# US 11,998,601 B2 · Messenger RNA therapy for treatment of articular disease

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- Number: US 11,998,601 B2
- Document ID: US11998601B2
- Status: Granted
- Kind: B2
- Application number: 17/117,981
- Filed: 2020-12-10
- Published: 2021-07-01
- Granted: 2024-06-04
- Earliest claimed: 2014-12-05
- Assignees: Translate Bio, Inc.
- Applicants: Translate Bio, Inc.
- Inventors: Frank DeRosa; Michael Heartlein
- Web page: https://patentgrep.com/patent/US11998601B2

## CPC

- A61K 39/3955: {against proteinaceous materials, e.g. enzymes, hormones, lymphokines}
- A61K 9/1272: comprising non-phosphatidyl surfactants as bilayer-forming substances, e.g. cationic lipids or non-phosphatidyl liposomes coated or grafted with polymers (lipids as modifying agents {A61K47/543})
- A61K 38/177: {Receptors; Cell surface antigens; Cell surface determinants}
- A61K 48/0025: {wherein the non-active part clearly interacts with the delivered nucleic acid}
- A61K 48/005: {characterised by an aspect of the 'active' part of the composition delivered, i.e. the nucleic acid delivered}
- A61K 48/0075: {characterised by an aspect of the delivery route, e.g. oral, subcutaneous}
- A61P 3/00: Drugs for disorders of the metabolism (of the blood or the extracellular fluid A61P7/00)
- A61P 17/06: Antipsoriatics
- A61P 19/02: for joint disorders, e.g. arthritis, arthrosis
- A61P 19/04: for non-specific disorders of the connective tissue
- A61P 19/06: Antigout agents, e.g. antihyperuricemic or uricosuric agents
- A61P 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- C07K 16/00: Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies
- A61K 48/00: Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy
- 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)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- C07K: PEPTIDES (peptides in foodstuffs A23; obtaining protein compositions for foodstuffs, working-up proteins for foodstuffs A23J; preparations for medicinal purposes A61K; peptides containing beta-lactam rings C07D; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, C07D; ergot alkaloids of the cyclic peptide type C07D519/02; macromolecular compounds having statistically distributed amino acid units in their molecules, i.e. when the preparation does not provide for a specific; but for a random sequence of the amino acid units, homopolyamides and block copolyamides derived from amino acids C08G69/00; macromolecular products derived from proteins C08H1/00; preparation of glue or gelatine C09H; single cell proteins, enzymes C12N; genetic engineering processes for obtaining peptides C12N15/00; compositions for measuring or testing processes involving enzymes C12Q; investigation or analysis of biological material G01N33/00)

## Abstract

The present invention provides, among other things, a method of intra-articular delivery of messenger RNA (mRNA), comprising administering into a joint of a subject in need of delivery a composition comprising an mRNA encoding a protein, such that the administering of the composition results in expression of the protein encoded by the mRNA in the joint.

## Claims

### Claim 1

A method for treating an articular disease, disorder or condition in a subject in need thereof, the method comprising administering into a joint of the subject a composition comprising one or more mRNAs encoding one or more polypeptides deficient in the articular disease, disorder, or condition, such that the administering of the composition results in increased expression or activity of the one or more proteins encoded by the one or more mRNAs in the joint sufficient to treat the protein deficiency,
wherein the one or more mRNAs are modified RNAs that comprise a backbone modification, a sugar modification, or a base modification,
wherein the mRNA encodes a wild-type or naturally occurring protein sequence that is normally present in a healthy joint, and
wherein the one or more mRNAs are encapsulated within one or more nanoparticles.

### Claim 2 (depends on 1)

The method of claim 1, wherein the composition is administered locally into the joint.

### Claim 3 (depends on 1)

The method of claim 1, wherein the composition is administered directly into the synovial cavity.

### Claim 4 (depends on 1)

The method of claim 1, wherein the expression and/or activity of the one or more polypeptides is detected in cartilage, ligament, muscle, synovial intimal cells, chondrocytes and/or fluids of the joint following administration.

### Claim 5 (depends on 1)

The method of claim 1, wherein the expression and/or activity of the one or more polypeptides is detectable at least about 6 hours, 12 hours, 18 hours, 24 hours, 2 days, 3 days, 4 days, 5 days, 6 days, 1 week, 2 weeks, 3 weeks, 4 weeks, or 1 month post-administration.

