rev. source

      Not checked in the free run.

    • cites [206] Zhang, 2019

      Not checked in the free run.

    • cites [207] Glass, 2018, Engineering the delivery system for CRISPR-based genome editing, Trends Biotechnol. source

      Not checked in the free run.

    • cites [208] Li, 2018, Non-viral delivery systems for CRISPR/Cas9-based genome editing: challenges and opportunities, Biomaterials source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Following a single i.v. injection of LP01-based LNPs delivering Cas9 mRNA and sgRNA to edit hepatic Ttr in mice and rats, over 90% reduction of serum TTR was observed and the knockdown effect persisted for at least 12 months.

    “Following a single intravenous (i.v.) injection, over 90% reduction of serum TTR was observed and the knockdown effect persisted for at least 12 months.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [48] Finn, 2018, A single administration of CRISPR/Cas9 lipid nanoparticles achieves robust and persistent in vivo genome editing, Cell Rep. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Lung pathohistological sections indicated no visible signs of inflammatory infiltrates and blood sample analysis showed a normal level of white blood cells after treatment.

    “Meanwhile, lung pathohistological sections indicated no visible signs of inflammatory infiltrates and blood sample analysis showed a normal level of white blood cells.[45]”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [45] Guan, 2019, Self-assembled peptide–poloxamine nanoparticles enable in vitro and in vivo genome restoration for cystic fibrosis, Nat. Nanotechnol. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Multiple administrations of LP01-based LNPs achieved cumulative editing efficacy without obvious cytokine stimulation and body weight loss.

    “Moreover, multiple administrations achieved cumulative editing efficacy without obvious cytokine stimulation and body weight loss.[48]”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [48] Finn, 2018, A single administration of CRISPR/Cas9 lipid nanoparticles achieves robust and persistent in vivo genome editing, Cell Rep. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    After two weeks of intramuscular injection of CRISPR-Gold with cardiotoxin in DMD mice, 5.4% of the dystrophin gene was repaired and obvious increase of dystrophin protein was observed in treated muscle tissues.

    “After two weeks of intramuscular injection of CRISPR-Gold with cardiotoxin in DMD mice, 5.4% of the dystrophin gene was repaired and obvious increase of dystrophin protein was observed in the treated muscle tissues.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [224] Lee, 2017, Nanoparticle delivery of Cas9 ribonucleoprotein and donor DNA in vivo induces homology-directed DNA repair, Nat. Biomed. Eng. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Lower auditory response thresholds and improved acoustic responses were observed in injected mice.

    “Additionally, lower auditory response thresholds and improved acoustic responses were observed in injected mice.[226]”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [226] Gao, 2018, Treatment of autosomal dominant hearing loss by in vivo delivery of genome editing agents, Nature source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    After a single treatment with C12-200 LNPs delivering Cas9 mRNA/sgRNA and AAV DNA donor, FAH expression in more than 6% of hepatocytes was repaired and symptoms of hepatic damage were prevented in the following 30 days in Fah knockout mice.

    “After a single treatment, the FAH expression in more than 6% of hepatocytes was repaired and the symptoms of hepatic damage were prevented in the following 30 days.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [141] Yin, 2016, Therapeutic genome editing by combined viral and non-viral delivery of CRISPR system components in vivo, Nat. Biotechnol. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Following i.t. co-administration of chitosan-PLGA nanoparticles encapsulating ZFN mRNA and AAV containing a DNA donor, SP-B expression was maintained for as long as 20 days in the lungs, which prevented deterioration of lung function and resulted in longer lifetimes compared with negative controls.

    “Following intratracheal (i.t.) co-administration of nanoparticles encapsulating ZFN mRNA and AAV containing a DNA donor, SP-B expression was maintained for as long as 20 days in the lungs, which prevented the deterioration of lung function and resulted in longer lifetimes compared with negative controls.[219]”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [219] Mahiny, 2015, In vivo genome editing using nuclease-encoding mRNA corrects SP-B deficiency, Nat. Biotechnol. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S2 (checkable). May combine two claims.

