A Novel Family of Small Molecules that Enhance the Intracellular Delivery and Pharmacological Effectiveness of Antisense and Splice Switching Oligonucleotides

Wang, Ling; Ariyarathna, Yamuna; Xin, Ming; Yang, Bing; James, Lindsey I.; Kreda, Silvia M.; Porter, Melissa A.; Janzen, William P.; Juliano, Rudolph L.

doi:10.1021/acschembio.7b00242

Cited by 23 publications

(33 citation statements)

References 32 publications

(98 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Thus, several groups have recently explored the use of small molecules to enhance the effectiveness of oligonucleotides ( 23 , 24 ). In our case we previously used high throughput screening to identify two novel families of oligonucleotide enhancing compounds (OECs) ( 22 , 25 ).…”

Section: Discussionmentioning

confidence: 99%

Structure–activity relationships and cellular mechanism of action of small molecules that enhance the delivery of oligonucleotides

Juliano

Tavares

Brown

et al. 2018

Nucleic Acids Research

Self Cite

View full text Add to dashboard Cite

The pharmacological effects of antisense and siRNA oligonucleotides are hindered by the tendency of these molecules to become entrapped in endomembrane compartments thus failing to reach their targets in the cytosol or nucleus. We have previously used high throughput screening to identify small molecules that enhance the escape of oligonucleotides from intracellular membrane compartments and have termed such molecules OECs (oligonucleotide enhancing compounds). Here, we report on the structure–activity relationships of a family of OECs that are analogs of a hit that emerged from our original screen. These studies demonstrate key roles for the lipophilic aromatic groups, the tertiary nitrogen, and the carbamate moiety of the parent compound. We have also investigated the intracellular site of action of the OECs and have shown that activity is due to the release of oligonucleotides from intermediate endosomal compartments rather than from early endosomes or from highly acidic downstream compartments. At high concentrations of OECs toxicity occurs in a manner that is independent of caspases or of lysosomal cathepsins but instead involves increased plasma membrane permeability. Thus, in addition to describing specific characteristics of this family of OECs, the current study provides insights into basic mechanisms of oligonucleotide trafficking and their implications for oligonucleotide delivery.

show abstract

Section: Discussionmentioning

confidence: 99%

Structure–activity relationships and cellular mechanism of action of small molecules that enhance the delivery of oligonucleotides

Juliano

Tavares

Brown

et al. 2018

Nucleic Acids Research

Self Cite

View full text Add to dashboard Cite

show abstract

“…We then tested three additional small molecules from a structurally-related family (UNC10217938A, UNC2383, and UNC4267 - Fig. 2a,b) which were previously identified to enhance the delivery of splice-switching oligonucleotides and ASOs by inducing endomembrane permeabilisation 27,28 . The response to UNC compounds was rapid with maximal mCherry-GAL9 recruitment occurring at 1-3 h post-dosing (Fig.…”

Section: Mcherry-gal9 Is Recruited To Small Molecule Induced Damagementioning

confidence: 99%

A high-throughput Galectin-9 imaging assay for quantifying nanoparticle uptake, endosomal escape and functional RNA delivery

Munson

O’Driscoll

Silva

et al. 2020

Preprint

View full text Add to dashboard Cite

RNA-based therapies have great potential to treat many undruggable human diseases. However, their efficacy, in particular for mRNA, remains hampered by poor cellular delivery and limited endosomal escape. Advances in the development and rational optimisation of delivery vectors, such as lipid nanoparticles (LNPs), are impeded by the limited availability of screening methods that probe the intracellular processing of LNPs in sufficient detail. We have developed a high-throughput imaging-based endosomal escape assay utilising a Galectin-9 reporter and fluorescently labelled mRNA to probe correlations between nanoparticle-mediated uptake, endosomal escape frequency, and mRNA translation. This assay has, furthermore, been integrated with a screening platform for nanoparticle formulation to optimise LNPs. We show that Galectin-9 recruitment is a robust, quantitative reporter of endosomal escape events induced by different mRNA delivery nanoparticles and small molecules. We also identify nanoparticles with superior escape properties and demonstrate significant cell line variances in endosomal escape response, highlighting the need for fine-tuning of delivery formulations for specific applications.

show abstract

“…Barriers to successful pulmonary delivery of nucleic acids the help of a high-throughput screen of chemical libraries. These molecules substantially enhanced the pharmacological activities of oligonucleotides both in cell culture and murine model (28,29). Although these endosomolytic agents significantly enhanced the delivery efficiency, they currently display a narrow therapeutic window for clinical use.…”

Section: Intracellular Barriers To Overcomementioning

confidence: 99%

Nucleic Acid-Based Therapeutics for Pulmonary Diseases

et al. 2018

View full text Add to dashboard Cite

Nucleic acid-based therapeutics present huge potential in the treatment of pulmonary diseases ranging from lung cancer to asthma and chronic pulmonary diseases, which are often fatal and widely prevalent. The susceptibility of nucleic acids to degradation and the complex structure of lungs retard the effective pulmonary delivery of nucleic acid drug. To overcome these barriers, different strategies have been exploited to increase the delivery efficiency using chemically synthesized nucleic acids, vector encapsulation, proper formulation, and administration route. However, several limitations regarding off-target effects and immune stimulation of nucleic acid drugs hamper their translation into the clinical practice. Therefore, their successful clinical application will ultimately rely on well-developed carriers and methods to ensure safety and efficacy. In this review, we provide a comprehensive overview of the nucleic acid application for pulmonary diseases, covering action mechanism of the nucleic acid drugs, the novel delivery systems, and the current formulation for the administration to lungs. The latest advances of nucleic acid drugs under clinical evaluation to treat pulmonary disorders will also be detailed.KEY WORDS: nucleic acid; antisense oligonucleotide (ASO); short interfering RNA (siRNA); microRNA (miRNA); pulmonary diseases.

show abstract

A Novel Family of Small Molecules that Enhance the Intracellular Delivery and Pharmacological Effectiveness of Antisense and Splice Switching Oligonucleotides

Cited by 23 publications

References 32 publications

Structure–activity relationships and cellular mechanism of action of small molecules that enhance the delivery of oligonucleotides

Structure–activity relationships and cellular mechanism of action of small molecules that enhance the delivery of oligonucleotides

A high-throughput Galectin-9 imaging assay for quantifying nanoparticle uptake, endosomal escape and functional RNA delivery

Nucleic Acid-Based Therapeutics for Pulmonary Diseases

Contact Info

Product

Resources

About