Systemic delivery of factor IX messenger RNA for protein replacement therapy
| Autor: | Nina Tonnu, Jerel Vega, Suvasini Ramaswamy, Pad Chivukula, Pattraranee Limphong, Inder M. Verma, Priya Prakash Karmali, Kiyoshi Tachikawa |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Male medicine.medical_treatment Drug Compounding Drug Evaluation Preclinical 02 engineering and technology Pharmacology Biology Hemophilia B Hepatic Diseases law.invention Factor IX 03 medical and health sciences Mice Immune system Protein replacement therapy law In vivo medicine Animals Humans RNA Messenger Mice Knockout Messenger RNA Drug Carriers Multidisciplinary Genetic Therapy Hydrogen-Ion Concentration 021001 nanoscience & nanotechnology Recombinant Proteins Disease Models Animal 030104 developmental biology Cytokine Cholesterol PNAS Plus Liver Immunology Injections Intravenous Recombinant DNA Phosphatidylcholines Cytokines Nanoparticles Female 0210 nano-technology medicine.drug |
| Popis: | Safe and efficient delivery of messenger RNAs for protein replacement therapies offers great promise but remains challenging. In this report, we demonstrate systemic, in vivo, nonviral mRNA delivery through lipid nanoparticles (LNPs) to treat a Factor IX (FIX)-deficient mouse model of hemophilia B. Delivery of human FIX (hFIX) mRNA encapsulated in our LUNAR LNPs results in a rapid pulse of FIX protein (within 4–6 h) that remains stable for up to 4–6 d and is therapeutically effective, like the recombinant human factor IX protein (rhFIX) that is the current standard of care. Extensive cytokine and liver enzyme profiling showed that repeated administration of the mRNA–LUNAR complex does not cause any adverse innate or adaptive immune responses in immune-competent, hemophilic mice. The levels of hFIX protein that were produced also remained consistent during repeated administrations. These results suggest that delivery of long mRNAs is a viable therapeutic alternative for many clotting disorders and for other hepatic diseases where recombinant proteins may be unaffordable or unsuitable. |
| Databáze: | OpenAIRE |
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