WO2020053200A1

WO2020053200A1 - Peptides for use in treatment of psoriasis

Info

Publication number: WO2020053200A1
Application number: PCT/EP2019/074088
Authority: WO
Inventors: Tommy Andersson
Original assignee: Wntresearch AB
Current assignee: Wntresearch AB
Priority date: 2018-09-10
Filing date: 2019-09-10
Publication date: 2020-03-19
Anticipated expiration: 2021-03-10

Abstract

The present application relates to Wnt5A peptides and derivatives thereof for use in the treatment of psoriasis. The Wnt5A peptide comprises XADGXBEL, wherein XA is methionine (M) or norleucine, XB is cysteine (C) or alanine (A), and wherein said Wnt5A peptide has a t-butoxycarbonyl protecting group in amino acid position 1. Amino acid residues of said Wnt5A peptide are either in the L- or D-stereoisomeric form and the total length of the peptide is equal to or less than 50 amino acids.

Description

Title of Invention

Peptides for use in Treatment of Psoriasis. Technical Field

The present invention relates to Wnt5A peptides, and derivatives thereof for use in the treatment of psoriasis. The present invention also re- lates to compositions for the treatment of psoriasis. Furthermore, this inven- tion relates to a composition for the administration of the Wnt5A peptide sys- temically or topically.

Background Art

Psoriasis is a chronic, noncontagious, autoimmune and multisystem disease, which most commonly manifests itself on the skin by red, raised plaques and papules with silvery and/or whitish scales. According to the Na- tional Institutes of Health (NIH), approximately 2.2% of the United States population has psoriasis. The incidence varies greatly among populations, from around 0.1 % to 3%, with approximately 2-3% of people being affected worldwide. Psoriatic patients have increased risk of early mortality and may develop comorbidities such as psoriatic arthritis, cardiovascular disease, and diabetes.

In moderate-to-severe cases the disease may cover large areas of skin, including areas such as the hands and face. In general, the disease is associated with anxiety, depression, and social isolation, and can negatively impact patients' personal relationships and professional careers.

The pathogenesis of this disease is not completely understood and multiple potential triggers of the disease have been hypothesized including trauma, stress and infection. It is believed that once triggered, keratinocyte proliferation is induced by a large number activated T cells that infiltrate the epidermis. A deregulated inflammatory process ensues with a significant pro- duction of cytokines, e.g. tumour necrosis factor-a [TNF-a], interferon- gamma, interleukin-12.

At large, most of the clinical features of psoriasis are explained by the significant production of cytokine mediators. Other key findings in the skin include vascular engorgement as a result of superficial blood vessel dilation, and altered epidermal cell cycle. Epidermal hyperplasia causes accelerated cell turnover rate, leading to improper cell maturation. Inadequate release of lipids from affected epidermal cells leads to poorly adherent stratum corneum forming the flaking, whitish and silvery scaly presentation of psoriasis lesions.

Currently, treatments for psoriasis include topical therapy, photothera- py, and non-biologic and biologic systemic drugs.

One example treatment utilises infliximab. A meta-analysis reported infliximab to be the most efficacious TNF-a inhibiting biological agent, in terms of mean psoriasis area and severity index. However, infliximab is adminis- tered intravenously, and patients generally does not prefer subcutaneous bio- logics. Moreover, although biologic agents present the most efficacious treatment currently available, a significant proportion of psoriatic patients do not respond or only partially respond to biological agents, or, over time, expe- rience a loss of responsiveness compared to the initial response.

Studies have shown that patient satisfaction with current treatments are low and therapy switching is common. There is therefore an ongoing need for alternative or improved means for treatment of psoriasis.

The present invention has been made from a consideration of this.

Summary of Invention

Thus, according to a first aspect of the present invention, there is provided a Wnt5A peptide and derivatives thereof for use in the treatment of psoriasis, the Wnt5A peptide comprising XADGXBEL (SEQ. ID. NO. 2), where- in XA is methionine (M) or norleucine, XB is cysteine (C) or alanine (A), wherein said Wnt5A peptide has a t-butoxycarbonyl protecting group in amino acid position 1 , wherein the amino acid residues of said Wnt5A peptide, ex- cept glycine, are either in the L- or D-stereoisomeric form, and wherein the total length of the peptide is equal to or less than 50 amino acids.

