# US 2022/0031807 A1 · Methods and pharmaceutical composition reducing skin inflammation

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- Number: US 2022/0031807 A1
- Document ID: US20220031807A1
- Status: Published application
- Kind: A1
- Application number: 17/280,550
- Filed: 2019-09-26
- Published: 2022-02-03
- Earliest claimed: 2018-09-27
- Assignees: Inserm (Institut National De La Sante Et De La Recherche Medicale); Universite D'Aix-Marseille; Centre National de la Recherche Scientifique (CNRS)
- Applicants: INSERM (Institut National de la Santé et de la Recherche Médicale; Université d'Aix Marseille; Centre National De La Recherche Scientifique (Cnrs)
- Inventors: Sophie UGOLINI; Guihaume DEBROAS; Guillaume HOEFFEL; Abdelaziz MOQRICH
- Web page: https://patentgrep.com/patent/US20220031807A1

## CPC

- A61K 38/195: {Chemokines, e.g. RANTES}
- A01K 67/0275: Genetically modified vertebrates, e.g. transgenic
- A01K 67/0276: Knock-out vertebrates
- A61K 31/573: substituted in position 21, e.g. cortisone, dexamethasone, prednisone or aldosterone
- A61K 35/761: Adenovirus
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- A61P 17/00: Drugs for dermatological disorders
- A61P 17/02: for treating wounds, ulcers, burns, scars, keloids, or the like
- A61P 17/06: Antipsoriatics
- A61P 17/10: Anti-acne agents
- A61P 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- A01K 2217/052: inducing gain of function
- A01K 2217/075: inducing loss of function, i.e. knock out
- A01K 2217/206: Animal model comprising tissue-specific expression system, e.g. tissue specific expression of transgene, of Cre recombinase
- A01K 2227/105: Murine
- A01K 2267/03: Animal model, e.g. for test or diseases
- A01K 2267/0368: Animal model for inflammation
- A61K 9/0014: {Skin, i.e. galenical aspects of topical compositions (non-active ingredients are additionally classified in A61K47/00; A61K9/0009, A61K9/0021, A61K9/7015, A61K9/7023 take precedence; cosmetic preparations A61K8/00, A61Q; preparations for wound dressings or bandages A61L26/00)}
- A61K 9/7023: {Transdermal patches and similar drug-containing composite devices, e.g. cataplasms (galenical aspects of iontophoretic devices A61K9/0009; microneedle arrays A61K9/0021; buccal patches A61K9/006)}
- C07K 2319/30: Non-immunoglobulin-derived peptide or protein having an immunoglobulin constant or Fc region, or a fragment thereof, attached thereto
- 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)
- A01K: ANIMAL HUSBANDRY; AVICULTURE; APICULTURE; PISCICULTURE; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
- 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 skin is one of first lines of defense against external threats. Tissue-resident macrophages have pivotal functions in tissue-barrier integrity and homeostasis. Upon skin inflammation, a functional crosstalk between the sensory nervous system and tissue-resident immune cells can regulate cutaneous immune responses. However, depending on the pathological context, sensory neurons display pro- or anti-inflammatory regulatory properties. Here the inventors identify, in a model of ultraviolet (UV)-induced skin N damage, a regulatory role for type C low-threshold mechanoreceptor (C-LTMR) sensory neurons on the dynamic of dermal macrophage replacement by inflammatory monocytes through the neuropeptide TAFA4. Tafa4-KO mice present an unresolved fibrotic dermis after UV irradiation. Increased fibrotic score correlates with the upstream persistency of inflammatory monocytes and their MHC-II+ macrophage progeny. Bone marrow chimera revealed that inflammatory monocyte differentiation towards CD206+ dermal macrophage is increased in Tafa4KO recipient. Finally, intradermal injection of TAFA4 at the site of UV irradiation reduces inflammatory monocytes accumulation and skin inflammation in Tafa4-KO mice. The results provide new insight about tissue-resident macrophages dynamic during the resolution of skin fibrosis and thus renders credible the use of TAFA4 for the treatment of skin inflammation.

## Claims

### Claim 1

A method of reducing skin inflammation in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a TAFA4 polypeptide or a nucleic acid molecule encoding the TAFA4 polypeptide.

### Claim 2 (depends on 1)

The method of claim 1 wherein the subject suffers from an inflammatory skin disease.

### Claim 3 (depends on 1)

The method of claim 1 wherein the subject suffers from an inflammatory skin disease selected from the group consisting of acne, rosacea, folliculitis, perioral dermatitis, photodamage, skin aging, psoriasis, ichtiosis, chronic wounds, bed sores, keratosis piralis, scars, including surgical and acne scars, sebaceous cysts, inflammatory dermatoses, post inflammatory hyperpigmentation, xerosis, pruritis, lichen planus, nodular prurigo, eczema, and miliaria.

### Claim 4 (depends on 1)

The method of claim 1 wherein the subject suffers from an inflammatory skin disease selected from the group consisting of scleroderma, atopic dermatitis, nephrogenic fibrosing dermopathy, mixed connective tissue disease, scleromyxedema, scleredema, keloid, sclerodactyly, and eosinophilic fasciitis.

### Claim 5 (depends on 1)

The method of claim 1 wherein the subject suffers from photodermatitis.

### Claim 6 (depends on 1)

The method of claim 1 wherein the subject suffers from a chronic wound.

### Claim 7 (depends on 1)

The method of claim 1 wherein the subject suffers from venous stasis ulcers or diabetic foot ulcers.

### Claim 8 (depends on 6)

The method of claim 6, wherein the chronic wound occurs in a subject suffering from sickle-cell disease or in an elderly subject.

### Claim 9

(canceled)

### Claim 10 (depends on 1)

The method of claim 1 wherein the TAFA4 polypeptide comprises a sequence having at least 90% sequence identity to the sequence as set forth in SEQ ID NO: 1.

### Claim 11 (depends on 1)

The method of claim 1 wherein the TAFA4 polypeptide is fused to an immunoglobulin constant domain to constitute an immunoadhesin.

### Claim 12 (depends on 1)

The method of claim 1 wherein the nucleic acid molecule is included in a vector.

### Claim 13 (depends on 1)

The method of claim 1 wherein the TAFA4 polypeptide or the nucleic acid molecule encoding thereof are formulated for topical administration.

### Claim 14 (depends on 13)

The method of claim 13 wherein the topical administration is performed via a transdermal device or a patch device.

### Claim 15 (depends on 1)

The method of claim 1 wherein the TAFA4 polypeptide or the nucleic acid molecule encoding the TAFA4 polypeptide is administered with at least one other active agent.

### Claim 16 (depends on 12)

The method of claim 12, wherein the vector is a viral vector.

### Claim 17 (depends on 16)

The method of claim 16, wherein the viral vector is an adeno-associated virus (AAV) vector.

### Claim 18 (depends on 15)

The method of claim 15, wherein the at least one other active agent is a glucocorticoid.

### Claim 19

A method of preventing skin fibrosis in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a TAFA4 polypeptide or a nucleic acid molecule encoding the TAFA4 polypeptide.