CFTR MRNA compositions and related methods and uses

• US 10,420,791 B2
• Filed: 06/16/2017
• Issued: 09/24/2019
• Est. Priority Date: 03/14/2013
• Status: Active Grant

• Current Assignee: Ethris Gmbh, Translate Bio, Inc. (Sanofi )
• Original Assignee: Translate Bio, Inc. (Sanofi )
• Inventors: Heartlein, Michael, Guild, Braydon Charles, DeRosa, Frank, Rudolph, Carsten, Plank, Christian, Smith, Lianne
• Primary Examiner(s): Chen, Shin Lin
• Application Number:
  US15/625,648
• Publication Number:
  US 20180015116A1
• Time in Patent Office: 830 Days
• Field of Search: 514 44 R, 435455, 536 235
• CPC Class Codes: A61K 31/7105 Natural ribonucleic acids, i.e. containing only riboses attached to adenine, guanine, cytosine or uracil and having 3'-5' phosphodiester links
• CPC Class Codes: A61K 31/7115 Nucleic acids or oligonucleotides having modified bases, i.e. other than adenine, guanine, cytosine, uracil or thymine
• CPC Class Codes: A61K 31/713 Double-stranded nucleic acids or oligonucleotides
• CPC Class Codes: A61K 47/6935 the polymer being obtained otherwise than by reactions involving carbon to carbon unsaturated bonds, e.g. polyesters, polyamides or polyglycerol
• 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 48/005 characterised by an aspect of the 'active' part of the composition delivered, i.e. the nucleic acid delivered
• 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 9/0078 for inhalation via a nebulizer such as a jet nebulizer, ultrasonic nebulizer, e.g. in the form of aqueous drug solutions or dispersions
• CPC Class Codes: A61K 9/127 Liposomes
• CPC Class Codes: A61K 9/1271 Non-conventional liposomes, e.g. PEGylated liposomes, liposomes coated with polymers liposome as conjugate A61K47/6911
• CPC Class Codes: A61K 9/5123 Organic compounds, e.g. fats, sugars
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07H 21/02 with ribosyl as saccharide radical
• CPC Class Codes: C07H 21/04 with deoxyribosyl as saccharide radical
• CPC Class Codes: C07K 14/4712 Cystic fibrosis
• CPC Class Codes: C07K 14/705 Receptors; Cell surface antigens; Cell surface determinants tumour specific antigens C07K14/4748
• CPC Class Codes: C12N 15/63 Introduction of foreign genetic material using vectors; Vectors; Use of hosts therefor; Regulation of expression
• CPC Class Codes: C12N 15/88 using microencapsulation, e.g. using amphiphile liposome vesicle
• CPC Class Codes: C12N 9/14 Hydrolases (3)
• CPC Class Codes: C12Y 306/03049 : Channel-conductance-controlling ATPase (3.6.3.49)

Abstract

The present invention is particularly useful for treating cystic fibrosis. The disclosure concerns method and compositions for treating cystic fibrosis. The method comprises inducing CFTR expression in epithelial cells in a lung of a mammal by contacting the epithelial cells in the lung of the mammal with a composition, where the composition is a pharmaceutical composition comprising in vitro transcribed mRNA.

Claims

1. A method of producing cystic fibrosis transmembrane conductance regulator (CFTR) protein in a lung of a mammal, the method comprising:

administering to the lung of the mammal by aerosolization a composition comprising an mRNA-loaded nanoparticle, wherein the nanoparticle is a liposome, wherein the mRNA is an in vitro transcribed mRNA and has a coding sequence at least 80% identical to SEQ ID NO;

3, wherein the mRNA encodes a human CFTR protein comprising the amino acid sequence of SEQ ID NO;

1, and wherein the mRNA is unmodified.

2. The method of claim 1, wherein the mRNA has the coding sequence at least 90% identical to SEQ ID NO:

3.

3. The method of claim 1, wherein the mRNA has the coding sequence 100% identical to SEQ ID NO:

3.

4. The method of claim 1, wherein the mRNA comprises a 5′

untranslated region (UTR) and/or a 3′

UTR.

5. The method of claim 4, wherein the 5′

-UTR comprises SEQ ID NO;

4 and/or the 3′

-UTR comprises SEQ ID NO;

5.

6. The method of claim 4, wherein the mRNA further comprises a poly-A tail.

7. The method of claim 6, wherein the poly-A tail is of at least 70, 100, 120, 150, 200, or 250 residues in length.

8. The method of claim 4, wherein the mRNA further comprises a 5′

cap.

9. The method of claim 1, wherein the aerosolization is nebulization.

10. The method of claim 1, wherein the human CFTR protein is expressed in the epithelial cells of the lung.

11. The method of claim 1, wherein the composition further comprises a pharmaceutically acceptable carrier.

12. The method of claim 1, wherein the liposome comprises one or more PEGylated lipids.

13. The method of claim 1, wherein the liposome further comprises one or more cationic lipids and one or more non-cationic lipids.