The inventors of the present invention have surprisingly found that Wnt5A peptides and derivatives of the form outlined above can be used in the treatment of psoriasis. The mechanism underlying this is not at present well understood. However, it is believed that t-butoxycarbonyl protected Wnt5A peptides act as an antagonist, thereby resulting in blockage of the Wnt5A hoh-b-catenin dependent signalling pathway in the affected cells.

In some embodiments, the total length of the peptide is equal to or less than 20 amino acids.

In one embodiment of the invention, the Wnt5A peptide or any deriva- tives thereof for use in the treatment of psoriasis comprises the amino acid sequence MDGCEL, wherein the Wnt5A peptide has a t-butoxycarbonyl pro- tecting group in amino acid position 1.

In another embodiment, at least one Wnt5A peptide and derivatives thereof for use in the treatment of psoriasis, is selected from the group con- sisting of:

MDGCEL (SEQ. ID. NO. 3),

GMDGCEL (SEQ. ID. NO. 4),

EGMDGCEL (SEQ. ID. NO. 5),

SEGMDGCEL (SEQ. ID. NO. 6),

TSEGMDGCEL (SEQ. ID. NO. 7),

KTSEGMDGCEL (SEQ. ID. NO. 8),

NKTSEGMDGCEL (SEQ. ID. NO. 9),

CNKTSEGMDGCEL (SEQ. ID. NO. 10),

LCNKTSEGMDGCEL (SEQ. ID. NO. 11 ),

RLCNKTSEGMDGCEL (SEQ. ID. NO. 12),

GRLCNKTSEGMDGCEL (SEQ. ID. NO. 13),

QGRLCNKTSEGMDGCEL (SEQ. ID. NO. 14),

TQGRLCNKTSEGMDGCEL (SEQ. ID. NO. 15),

GTQGRLCNKTSEGMDGCEL (SEQ. ID. NO. 16), and

LGTQGRLCNKTSEGMDGCEL (SEQ. ID. NO. 17),

wherein said Wnt5A peptide has a t-butoxycarbonyl protecting group in amino acid position 1.

In yet another embodiment, the Wnt5A peptide and derivatives thereof for use in the treatment of psoriasis the peptide is hexapeptide MDGCEL, wherein M of the hexapeptide has a t-butoxycarbonyl protecting group (SEQ. ID. NO. 3). This particular hexapeptide is also denoted BOX5.

It is further contemplated that the Wnt5A peptide and derivatives thereof for use in the treatment of psoriasis, and wherein said Wnt5A peptide has a t-butoxycarbonyl protecting group in amino acid position 1 , may corn- prise the amino acid sequence MDGAEL, NleDGAEL or NleDGCEL, wherein Nle is norleucine.

Furthermore, the Wnt5A peptide according to the invention may be used in the treatment of psoriasis, wherein the psoriasis is vulgaris/plaque, guttate, inverse, pustular, palmoplantar or erythrodermic psoriasis.

The Wnt5A peptide according to the invention may be formulated for systemically, locally or topically administration.

For the purpose of this invention, the pharmaceutically acceptable agent can be administered by various routes, either systemically or topically. The suitable administration forms include, for example, oral formulations; par- enteral injections including intravenous, intramuscular, intradermal and sub- cutaneous injections; and mucosal, topical, transdermal, inhalation, nasal or rectal formulations. Particularly suitable formulations are formulations for local delivery such as topical formulations in the form of ointments, gels, creams, pastes, solutions, suspensions, lotions and emulsions.

The required dosage of the Wnt5A peptide will vary with the particular condition being treated, the severity of the condition, the duration of the treatment, the administration route and the specific compound being em- ployed. The amount of the Wnt5A peptide in the formulation according to the invention can typically range from 100 to 3,200 pg/mL, for example 200, 500, 800, 1 ,600, 1 ,800, 2,000, 2500 or 3,000 pg/mL. In one preferred embodiment, the formulation is a topical formulation comprising 800 pg/mL of Wnt5A. The Wnt5A peptide may be administered once to four times a day and until symp- toms disappear.

