The current landscape of nucleic acid therapeutics

Kulkarni, Jayesh A.; Witzigmann, Dominik; Thomson, Sarah B.; Chen, Sam; Leavitt, Blair R.; Cullis, Pieter R.; Meel, Roy van der

doi:10.1038/s41565-021-00898-0

Cited by 759 publications

(750 citation statements)

References 158 publications

(183 reference statements)

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“…In this sense, we decided to further exploit the potential of lncRNA TP53TG1, unveiled by Diaz-Lagares et al As it is well known, genetic material faces different obstacles upon administration to reach the target cell, such as the degradation by nucleases, instability in the systemic circulation and inability to enter cells. In this regard, different types of nanocarriers, either inorganic, polymeric or lipidic, have been developed to deliver a variety of polynucleotides aimed for the treatment of several human conditions [56,57]. There are already some examples showing that nanotechnology can successfully overcome such obstacles, such as Onpattro ® (Alnylam ® pharmaceuticals), Spikevax (Moderna Inc.), Vaxzevria (Astrazeneca/Oxford) which are approved by the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA).…”

Section: Discussionmentioning

confidence: 99%

Modulation of Colorectal Tumor Behavior via lncRNA TP53TG1-Lipidic Nanosystem

et al. 2021

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Long non-coding RNAs (lncRNAs) are an emerging group of RNAs with a crucial role in cancer pathogenesis. In gastrointestinal cancers, TP53 target 1 (TP53TG1) is an epigenetically regulated lncRNA that represents a promising therapeutic target due to its tumor suppressor properties regulating the p53-mediated DNA damage and the intracellular localization of the oncogenic YBX1 protein. However, to translate this finding into the clinic as a gene therapy, it is important to develop effective carriers able to deliver exogenous lncRNAs to the targeted cancer cells. Here, we propose the use of biocompatible sphingomyelin nanosystems comprising DOTAP (DSNs) to carry and deliver a plasmid vector encoding for TP53TG1 (pc(TP53TG1)-DSNs) to a colorectal cancer cell line (HCT-116). DSNs presented a high association capacity and convenient physicochemical properties. In addition, pc(TP53TG1)-DSNs showed anti-tumor activities in vitro, specifically a decrease in the proliferation rate, a diminished colony-forming capacity, and hampered migration and invasiveness of the treated cancer cells. Consequently, the proposed strategy displays a high potential as a therapeutic approach for colorectal cancer.

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Section: Discussionmentioning

confidence: 99%

Modulation of Colorectal Tumor Behavior via lncRNA TP53TG1-Lipidic Nanosystem

et al. 2021

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“…These molecules provide an excellent opportunity for use in therapeutic interventions due to their rational design and accessibility to targets unavailable to conventional pharmaceuticals [ 1 , 2 , 3 ]. Although various applications for therapeutic oligonucleotides exist, the common mechanism of action is based on either the complementary Watson–Crick base pairing between the drug and the target mRNA or protein interaction through a three-dimensional structure [ 2 , 3 , 4 , 5 ].…”

Section: An Introduction To the Next Generation Of Treatmentsmentioning

confidence: 99%

Section: An Introduction To the Next Generation Of Treatmentsmentioning

confidence: 99%

“…Gene regulation is an application for antisense oligonucleotides (ASO) and RNA interference (RNAi) in which the oligonucleotide binds to its designated target that contains a complementary sequence [ 2 , 3 , 4 ]. For ASOs, binding of the target mRNA by a single-stranded oligonucleotide can either facilitate ribonuclease-mediated degradation or cause a steric blockage that disrupts RNA–RNA and/or RNA–DNA interaction, thereby interfering with RNA splicing [ 4 , 5 ]. In contrast, RNAi relies on the introduction of RNA molecules including small interfering RNA (siRNA) and microRNA (miRNA) into the cell cytoplasm where the guide strand is incorporated into the RNA-induced silencing complex (RISC), which can then target mRNA for degradation [ 3 , 6 ].…”

Section: An Introduction To the Next Generation Of Treatmentsmentioning

confidence: 99%

“…These modifications can be broadly categorized into backbone, base, sugar, and conjugate modifications on the oligonucleotide ( Figure 1 ) [ 3 , 14 , 15 , 16 ]. Commonly known and used modifications include phosphorothioate, 2′-O-methyl, and locked nucleic acids to address stability, toxicity, and nuclease resistance while conjugations like N-acetylgalactosamine (GalNAc) have been used to direct targeted tissue delivery [ 2 , 3 , 4 , 14 , 17 , 18 ].…”

Section: An Introduction To the Next Generation Of Treatmentsmentioning

confidence: 99%

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Future Perspectives of Oral Delivery of Next Generation Therapies for Treatment of Skin Diseases

et al. 2021

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Gene therapies have conspicuously bloomed in recent years as evidenced by the increasing number of cell-, gene-, and oligo-based approved therapies. These therapies hold great promise for dermatological disorders with high unmet need, for example, epidermolysis bullosa or pachyonychia congenita. Furthermore, the recent clinical success of clustered regularly interspaced short palindromic repeats (CRISPR) for genome editing in humans will undoubtedly contribute to defining a new wave of therapies. Like biologics, naked nucleic acids are denatured inside the gastrointestinal tract and need to be administered via injections. For a treatment to be effective, a sufficient amount of a given regimen needs to reach systemic circulation. Multiple companies are racing to develop novel oral drug delivery approaches to circumvent the proteolytic and acidic milieu of the gastrointestinal tract. In this review, we provide an overview of the evolution of the gene therapy landscape, with a deep focus on gene and oligonucleotide therapies in clinical trials aimed at treating skin diseases. We then examine the progress made in drug delivery, with particular attention on the peptide field and drug-device combinations that deliver macromolecules into the gastrointestinal tract. Such novel devices could potentially be applied to administer other therapeutics including genes and CRISPR-based systems.

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Lipid Nanoparticle Technologies for Nucleic Acid Delivery: A Nanoarchitectonics Perspective

Ferhan

Park

et al. 2022

Adv Funct Materials

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Lipid-based nanoparticles have emerged as a clinically viable platform technology to deliver nucleic acids for a wide range of healthcare applications. Within this scope, one of the most exciting areas of recent progress and future innovation potential lies in the material science of lipid-based nanoparticles, both to refine existing nanoparticle strategies and to develop new ones. Herein, the latest efforts to develop next-generation lipid-based nanoparticles are covered by taking a nanoarchitectonics perspective and the design, nucleic acid encapsulation methods, scalable production, and application prospects are critically analyzed for three classes of lipid-based nanoparticles: 1) traditional lipid nanoparticles (LNPs); 2) lipoplexes; and 3) bicelles. Particular focus is placed on rationalizing how molecular self-assembly principles enable advanced functionalities along with comparing and contrasting the different nanoarchitectures. The current development status of each class of lipid-based nanoparticle is also evaluated and possible future directions in terms of overcoming clinical translation challenges and realizing new application opportunities are suggested.

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The current landscape of nucleic acid therapeutics

Cited by 759 publications

References 158 publications

Modulation of Colorectal Tumor Behavior via lncRNA TP53TG1-Lipidic Nanosystem

Modulation of Colorectal Tumor Behavior via lncRNA TP53TG1-Lipidic Nanosystem

Future Perspectives of Oral Delivery of Next Generation Therapies for Treatment of Skin Diseases

Lipid Nanoparticle Technologies for Nucleic Acid Delivery: A Nanoarchitectonics Perspective

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