Lipid formulations for delivery of messenger RNA

• US 10,493,031 B2
• Filed: 07/03/2018
• Issued: 12/03/2019
• Est. Priority Date: 10/22/2013
• Status: Active Grant

• Current Assignee: Massachusetts Institute of Technology, Translate Bio, Inc. (Sanofi )
• Original Assignee: Translate Bio, Inc. (Sanofi )
• Inventors: Heartlein, Michael, Anderson, Daniel, Dong, Yizhou, DeRosa, Frank
• Primary Examiner(s): Shiao, Rei Tsang
• Application Number:
  US16/026,577
• Publication Number:
  US 20180369144A1
• Time in Patent Office: 518 Days
• CPC Class Codes: A61K 38/1709 from mammals
• CPC Class Codes: A61K 38/177 Receptors; Cell surface antigens; Cell surface determinants
• CPC Class Codes: A61K 38/4846 Factor VII (3.4.21.21); Factor IX (3.4.21.22); Factor Xa (3.4.21.6); Factor XI (3.4.21.27); Factor XII (3.4.21.38)
• CPC Class Codes: A61K 38/53 Ligases (6)
• CPC Class Codes: A61K 48/00 Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy
• CPC Class Codes: A61K 48/0033 the non-active part being non-polymeric
• CPC Class Codes: A61K 48/005 characterised by an aspect of the 'active' part of the composition delivered, i.e. the nucleic acid delivered
• CPC Class Codes: A61K 9/0019 Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner non-active ingredients are additionally classified in A61K47/00
• CPC Class Codes: A61K 9/0073 Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy; nasal sprays A61K9/0043; inhalation of vapours of volatile or heated drugs, e.g. essential oils or nicotine, A61K9/007; devices A61M
• CPC Class Codes: A61K 9/12 Aerosols; Foams A61K9/0043, A61K9/0056, A61K9/006, A61K9/0073 take precedence; spray-films A61K9/7015
• CPC Class Codes: A61K 9/1272 with substantial amounts of non-phosphatidyl, i.e. non-acylglycerophosphate, surfactants as bilayer-forming substances, e.g. cationic lipids with cholesterol as the only non-phosphatidyl surfactant A61K9/127; lipids as modifying agent A61K47/543
• CPC Class Codes: A61P 25/02 for peripheral neuropathies
• CPC Class Codes: A61P 7/04 Antihaemorrhagics; Procoagulants; Haemostatic agents; Antifibrinolytic agents

Abstract

The present invention provides, among other things, methods of delivering mRNA in vivo, including administering to a subject in need of delivery a composition comprising an mRNA encoding a protein, encapsulated within a liposome such that the administering of the composition results in the expression of the protein encoded by the mRNA in vivo, wherein the liposome comprises a cationic lipid of formula I-c:

or a pharmaceutically acceptable salt thereof.

Claims

1. A method of delivery of messenger RNA (mRNA) in vivo, comprising administering to a subject in need of delivery a composition comprising an mRNA encoding a human survival of motor neuron-1 (hSMN-1) protein, encapsulated within a liposome such that the administering of the composition results in the expression of the protein encoded by the mRNA in vivo;

wherein the liposome comprises a cationic lipid of formula I-c;

2. The method of claim 1, wherein the cationic lipid is cKK-E12:

3. The method of claim 1, wherein the liposome further comprises one or more non-cationic lipids, one or more cholesterol-based lipids and/or one or more PEG-modified lipids.

4. The method of claim 1, wherein the expression of the human survival of motor neuron-1 (hSMN-1) protein encoded by the mRNA is detectable in brain and cerebrospinal fluid.

5. The method of claim 1, wherein the mRNA comprises one or more modified nucleotides, and wherein the one or more modified nucleotides comprise pseudouridine, N-1-methyl-pseudouridine, 2-aminoadenosine, 2-thiothymidine, inosine, pyrrolo-pyrimidine, 3-methyl adenosine, 5-methylcytidine, C-5 propynyl-cytidine, C-5 propynyl-uridine, 2-aminoadenosine, C5-bromouridine, C5-fluorouridine, C5-iodouridine, C5-propynyl-uridine, C5-propynyl-cytidine, C5-methylcytidine, 2-aminoadenosine, 7-deazadenosine, 7-deazaguanosine, 8-oxoadenosine, 8-oxoguanosine, O(6)-methylguanine, and/or 2-thiocytidine.

6. A method of treating spinal muscular atrophy comprising:

administering to subject in need of treatment a composition comprising an mRNA encoding a human survival of motor neuron-1 (hSMN

     1) protein encapsulated within a liposome such that the administering of the composition results in the expression of the hSMN-1 protein encoded by the mRNA in one or more tissues affected by spinal muscular atrophy;

wherein the liposome comprises a cationic lipid of formula I-c;

7. The method of claim 6, wherein the cationic lipid is cKK-E12:

8. A composition for delivery of messenger RNA (mRNA) comprising an mRNA encoding a human survival of motor neuron-1 (hSMN-1) protein encapsulated within a liposome, wherein the liposome comprises a cationic lipid of formula I-c:

9. The composition of claim 8, wherein the cationic lipid is cKK-E12:

10. The composition of claim 8, wherein the liposome further comprises one or more non-cationic lipids, one or more cholesterol-based lipids and/or one or more PEG-modified lipids.

11. The composition of claim 10, wherein the cationic lipid constitutes about 30-50% of the liposome by molar ratio.

12. The composition of claim 8, wherein the liposome has a size less than about 250 nm, 200 nm, 150 nm, 100 nm, 75 nm, or 50 nm.

13. The composition of claim 8, wherein the composition is formulated for intrathecal administration.