In another aspect of the invention is provided a composition comprising a therapeutically active amount of the Wnt5A peptide or derivatives thereof according to the invention and at least one carrier component. In another embodiment where the peptide is for systemic or locally administration, the composition according to the invention comprises a carrier component that comprises one or more pharmaceutically acceptable excipi- ents adapted for systemically administration. Such carrier components suita- ble for both local and systemic administration may be chosen from the group of vesicular systems such as transfersomes, ethosomes, penetration enhanc- er-containing vesicles (PEVs), or surfactant based systems such as micro- emulsions, or polymeric nanoparticles such as dendrimers.

In another embodiment where the peptide is for topical administration, the composition according to the invention comprises a carrier component that comprises one or more pharmaceutically acceptable excipients adapted for topical administration. Such carrier components for topical administration may be chosen from the group of liposomes, niosomes, solid lipid nanoparti- cles (SLNs), nanostructured lipid carriers (NLCs), lipospheres, nanoemul- sions, polymeric micelles, polymeric nano and microsperes, nanocapsules. The SLNs may be triglycerides, carnauba wax, beeswax, cetyl alcohol, emul- sifying wax, cholesterol, or cholesterol butyrate. NLCs are tailored SLNs (oil loaded SLNs) composed of solid lipid matrix incorporating a liquid lipid such as soya bean oil, oleic acid, corn oil in the presence of an emulsifier. Owing to their highly lipidic and non-flexible nature, SLNs and NLCs are confined to the topical rather than the transdermal treatment of skin diseases.

The composition according to the invention may be for use in topical administration and may be in form of cream, gel, ointment, paste, lotion, spray, solution, suspension, emulsion and roll-on formulations.

In further embodiments, the composition comprises a Wnt5A peptide or derivatives thereof wherein XA is M and XB is C and, optionally, the peptide is selected from the group consisting of:

MDGCEL (SEQ. ID. NO. 3),

GMDGCEL (SEQ. ID. NO. 4),

EGMDGCEL (SEQ. ID. NO. 5),

SEGMDGCEL (SEQ. ID. NO. 6),

TSEGMDGCEL (SEQ. ID. NO. 7), KTSEGMDGCEL (SEQ. ID. NO. 8),

NKTSEGMDGCEL (SEQ. ID. NO. 9),

CNKTSEGMDGCEL (SEQ. ID. NO. 10),

LCNKTSEGMDGCEL (SEQ. ID. NO. 11 ),

RLCNKTSEGMDGCEL (SEQ. ID. NO. 12),

GRLCNKTSEGMDGCEL (SEQ. ID. NO. 13),

QGRLCNKTSEGMDGCEL (SEQ. ID. NO. 14),

TQGRLCNKTSEGMDGCEL (SEQ. ID. NO. 15),

GTQGRLCNKTSEGMDGCEL (SEQ. ID. NO. 16), and

LGTQGRLCNKTSEGMDGCEL (SEQ. ID. NO. 17).

In further embodiments, the composition comprises a Wnt5A peptide or derivatives thereof wherein

XA is M and XB is A, or

XA is norleucine and XB is A, or

XA is norleucine and XB is C.

In yet an aspect of the invention a pad, patch, strip, or bandage corn- prising a Wnt5A peptide or composition according to the invention is provided.

Brief Description of Figures

The invention will be described in more detail below by means of non- limiting example of embodiments and with reference to the figures, in which: Fig. 1 shows Box5 as a Wnt5a antagonist by inhibiting Wnt5a-mediated Ca²⁺ signalling in skin cells.

(A) Preincubation with Box5 (100 mM) overnight blocks rWnt5a-induced (0.1 pg/mL) Ca²⁺ release, which an essential signal of the hoh-b-catenin signalling pathway. Representative Ca²⁺ traces of A2058 cells stimulated with rWnt5a (first arrow), and then with either endothelin-1 (ET-1 ; 10 nM) or carbacol (5 pM) (second arrow). (B) Accumulated ACa²⁺ changes in ratio values recorded from A2058 cells stimulated with the various ligands described for A, either in the presence or absence of 100 mM Box5. Error bars, SEM. Paired t-test; ^***, P<0.001.