    Premisecitation

    Genome editing components should be delivered to target tissues and edit specific sequences in a controllable manner to prevent off-target events and immune responses.

    “Thirdly, genome editing components should be delivered to target tissues and edit specific sequences in a controllable manner to prevent off-target events and immune responses.”
    Quote in the paperNot a substantial claim0 of 4 sources checked
    • cites [205] Wang, 2017, CRISPR/Cas9-based genome editing for disease modeling and therapy: challenges and opportunities for nonviral delivery, Chem. Rev. source

      Not checked in the free run.

    • cites [206] Zhang, 2019

      Not checked in the free run.

    • cites [207] Glass, 2018, Engineering the delivery system for CRISPR-based genome editing, Trends Biotechnol. source

      Not checked in the free run.

    • cites [208] Li, 2018, Non-viral delivery systems for CRISPR/Cas9-based genome editing: challenges and opportunities, Biomaterials source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Two weeks after intramuscular injection of PAsp(DET) polymer encapsulating 200 pmol Cpf1 and 200 pmol 5′ extended crRNA on Rosa26tdTomato mice, stop sequences of tdTomato were effectively deleted and robust tdTomato signal was observed.

    “Two weeks after intramuscular injection of PAsp(DET) polymer encapsulating 200 pmol Cpf1 and 200 pmol 5′ extended crRNA on Rosa26tdTomato mice, the stop sequences of tdTomato were effectively deleted, and robust tdTomato signal was observed.[157]”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [157] Park, 2018, Extension of the crRNA enhances Cpf1 gene editing in vitro and in vivo, Nat. Commun. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Following a single i.v. injection of Cas9 mRNA and e-sgRNA targeting Pcsk9 with cKK-E12 LNPs, hepatic PCSK9 protein was reduced by 80% and plasma cholesterol levels were reduced by about 40%.

    “Following a single i.v. injection, hepatic PCSK9 protein was reduced by 80% and plasma cholesterol levels were reduced by about 40%.[135]”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [135] Yin, 2017, Structure-guided chemical modification of guide RNA enables potent non-viral in vivo genome editing, Nat. Biotechnol. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The 5′ extension of crRNA improved serum stability and enhanced nanoparticle formulation with PAsp(DET) polymer, resulting in higher in vivo delivery efficiency than wild type Cpf1 RNPs.

    “The 5′ extension of crRNA improved the serum stability and enhanced the nanoparticle formulation with PAsp(DET) polymer, resulting in a higher in vivo delivery efficiency than wild type Cpf1 RNPs.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [157] Park, 2018, Extension of the crRNA enhances Cpf1 gene editing in vitro and in vivo, Nat. Commun. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    After three-time i.t. administration of peptide-poloxamine nanoparticles containing the Sleeping Beauty transposon system, CFTR expression lasted for 18 weeks in CF mice and the level was similar to that of the wild type group.

    “After three-time i.t. administration, CFTR expression lasted for 18 weeks in CF mice and the level was similar to that of the wild type group.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [45] Guan, 2019, Self-assembled peptide–poloxamine nanoparticles enable in vitro and in vivo genome restoration for cystic fibrosis, Nat. Nanotechnol. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    MRG-201 is now in Phase 2 clinical trials (NCT03601052).

    “MRG-201 is now in Phase 2 clinical trials (NCT03601052).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites NCT03601052

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Premisenone given

    Many other biomaterials, such as cell derived vehicles, gold nanoparticles, polymeric nanoparticles, and DNA/RNA nanotechnology, were also used as delivery systems for in vivo RNA therapeutics.

    “In addition, many other biomaterials, such as cell derived vehicles, gold nanoparticles, polymeric nanoparticles, and DNA/RNA nanotechnology, were also used as delivery systems for in vivo RNA therapeutics.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Interpretationnone given

    Ligand conjugations have achieved prominent success in delivering small RNA molecules with the development of RNA chemical modification technology.

    “Ligand conjugations have achieved prominent success in delivering small RNA molecules with the development of RNA chemical modification technology.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Interpretationreasoning

    By exploring diverse chemical scaffolds of lipids, researchers can develop LNPs with optimized physiochemical and biological properties to match a specific application.