### Claim 6 (depends on 1)

The method of claim 1, wherein the one or more polypeptides encoded by the one or more mRNAs are anti-inflammatory.

### Claim 7 (depends on 1)

The method of claim 1, wherein the joint disease, disorder or condition is an inflammatory disease, disorder or condition.

### Claim 8 (depends on 7)

The method of claim 7, wherein the inflammatory disease, disorder or condition is arthritis.

### Claim 9 (depends on 1)

The method of claim 1, wherein the composition is administered once a week.

### Claim 10 (depends on 1)

The method of claim 1, wherein the composition is administered twice a month.

### Claim 11 (depends on 1)

The method of claim 1, wherein the composition is administered once a month.

### Claim 12 (depends on 1)

The method of claim 1, wherein the one or more nanoparticles comprise a liposome, and wherein the liposome comprises one or more cationic lipids, one or more non-cationic lipids, one or more cholesterol-based lipids and one or more PEG-modified lipids.

### Claim 13 (depends on 12)

The method of claim 12, wherein the one or more cationic lipids comprise cKK-E12:

### Claim 14 (depends on 1)

The method of claim 1, wherein the nanoparticles have a size less than about 40-100 nm.

### Claim 15 (depends on 1)

The method of claim 1, wherein the one or more mRNAs comprise a backbone modification selected from the group consisting of a modification of the phosphates of the backbone into methylphosphonates, methylphosphoramidates, phosphoramidates, phosphorothioates, cytidine 5′-O-(1-thiophosphate), boranophosphates, and positively charged guanidinium groups.

### Claim 16 (depends on 1)

The method of claim 1, wherein the one or more mRNAs comprise a sugar modification selected from the group consisting of 2′-deoxy-2′-fluoro-oligoribonucleotide (2′-fluoro-2′-deoxycytidine 5′-triphosphate, 2′-fluoro-2′-deoxyuridine 5′-triphosphate), 2′-deoxy-2′-deamine-oligoribonucleotide (2′-amino-2′-deoxycytidine 5′-triphosphate, 2′-amino-2′-deoxyuridine 5′-triphosphate), 2′-O-alkyloligoribonucleotide, 2′-deoxy-2′-C-alkyloligoribonucleotide (2′-O-methylcytidine 5′-triphosphate, 2′-methyluridine 5′-triphosphate), 2′-C-alkyloligoribonucleotide, and isomers thereof (2′-aracytidine 5′-triphosphate, 2′-arauridine 5′-triphosphate), and azidotriphosphates (2′-azido-2′-deoxycytidine 5′-triphosphate, 2′-azido-2′-deoxyuridine 5′-triphosphate).

### Claim 17 (depends on 1)

The method of claim 1, wherein the one or more mRNAs comprise a base modification selected from the group consisting of 2-amino-6-chloropurine riboside 5′-triphosphate, 2-aminoadenosine 5′-triphosphate, 2-thiocytidine 5′-triphosphate, 2-thiouridine 5′-triphosphate, 4-thiouridine 5′-triphosphate, 5-aminoallylcytidine 5′-triphosphate, 5-aminoallyluridine 5′-triphosphate, 5-bromocytidine 5′-triphosphate, 5-bromouridine 5′-triphosphate, 5-iodocytidine 5′-triphosphate, 5-iodouridine 5′-triphosphate, 5-methylcytidine 5′-triphosphate, 5-methyluridine 5′-triphosphate, 6-azacytidine 5′-triphosphate, 6-azauridine 5′-triphosphate, 6-chloropurine riboside 5′-triphosphate, 7-deazaadenosine 5′-triphosphate, 7-deazaguanosine 5′-triphosphate, 8-azaadenosine 5′-triphosphate, 8-azidoadenosine 5′-triphosphate, benzimidazole riboside 5′-triphosphate, N1-methyladenosine 5′-triphosphate, N1-methylguanosine 5′-triphosphate, N6-methyladenosine 5′-triphosphate, 06-methylguanosine 5′-triphosphate, pseudouridine 5′-triphosphate, puromycin 5′-triphosphate and xanthosine 5′-triphosphate.

### Claim 18 (depends on 1)

The method of claim 1, wherein modified nucleotide is selected from the group consisting of 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-deazaadenosine, 7-deazaguanosine, 8-oxoadenosine, 8-oxoguanosine, 0(6)-methylguanine, and/or 2-thiocytidine.