(C) Preincubation with Box5 (100 pM) overnight inhibits myristoylated alanine- rich C kinase substrate (MARCKS) phosphorylation after 45 min of rWnt5a stimulation (0.2 pg/mL). 1 nM of the PKC activator, phorbol 12-myristate 13- acetate (PMA) was used as a positive indicator for MARCKS phosphorylation.

Fig. 2 shows examples of the sectioned and stained animal skin samples at 20x magnification.

(A) epidermis thickness of imiquimod-treated skin

(B) Wnt5A staining of imiquimod-treated skin.

(C) epidermis thickness of vehicle-treated skin.

(D) Wnt5A staining of vehicle-treated skin

Fig. 3 shows the average of epidermic thickness and Wnt5A staining of skin from vehicle-treated (normal skin) and imiquimod-treated (psoriasis- like skin) mice.

Fig. 4 shows the average of epidermic thickness of skin from 4 different mice treated with imiquimod and Box5 (the dotted line indicates the thickness of only imiquimod-treated mice).

Detailed Description

Definitions

In the context of the present disclosure, the following definitions are in tended. The term“peptide” refers to a compound consisting of two or more amino ac- ids linked in a chain, the carboxyl group of each acid being joined to the ami- no group of the next by a bond of the type -OC-NH-.

The term“polypeptide” refers to a chain in which there are numerous linked amino acids.

The term“hexapeptide” refers to a subset of peptides in which there are six amino acids linked in a chain. Other examples include“dipeptides” in which there are two amino acids,“tripeptides” in which there are three amino acids and so forth.

The N-terminal or N-terminus is the end of the peptide chain with a free amine (-NH2) group.

The C-terminal of C-terminus is the end of the peptide chain with a free car- boxyl (-COOH) group.

A t-butoxycarbonyl, or tert-butoxycarbonyl (t-BOC) group is a protecting group having the following structure:

- (C=0)-0-C(CH₃)3

An agonist is a species that binds to a receptor and activates the receptor to produce a biological response. In contrast, an antagonist is a species that blocks or dampens a biological response by blocking downstream Wnt- 5a signalling, such as Ca²⁺ and PKC signalling.

Single letter codes have been used to represent the amino acids, as is usual in the field.

The term“systemic administration” is a route of administration of an active ingredient, i.e. Wnt5A peptide, into the circulatory system so that the entire body is affected. Administration can take place via enteral administration, i.e. absorption of the drug through the gastrointestinal tract, or parenteral admin- istration, i.e. generally injection, infusion, or implantation.

The term“topical administration” means application to body surfaces such as the skin or mucous membranes in order to treat a disease such as psoriasis.

Examples

Example 1 : Ability of Box5 to reduce the Wnt5a signalling pathway in skin cells.

Materials and Methods:

Cells, Chemicals, and Peptides

Details of cells, culture conditions, and chemicals are provided in SI Materials and Methods. The Box5 peptide was synthesized by Inbiolabs (sev- eral different production batches of the peptides were used). Peptides were purified by reverse-phase high performance liquid chromatography and the purity of each synthesis was >95% (mass spectrometry, Inbiolabs).

Determination of Cytosolic Free Calcium Levels

This was carried out as previously described (Dejmek J, Safholm A, Kamp Nielsen C, Andersson T, Leandersson K (2006) Wnt-5a/Ca2+-induced NFAT activity is counteracted by Wnt-5a/Yes-Cdc42-casein kinase 1 alpha signaling in human mammary epithelial cells. Mol Cell Biol 26:6024- 6036). Fura-2 fluorescence was measured during stimulations with Wnt5a, endothelin-1 , or carbachol. Cells were stimulated with half the concentration of rWnt5a as used for most other assays, so that similar Ca²⁺ responses as with ET-1 (10 nM) and carbachol (5 mM) could be observed. For experiments with the intracellular Ca²⁺ chelator MAPT/AM, cells were incubated with 10 mM MAPT/AM in Ca²⁺-containing medium for 30 min, after initial incubation with 4 pM Fura- 2/AM. All Ca²⁺ traces shown are representative of a minimum of three repeats for each experimental condition tested.