    “By exploring diverse chemical scaffolds of lipids, researchers can develop LNPs with optimized physiochemical and biological properties to match a specific application.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: A majority of LNPs accumulate in the liver, which limits the use of LNPs to treatment of liver-oriented diseases.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    LncRNA is involved in many different biological processes.

    “While only a small proportion of lncRNA transcripts have been functionally characterized to date, lncRNA is found to be involved in many different biological processes.[244]”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [244] Bonetti, 2017, From bench to bedside: the long journey of long non-coding RNAs, Curr. Opin. Struct. Biol.

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    miRNA may regulate multiple mRNA targets whereas siRNA inhibits one specific mRNA target.

    “However, miRNA may regulate multiple mRNA targets whereas siRNA inhibits one specific mRNA target.[237]”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [237] Lam, 2015, siRNA versus miRNA as therapeutics for gene silencing, Mol. Ther. Nucleic Acids source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Mutations affecting lncRNA expression could lead to diseases, as do protein coding genes.

    “Therefore, it is realized that mutations affecting lncRNA expression could lead to diseases, as do protein coding genes.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S4 (based).

    Interpretationnone given

    Applications of these other biomaterials in treating GARDs have not been widely explored yet.

    “Their applications in treating GARDs have not been widely explored yet.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    An increasing number of RNA molecules are emerging as promising breakthrough therapies for many diseases.

    “Recently, an increasing number of RNA molecules are emerging as promising breakthrough therapies for many diseases.[3]”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [3] Sun, 2017, Drug discovery and development for rare genetic disorders, Am. J. Med. Genet. source

      Not checked in the free run.

72 of 72

  • The paper relies on this without support.

    Targeted delivery is crucial for achieving genome editing specificity and reducing off-target effects.

    “Targeted delivery is crucial for achieving genome editing specificity and reducing off-target effects.”

  • The paper relies on this without support.

    Many targeting strategies developed for drug delivery have not been thoroughly applied to genome editing delivery systems.

    “Although many targeting strategies have been developed for drug delivery, they have not be thoroughly applied to genome editing delivery systems.”

  • The paper relies on this without support.

    Currently, tissue targeting genome editing delivery has been limited to topical administration except the liver.

    “Currently, tissue targeting genome editing delivery has been limited to topical administration except the liver.”

  • The paper relies on this without support.

    For non-viral vectors, good biocompatibility enables the reduction of side effects and improves tolerability.

    “For non-viral vectors, good biocompatibility enables the reduction of side effects and improves tolerability.”

  • The paper relies on this without support.

    A majority of LNPs accumulate in the liver, which limits the use of LNPs to treatment of liver-oriented diseases.

    “For example, a majority of LNPs accumulate in the liver which, to some extent, limits the use of LNPs to treatment of liver-oriented diseases.”

  • The paper relies on this without support.

    A large number of rare diseases are still awaiting effective treatments.

    “Although many RNA delivery biomaterials have been explored for treating GARDs, a large number of rare diseases are still awaiting effective treatments.”
6 of 6

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • mRNA has therapeutic potential in viral vaccines, protein replacement therapies, cancer immunotherapies, cellular reprogramming and genome editing.

    “mRNA has shown therapeutic potential in a range of applications, including viral vaccines, protein replacement therapies, cancer immunotherapies, cellular reprogramming and genome editing2,4,7–17.”

    From Lipid nanoparticles for mRNA delivery (2021) · cites this paper as [12]

  • Many other lipid nanoparticle-mRNA formulations are in clinical trials for the treatment of infectious diseases, cancer and genetic disorders.

    “Many other lipid nanoparticle–mRNA formulations are in clinical trials for the treatment of infectious diseases, cancer and genetic disorders2,4,8,12–14 (Tables 1,2).”

    From Lipid nanoparticles for mRNA delivery (2021) · cites this paper as [12]

  • Engineering of mRNA molecules and design of lipid nanoparticles have been optimized, contributing to the rapid development and clinical assessment of the two COVID-19 mRNA vaccines.

