Inhaled siRNA Formulations for Respiratory Diseases: From Basic Research to Clinical Application
Abstract
:1. Introduction
2. Respiratory Diseases Treated with Inhaled siRNA Formulations
2.1. Lung Cancer
2.2. Respiratory Infection
Disease | Target | Administration | Delivery System | Ref. |
---|---|---|---|---|
Influenza | Nucleoprotein | Intranasal administration | Chitosan nanoparticles | [31] |
Influenza | Nucleoprotein, acidic polymerase | Intranasal administration | Oligofectamine | [32] |
H1N1 | Nucleoprotein, acidic polymerase | Inhalation | PH-responsive peptides | [33] |
RSV | N-protein | Intranasal administration | Naked siRNA | [34] |
RSV | RSV-protein | Intranasal administration | Naked siRNA | [35] |
RSV | NSP1 | Intranasal administration | Chitosan nanoparticles | [36] |
Pneumonia | TNF-α | Intratracheal delivery | RC-NCs | [30] |
Tuberculosis | TGFβ1 | Inhalation | Naked siRNA | [37] |
Tuberculosis | XCL1 | Oro-tracheal administration | Naked siRNA | [29] |
2.3. Chronic Respiratory Disease
Disease | Target | Administration | Delivery System | Ref. |
---|---|---|---|---|
Asthma | GATA3 | Inhalation | Tf-Mel-PEI | [40] |
Asthma | Chil3, Chil4 | Intratracheal Administration | HMG-OR | [43] |
Asthma | VDBP | Intra-tracheal instillation | DEXA-PEI | [44] |
Asthma | c-Kit | Intranasal administration | Modified siRNA | [45] |
Asthma | SOCS3 | Intranasal administration | Naked siRNA | [46] |
Asthma | Syk | Intranasal administration | Naked siRNA | [47] |
COPD | RIP2 | Intratracheal administration | Naked siRNA | [48] |
COPD | RPS3 | Intratracheal administration | Naked siRNA | [49] |
COPD/ILD | Cytokine Signaling | Nasal instillation | CaP-PLGA | [41] |
COPD | MAP3K19 | Intratracheal administration | Naked siRNA | [50] |
3. Inhaled siRNA Barriers
3.1. Pulmonary Barriers
3.1.1. Airway Defense
3.1.2. Alveolar Defense
3.2. Cell Barriers
4. siRNA Structural Modification
4.1. Ribose Modification
4.2. Phosphate Backbone Modification
4.3. Base Modification
5. siRNA Inhalation Delivery Systems
5.1. Lipid Nanoparticles
5.1.1. Liposomes
5.1.2. Solid Lipid Nanoparticles
5.1.3. Nanostructured Lipid Carriers
5.1.4. Nanoemulsions
5.2. Polymeric Nanoparticles
5.2.1. Polymeric Micelles
5.2.2. Polymer Nanocapsules
5.2.3. Nanospheres
5.2.4. Dendrimers
5.3. Pulmonary Surfactants
6. Clinical Application
Year | Therapeutic Name | Disease | Delivery Route | Phase Stage | Target | NCT ID | Ref. |
---|---|---|---|---|---|---|---|
2020 | ALN-HSD | NASH | Subcutaneous | I | HSD17B13 | NCT04565717 | [153] |
2020 | DCR-PHXC | PH3 | Subcutaneous | I | LDHA | NCT04555486 | [154] |
2019 | Vutrisiran | ATTR With Cardiomyopathy | Subcutaneous | III | TTR | NCT04153149 | [155] |
2019 | DCR-PHXC | PH1, PH2, Kidney Diseases | Subcutaneous | II | LDHA | NCT03847909 | [154] |
2018 | Lumasiran | PH1 | Subcutaneous | II | Glycolate oxidase | NCT03350451 | [156] |
2018 | DCR-HBVS | Chronic Hepatitis B | Subcutaneous | I | HBV transcripts | NCT03772249 | [157] |
2018 | siG12D-LODER | Pancreatic Cancer | Intravenous | II | KRAS G12D, all additional G12X mutations | NCT01676259 | [6] |
2018 | Inclisiran | ACD | Intravenous | III | PCSK9 | NCT03705234 | [158] |
2016 | ARC-AAT | AATD | Intravenous | II | Z-AAT | NCT02900183 | [159] |
2016 | ALN-HBV | HBV | Subcutaneous | I | HBV RNA | NCT02826018 | [160] |
2016 | DCR-PH1 | PH1 | Intravenous | I | GO | NCT02795325 | [161] |
2016 | ALN-TTRSC02 | ATTR Amyloidosis | Subcutaneous | I | TTR | NCT02797847 | [162] |
