Non-Immunotherapy Application of LNP-mRNA: Maximizing Efficacy and Safety
Abstract
:1. Introduction
2. IVT mRNA and Byproducts Induced Immune Activation
3. LNP Induced Immune Activation
4. LNP-mRNA in RNA Protein Replacement and Other Non-Immunotherapy Applications
5. Boosting the Efficacy and Safety of LNP-mRNA Applications
5.1. mRNA Nucleoside Modification
5.2. mRNA Sequence and Structure Optimization
5.3. IVT mRNA Production and Purification Methods
5.4. LNP Optimization
6. Conclusions
Author Contributions
Funding
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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---|---|---|---|---|---|
LNP | Frataxin (FXN) | Friedreich’s ataxia | Pfizer | no | Nabhan et al., Scientific Reports, 2016 [81] |
LNP | Factor IX | Hemophilia B | Shire | no | DeRosa F. et al., Gene Therapy, 2016 [82] |
LNP | Factor IX | Hemophilia B | Arcturus | cytokines, liver toxicity, liver histopathology | Ramaswamy S. et al., PNAS 3, 2017 [83] |
LNP | cystic fibrosis trans-membrane conductance regulator (CFTR) | Cystic Fibrosis | Arcturus, Translate Bio | no | Robinson et al., Mol Therapy, 2018 [84] |
LNP | methylmalonyl-CoA mutase (MUT) | Methylmalonic Acidemia | Moderna | cytokines, ADA 1, liver toxicity | An D. et al., Cell reports, 2018 [85] |
LNP/ HMT 2 | ornithine transcarbamylase (OTC) | OTC Deficiency | PhaseRx | cytokines, liver toxicity, liver histopathology | Prieve M. et al., Molecular Therapy, 2018 [86] |
LNP | porphobilinogen deaminase (PBGD) | Acute intermittent porphyria | Moderna | liver toxicity, ADA 1 | Jiang L. et al., Nature Medicine, 2018 [87] |
LNP | disintegrin and metalloprotease with thrombospondin type 1 repeats, member 13 (ADAMTS13) | Thrombotic thrombocytopenic purpura | Alexion | no | Liu-Chen S. et al., Scientific Reports, 2018 [88] |
LNP | uridine-diphosphateglucuronosyltransferase (UGT1A1) | Crigler-Najjar Syndrome Type 1 | Alexion | no | Apgar J. et al., CPT Pharmacometrics Syst. Pharmacol, 2018 [89] |
LNP | serine protease inhibitor, group A, member 1 (SERPINA1) | Alpha-1 Antitrypsin Deficiency | Alexion | no | Connolly B. et al., Journal of Nucleic Acids, 2018 [90] |
LNP | glucose-6-phosphatase (G6Pase) | Glycogen storage disease type Ia | Alexion | no | Roseman D. et al., Molecular Therapy, 2018 [91] |
LNP | arginase I (ARG1) | Arginase I deficiency | Alexion | no | Asrani et al., RNA Biology, 2018 [92] |
LNP | citrin (aspartate/glutamate transporter) | Citrin deficiency | Moderna | no | Cao J. et al., Molecular Therapy, 2019 [93] |
LNP | alpha galactosidase A (a-Gal A) | Fabry Disease | Translate Bio, Shire | no | De Rosa et al., Molecular Therapy, 2019 [94] |
LNP | oxysterol 7-a-hydroxylase (CYP7B1) | Hereditary Spastic Paraplegia Type 5 | CureVac | liver toxicity | Hauser S. et al., Molecular Therapy, 2019 [95] |
LNP | alpha galactosidase A (a-Gal A) | Fabry Disease | Moderna | liver toxicity, ADA 1 | Zhu et al., The American Journal of Human Genetics, 2019 [96] |
LNP | arginase 1 (ARG1) | Arginase deficiency | Moderna | liver histopathology | Truong B. et al., PNAS3, 2019 [97] |
LNP | methylmalonyl-CoA mutase (MUT) | Methylmalonic Acidemia | Moderna | liver toxicity, liver histopathology | An et al., EbioMedicine, 2019 [98] |
LNP | galactose-1 phosphate uridylyltransferase (GALT) | Galactosemia | Moderna | no | Balakrishnan B. et al., Molecular Therapy, 2020 [99] |
LNP | serine protease inhibitor, group A, member 1 (SERPINA1) | Alpha-1 Antitrypsin Deficiency | Moderna | liver toxicity, liver histopathology | Karadagi A. et al., Scientific Reports, 2020 [100] |