    “To address these concerns, the engineering of mRNA molecules (Box 1) and the design of lipid nanoparticles have been optimized2,4,7–17, which has contributed to the rapid development and clinical assessment15,17 of the two COVID-19 mRNA vaccines, mRNA-1273 (NCT04470427)19,20 and BNT162b2 (NCT04368728)21.”

    From Lipid nanoparticles for mRNA delivery (2021) · cites this paper as [12]

  • mRNA-based cellular reprogramming, tissue regeneration and genome editing have shown therapeutic potential in preclinical studies.

    “Moreover, mRNA-based cellular reprogramming, tissue regeneration and genome editing have shown therapeutic potential in preclinical studies2,4,8,12–14.”

    From Lipid nanoparticles for mRNA delivery (2021) · cites this paper as [12]

  • mRNA-based protein replacement therapies have emerged as a promising alternative to protein drugs because mRNA can be translated into desired proteins with in situ post-translational modifications in host cells.

    “mRNA-based protein replacement therapies have also emerged as a promising alternative to protein drugs, because mRNA can be translated into desired proteins with in situ post-translational modifications in host cells12.”

    From Lipid nanoparticles for mRNA delivery (2021) · cites this paper as [12]

The citation lists haven’t been fetched yet

References 236 · Cited by 82

Research works printed but not linked: 7

  1. Frishberg, 2018, vol. 1
  2. Jayaraman, 2012, Maximizing the potency of siRNA lipid nanoparticles for hepatic gene silencing in vivo, Angew Chem. Int. Ed. Engl., 51, 8529, 10.1002/anie.201203263 · DOI · Paper page
  3. DeRosa, 2016, Therapeutic efficacy in a hemophilia B model using a biosynthetic mRNA liver depot system, Gene Ther., 23, 699, 10.1038/gt.2016.46 · DOI · Paper page
  4. Liu-Chen, 2018, mRNA treatment produces sustained expression of enzymatically active human ADAMTS13 in mice, Sci. Rep., 8, 7859, 10.1038/s41598-018-26298-4 · DOI · Paper page
  5. Kaczmarek, 2018, Optimization of a degradable polymer–lipid nanoparticle for potent systemic delivery of mRNA to the lung endothelium and immune cells, Nano Lett., 18, 6449, 10.1021/acs.nanolett.8b02917 · DOI · Paper page
  6. Dong, 2014, Lipopeptide nanoparticles for potent and selective siRNA delivery in rodents and nonhuman primates, Proc. Natl. Acad. Sci. Unit. States Am., 111, 3955, 10.1073/pnas.1322937111 · DOI · Paper page
  7. Lee, 2017, Nanoparticle delivery of Cas9 ribonucleoprotein and donor DNA in vivo induces homology-directed DNA repair, Nat. Biomed. Eng., 1, 889, 10.1038/s41551-017-0137-2 · DOI · Paper page

Authors
Zhao, W., Hou, X., Vick, O. G., & Dong, Y.
Affiliations
The Ohio State University (US)
Corresponding author
Dong, Yizhou
ORCID
Venue
Biomaterials
Publisher
Elsevier BV
Published
2019-10
Volume
217
Pages
119291
ISSN
0142-9612 (ISSN-L)
DOI
10.1016/j.biomaterials.2019.119291
PMC
PMC6635005
OpenAlex
W2951938208
Cited by
82
References
236
Citations by year
2026: 3 · 2025: 14 · 2024: 16 · 2023: 15 · 2022: 16 · 2021: 12 · 2020: 5 · 2019: 1
FWCI
0.75
Type
journal article
Language
en
Open access
Licence
Locations
  • Biomaterials (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • Ohio State University
  • National Institute of General Medical Sciences
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Interference and Gene Delivery
  • Physical Sciences › Materials Science › Biomaterials › Nanoparticle-Based Drug Delivery
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA and protein synthesis mechanisms
Keywords
RNA therapeutics, RNA interference, mRNA therapeutics, genome editing, gene therapy
MeSH terms
Gene Editing, Animals, Biocompatible Materials, Humans, RNA, Gene Transfer Techniques, Genetic Diseases, Inborn, Rare Diseases

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-10.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-10.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

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