Lipid nanoparticles for delivering modified RNA encoding a VEGF-A polypeptide
The disclosure relates to nanoparticles comprising a lipid component and a modified RNA encoding a VEGF-A polypeptide. Aspects of the disclosure further relate to uses of nanoparticles comprising a lipid component and a modified RNA encoding a VEGF-A polypeptide, for improving wound healing in a subject.
1. A lipid nanoparticle comprising
a modified mRNA comprising any one of SEQ ID NOs: 1 or 3-5, encoding a VEGF-A polypeptide of SEQ ID NO: 2.
2. The lipid nanoparticle of claim 1 , wherein the lipid nanoparticle has a mean diameter from about 50 nm to about 100 nm.
3. A pharmaceutical composition comprising
(a) at least one lipid nanoparticle comprising
a modified mRNA comprising any one of SEQ ID NOs: 1 or 3-5, encoding a VEGF-A polypeptide of SEQ ID NO: 2; and
(b) a pharmaceutically acceptable excipient.
4. The pharmaceutical composition of claim 3 , wherein the lipid nanoparticle has a mean diameter from about 50 nm to about 100 nm.
5. The pharmaceutical composition of claim 3 , wherein the pharmaceutically acceptable excipient is a solvent, dispersion media, diluent, dispersion, suspension aid, surface active agent, isotonic agent, thickening or emulsifying agent, preservative, polymer, peptide, protein, cell, hyaluronidase, or mixtures thereof.
6. A method for (i) promoting and/or improving wound healing, (ii) inducing neovascularization, (iii) inducing angiogenesis, or (iv) increasing capillary and/or arteriole density comprising administering to a human subject in need thereof an effective amount of the lipid nanoparticle of claim 1 .
7. The method of claim 6 , wherein the lipid nanoparticle has a mean diameter from about 70 nm to about 80 nm.
8. The method of claim 6 , wherein the administration results in a maximum observed plasma and/or tissue concentration (C max ) of the VEGF-A polypeptide of SEQ ID NO: 2 up to about 450 pg/ml plasma or pg/mg tissue.
9. The method of claim 6 , wherein the administration results in a plasma and/or tissue total area under the concentration curve (AUC 0-t ) of the VEGF-A polypeptide of SEQ ID NO: 2 up to about 5,500 pg*h/m1 plasma or pg*h/mg tissue.
10. The method of claim 6 , wherein the administration results in the production of more than about 400 pg/mg tissue of the VEGF-A polypeptide of SEQ ID NO: 2 within 8 hours.
11. The method of claim 6 , wherein the administration results in the production of more than about 1 pg/mg tissue of the VEGF-A polypeptide of SEQ ID NO: 2 for up to 6 days.
12. The method of claim 6 , wherein the lipid nanoparticle is administered intradermally.
13. The method of claim 6 , wherein the concentration of the modified mRNA is from about 0.01 mg/kg to about 10 mg/kg.
14. The method of claim 6 , wherein the administration results in an increase of the production of the VEGF-A polypeptide of SEQ ID NO: 2 by a factor of about 5 to about 100, when compared to an administration of the modified mRNA in a citrate saline buffer.
15. The method of claim 6 , wherein the human subject suffers from diabetes.
16. The method of claim 6 , wherein the human subject in need thereof has a wound, and wherein the wound is a surgical wound, a burn, an abrasive wound, a skin biopsy site, a chronic wound, an injury, a graft wound, a diabetic wound, a diabetic ulcer, a pressure ulcer, bed sore, and combinations thereof.