Drug Candidate | Animal, Dose, Time | Cytokines/Chemokines | Significant Upregulation Compared to Control | Assay | Reference |
---|---|---|---|---|---|
LNP-Factor IX mRNA | mouse, 4 mg/kg i.v.; 4 h, 7 h, 24 h and 48 h after third dose | IL-1α, IL-1β, IL-2, IL-3, IL-4, IL-5, MIP-1α, IL-10, IL-12 p40, IL-12 p70, IL-13, IL-17α, G-CSF, GM-CSF, IFNγ, KC, MCP-1, MIP-1β, RANTES, TNFα, IL-6, Eotaxin | yes (4 h and 7 h): G-CSF, MCP-1, MIP-1β, IL-6, RANTES; no (24 h and 48 h) | Biorad multiplex | Ramaswamy S. et al., PNAS, 2017 [83] |
LNP-MUT 1 mRNA | mouse, 0.2 mg/kg i.v.; 24 h after third or fifth weekly dose | IL-6, IFNγ, TNFα, IL-1β | no (24 h) | MSD 4 multiplex | An D., et al., Cell reports, 2018 [85] |
LNP/HMT 2 OTC 3 mRNA | mouse, 3 mg/kg i.v.; 3 h and 24 h after ninth repeat dose | IL-6, IL-12, GM-CSF, IFNγ, TNFα, CXCL10, MCP-1 | yes (3 h and 24 h): IL-12 | Luminex multiplex, ELISA 5 (CXCL10) | Prieve M. et al., Molecular Therapy, 2018 [86] |
Candidate | Biological Target | Disease | Company | Year Start | Clinical Phase | Number |
---|---|---|---|---|---|---|
MRT5005 | CFTR 1 | Cystic Fibrosis | Translate Bio | 2017 | Phase 1/2 | NCT03375047 |
MRT5201 | OTC 2 | OTC Deficiency | Translate Bio | 2018 | Phase 1/2 | NCT03767270 (program discontinued) |
mRNA-3704 | MUT 3 | Methylmalonic Acidemia | ModernaTX, Inc. | 2019 | Phase 1/2 | NCT03810690 EU 2019-001061-32 (Terminated due to business decision) |
mRNA-3927 | PCCA and PCCB 4 | Propionic Acidemia | ModernaTX, Inc. | 2019 (US), 2020 (EU) | Phase 1/2 | NCT04159103 (not yet recruiting) EU 2019-003529-36 |
ARCT-810 | OTC 2 | OTC Deficiency | Arcturus | 2020 | Phase 1 |
NCT04416126 (completed, healthy adult subjects)
NCT04442347 (recruiting) |
Drug Candidate | Biological Target | Disease | Company | Website |
---|---|---|---|---|
LUNAR-CF | CFTR 1 | Cystic Fibrosis | Arcturus | https://arcturusrx.com/pipeline/ |
LUNAR-CV | undisclosed | rare cardiovascular disease | Arcturus | https://arcturusrx.com/pipeline/ |
undisclosed | CFTR 1 | Cystic Fibrosis | Translate Bio | https://translate.bio/pipeline/ |
undisclosed | undisclosed | Primary Ciliary Dyskinesia | Translate Bio | https://translate.bio/pipeline/ |
undisclosed | undisclosed | Pulmonary Arterial Hypertension | Translate Bio | https://translate.bio/pipeline/ |
undisclosed | undisclosed | Idiopathic Pulmonary Fibrosis | Translate Bio | https://translate.bio/pipeline/ |
undisclosed | undisclosed | Ocular diseases | CureVac | https://www.curevac.com/en/pipeline/ |
undisclosed | undisclosed | Lung respiratory diseases | CureVac | https://www.curevac.com/en/pipeline/ |
BNT171 | undisclosed | undisclosed | BioNTech/Genevant | https://biontech.de/de/science/pipeline |
4 rare disease indications | undisclosed | undisclosed | BioNTech/Genevant | https://biontech.de/de/science/pipeline |
mRNA-3283 | PAH 2 | Phenylketonuria | Moderna | https://www.modernatx.com/pipeline |
mRNA-3745 | G6Pase 3 | Glycogen Storage Disorder Type 1a | Moderna | https://www.modernatx.com/pipeline |
AZD7970 | Relaxin-2 | Heart Failure | Moderna/AstraZeneca | https://www.modernatx.com/pipeline |
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Vlatkovic, I. Non-Immunotherapy Application of LNP-mRNA: Maximizing Efficacy and Safety. Biomedicines 2021, 9, 530. https://doi.org/10.3390/biomedicines9050530
Vlatkovic I. Non-Immunotherapy Application of LNP-mRNA: Maximizing Efficacy and Safety. Biomedicines. 2021; 9(5):530. https://doi.org/10.3390/biomedicines9050530
Chicago/Turabian StyleVlatkovic, Irena. 2021. "Non-Immunotherapy Application of LNP-mRNA: Maximizing Efficacy and Safety" Biomedicines 9, no. 5: 530. https://doi.org/10.3390/biomedicines9050530