# US 10,245,229 B2 · Pulmonary delivery of mRNA to non-lung target cells

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- Number: US 10,245,229 B2
- Document ID: US10245229B2
- Status: Granted
- Kind: B2
- Application number: 14/406,504
- Filed: 2013-06-07
- Published: 2015-06-11
- Granted: 2019-04-02
- Earliest claimed: 2012-06-08
- Assignees: Translate Bio, Inc.; ethris GmbH
- Applicants: Shire Human Genetic Therapies, Inc.; Ethris GmbH
- Inventors: Michael Heartlein; Braydon Charles Guild; Frank DeRosa; Carsten Rudolph; Christian Plank
- Web page: https://patentgrep.com/patent/US10245229B2

## CPC

- 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)}
- A61K 31/7088: Compounds having three or more nucleosides or nucleotides
- A61M 15/009: {using medicine packages with incorporated spraying means, e.g. aerosol cans (pocket atomiser of the injector type A61M11/08)}
- A61M 16/14: by mixing different fluids, one of them being in a liquid phase
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C12N 15/88: using microencapsulation, e.g. using {amphiphile} liposome vesicle
- A61K 48/0075: {characterised by an aspect of the delivery route, e.g. oral, subcutaneous}
- A61K 2039/53: {DNA (RNA) vaccination}
- A61K 2039/544: {to the airways}
- A61K 2039/6018: {Lipids, e.g. in lipopeptides}
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61M: DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY (introducing media into or onto the bodies of animals A61D7/00; means for inserting tampons A61F13/26; devices for administering food or medicines orally A61J; containers for collecting, storing or administering blood or medical fluids A61J1/05); DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY (surgery A61B; chemical aspects of surgical articles A61L); DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR {(Electrotherapy, e.g. producing anaesthesia by the use of alternating or intermittent currents A61N1/36021)}
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- C12N: MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA (microbiological testing media C12Q1/00)

## Abstract

Compositions comprising mRNA formulated for pulmonary administration and related methods for delivery of the mRNA and/or encoded protein to a non-lung cell or tissue. The compositions and methods may be used to prevent or ameliorate the symptoms of diseases associated with the mRNA encoded protein.

## Claims

### Claim 1

A method of delivery of messenger RNA (mRNA) to a non-lung cell or tissue comprising administering to the lung by nebulization a composition comprising mRNA encoding a protein and a lipid carrier vehicle comprising one or more PEG-modified lipids, wherein the administering to the lung results in the delivery of the mRNA to a non-lung cell or tissue, and wherein the protein encoded by the mRNA is detectable in the non-lung cell or tissue for at least 6 hours following the administration to the lung.

### Claim 2 (depends on 1)

The method of claim 1, wherein the non-lung cell is selected from the group consisting of hepatocytes, epithelial cells, hematopoietic cells, epithelial cells, endothelial cells, bone cells, stem cells, mesenchymal cells, neural cells, cardiac cells, adipocytes, vascular smooth muscle cells, cardiomyocytes, skeletal muscle cells, beta cells, pituitary cells, synovial lining cells, ovarian cells, testicular cells, fibroblasts, B cells, T cells, reticulocytes, leukocytes, granulocytes, macrophages, neutrophils, antigen presenting cells (dendritic cells), fibroblasts, tumor cells and combination thereof.

### Claim 3 (depends on 1)

The method of claim 1, wherein the non-lung tissue is selected from the group consisting of heart, liver, spleen, kidneys, skeletal muscle, lymph nodes, skin, brain, cerebrospinal fluid, plasma and combination thereof.

### Claim 4 (depends on 1)

The method of claim 1, wherein the mRNA encodes a protein selected from the group consisting of a cytosolic protein, a secreted protein and a therapeutic protein.

### Claim 5 (depends on 4)

The method of claim 4, wherein the cytosolic protein is selected from the group consisting of enzymes, transcription factors, chaperones, and combination thereof.

### Claim 6 (depends on 4)

The method of claim 4, wherein the therapeutic protein is selected from the group consisting of alpha galactosidase, erythropoietin, a1-antitrypsin, carboxypeptidase N, alpha-L-iduronidase, iduronate-2-sulfatase, N-acetylglucosamine-1-phosphate transferase, N-acetylglucosaminidase, lysosomal acid lipase, arylsulfatase-A alpha-glucosaminide acetyltransferase, N-acetylglucosamine 6-sulfatase, N-acetylgalactosamine-4-sulfatase, beta-glucosidase, galactose-6-sulfate sulfatase, beta-galactosidase, beta-glucuronidase, glucocerebrosidase, heparan sulfamidase, hyaluronidase, galactocerebrosidase, human growth hormone, ornithine transcarbamylase (OTC), carbamyl phosphate synthetase-1 (CPS1), argininosuccinate synthetase-1 (ASS1), argininosuccinate lyase (ASL), arginase-1 (ARG1), cystic fibrosis transmembrane conductance regulator (CFTR), Factor VII, Factor VIII, Factor IX, heparan-N-sulfatase, and combination thereof.

### Claim 7 (depends on 1)

The method of claim 1, wherein the protein is detectable in the non-lung cell or tissue for at least about 1 day or for at least about 2 days following the administration to the lung.

### Claim 8 (depends on 1)

The method of claim 1, wherein the mRNA is delivered at an amount greater than about 0.5 mg/kg of mRNA per dose.

### Claim 9 (depends on 1)

The method of claim 1, wherein the lipid carrier vehicle is a liposome.

### Claim 10 (depends on 9)

The method of claim 9, wherein the liposome further comprises one or more cationic lipids, one or more non-cationic lipids, and one or more cholesterol-based lipids.

### Claim 11 (depends on 10)

The method of claim 10, wherein the one or more cationic lipids are selected from the group consisting of C12-200, HGT4003, HGT5000, HGT5001, ICE, DLinKC2-DMA, DODAP, DODMA, DLinDMA, CLinDMA, and combination thereof.

### Claim 12 (depends on 1)

The method of claim 1, wherein the composition further comprises one or more pulmonary surfactants.

### Claim 13 (depends on 1)

The method of claim 1, wherein the composition is formulated as respirable particles.

### Claim 14 (depends on 13)

The method of claim 13, wherein the respirable particles have a size less than about 500 μm.

### Claim 15 (depends on 1)

The method of claim 1, wherein the composition is formulated as nebulizable lipid or as dry powder.

### Claim 16 (depends on 1)

The method of claim 1, wherein the non-lung cell or tissue is affected by a disease or disorder.

### Claim 17 (depends on 16)

The method of claim 16, wherein the disease or disorder is selected from Table 4.

### Claim 18 (depends on 1)

The method of claim 1, wherein the mRNA is unmodified.