2015 | ARC-520 | Chronic Hepatitis B | Intravenous | II | HBV DNA | NCT02349126 | [163] |
2015 | ALN-CC5 | PNH | Subcutaneous | I, II | C5 | NCT02352493 | [164] |
2015 | Fitusiran | Hemophilia A, B | Subcutaneous | I, II | AT | NCT02554773 | [165] |
2015 | ALN-AS1 | AIP | Subcutaneous | I | ALAS1 | NCT02452372 | [166] |
2014 | SYL040012 | Open Angle Glaucoma | Ocular topical | II | ADRβ2 | NCT02250612 | [68] |
2014 | ALN-TTR02 | TTR-Mediated Amyloidosis | Intravenous | I | TTR | NCT02053454 | [167] |
2014 | ALN-PCSSC | Hypercholesterolemia | Subcutaneous | I | PCSK9 | NCT02314442 | [168] |
2013 | ALN-TTRSC | TTR-Mediated Amyloidosis | Subcutaneous | II | TTR | NCT01981837 | [169] |
2012 | SYL1001 | Ocular Pain | Ocular topical | I, II | TRPV1 | NCT01776658 | [170] |
2012 | AVI-7100 | Influenza | Intravenous | I | Influenza A M1/M2 | NCT01747148 | [171] |
Approval Date | Company | Therapeutic Name | Disease | Target | Delivery Route | Chemical Modification | Delivery System |
---|---|---|---|---|---|---|---|
August 2018 | Alnylam | Patisiran | hATTR | TTR | Intravenous | 2′-OMe modification | Second-generation LNPs |
November 2019 | Alnylam | Givosiran | AHP | ALAS1 | Subcutaneous | PS linkages, 2′-OMe, 2′-F modification | GalNAc ligand conjugate |
November 2020 | Alnylam | Lumasiran | PH1 | HAO1 | Subcutaneous | PS linkages, 2′-OMe, 2′-F modification | GalNAc ligand conjugate |
December 2020 | Alnylam Novartis | Inclisiran | ACD | PCSK9 | Subcutaneous | PS linkages, 2′-OMe, 2′-OMOE, 2′-F modification | GalNAc ligand conjugate |
7. Conclusions
Author Contributions
Funding
Conflicts of Interest
References
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Disease | Target | Administration | Delivery System | Ref. |
---|---|---|---|---|
MDR-lung cancer | ABCC3 | Inhalation | LPNs | [17] |
Lung adenocarcinoma | VEGF | Inhalation | UCNP | [18] |
Lung cancer | TUBB3 | Oro-tracheal administration | NPs | [19] |
Lung cancer | MRP1, BCL2 | Inhalation | NLC | [20] |
Lung cancer | Akt1 | Inhalation | Nanosized polymer | [21] |
Lung cancer | Mcl1 | Intratracheal Instillation | Nanoliposomes | [22] |
Lung metastasis | STAT3 | Inhalation | PFC | [23] |
NSCLC | EGFR-TKs | Inhalation | NLC | [15] |
NSCLC | MRP1, BCL2 | Inhalation | MSN | [24] |
Delivery Systems | Characteristics | |
---|---|---|
Advantages | Disadvantages | |
Liposome |
|
|
Solid lipid nanoparticle |
|
|
Nanostructured lipid carrier |
|
|
Nanoemulsion |
|
|
Polymeric micelle |
|
|
Polymer nanocapsule |
|
|
Nanosphere |
|
|
Dendrimer |
|
|
Pulmonary surfactant |
| / |
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Fan, Y.; Yang, Z. Inhaled siRNA Formulations for Respiratory Diseases: From Basic Research to Clinical Application. Pharmaceutics 2022, 14, 1193. https://doi.org/10.3390/pharmaceutics14061193
Fan Y, Yang Z. Inhaled siRNA Formulations for Respiratory Diseases: From Basic Research to Clinical Application. Pharmaceutics. 2022; 14(6):1193. https://doi.org/10.3390/pharmaceutics14061193
Chicago/Turabian StyleFan, Yulin, and Zhijun Yang. 2022. "Inhaled siRNA Formulations for Respiratory Diseases: From Basic Research to Clinical Application" Pharmaceutics 14, no. 6: 1193. https://doi.org/10.3390/pharmaceutics14061193
APA StyleFan, Y., & Yang, Z. (2022). Inhaled siRNA Formulations for Respiratory Diseases: From Basic Research to Clinical Application. Pharmaceutics, 14(6), 1193. https://doi.org/10.3390/pharmaceutics14061193