Western Blotting Cells were lysed in 50 mM Tris-HCI (pH 7.5), 1 % Triton X-100,100 mM NaCI, 10 mM MgCI2, 20% glycerol, 1 mM Na3V04, and protease inhibi tors (20 pg/rriL aprotinin, 1 pg/rriL leupeptin, 2.5 mM benzamidine, and 2 mM pefbloc), and spun at 15,000 rpm for 5 min at 4 °C. For blotting of secreted proteins, cell medium was first concentrated in Amicon Ultra-15 concentrator columns (Millipore), according to the manufacturer’s instructions. Immunoblot- ting was conducted as previously described (Safholm A, Leandersson K, Dejmek J, Nielsen CK, Villoutreix BO, Andersson T (2006) A formylated hex- apeptide ligand mimics the ability of Wnt-5a to impair migration of human breast epithelial cells. J Biol Chem 281 :2740-2749).

Statistical Analysis

Means and standard error of the means (SEM; indicated as error bars on all graphs), were calculated and plotted using GraphPad Prism 4. Several repeats were carried out of each experiment (all experiments were conducted at least in triplicate). Two-tailed, unpaired t-tests were used to de- termine the significance of experimental data. The following symbols were used to denote statistical significance on the graphs: ^*, P < 0.05; ^**, P < 0.01 ; ***, P < 0.001.

Results:

The ability of Box5 to modulate Wnt5a-induced Ca²⁺ signalling in melanoma cells was analysed. Box5 was shown to selectively inhibit Wnt5a-induced in- tracellular Ca²⁺ signalling, but not the intracellular Ca²⁺ signalling induced by endothelin-1 (ET-1 ) or carbachol (Fig. 1A), both of which trigger G protein coupled receptor-induced increases in cytosolic Ca²⁺. Accumulated results revealed that there was >70% inhibition of Wnt5a-induced Ca²⁺ signalling by Box5, but the peptide had no such effect on the Ca²⁺ signal induced by either ET-1 or carbachol (Fig. 1 B).

Previous studies have suggested that there is a downstream effect of Wnt5a-induced Protein Kinase C (PKC) activation on the regulation of mela- noma cell migration. In the present study, we assessed Ser-152/156 phos- phorylations of the endogenous PKC substrate, Myristoylated Alanine-Rich C Kinase Substrate (MARCKS), as a direct means of estimating the level of PKC activity. Wnt5a stimulation of A2058 cells resulted in increased phos- phorylation of MARCKS, which was inhibited in the presence of the Box5 pep- tide (Fig. 1 C).

Conclusion:

The Box5 peptide significantly and selectively inhibited Wnt5a- induced Ca²⁺ and PKC signalling, both of which are necessary for Wnt5a- mediated functional responses. Thus, Box5 functions as a selective antago- nist of Wnt5a-induced melanoma cell migration and invasion by inhibiting Wnt5a signalling in skin cells.

Example 2: A thicker epidermis and increased Wnt5a is found in animals topically treated with imiquimod, a compound used to induce psoriasislike conditions in animals.

Methods:

C57BL/6 mice were topically treated with vehicle/control or an imiquimod so- lution. The solutions were applied on the shaved and depilated backs of the animals. The animals were treated once daily for 6 days before the experi- ments were terminated on day 7. Samples from vehicle and imiquimod treat- ed skin were fixed and embedded in paraffin. These embedded samples were sectioned (3-4 pm) and stained with Hematoxylin & Eosin (H&E) or with an anti-Wnt5a antibody. The samples were scored blindly.

Results:

Fig. 2 shows examples of the sectioned and stained animal skin samples at 20x magnification. Fig. 2 (A) shows the epidermis thickness in imiquimod- treated skin, where a thickness of the epidermis is marked with a green line, showing in this sample a thickness of 110.4 pm. Fig. 2 (B) shows Wnt5a staining of imiquimod-treated skin. Fig. 2 (C) shows the epidermis thickness of normal not imiquimod-treated skin where the thickness of the epidermis is marked with a green line, showing in this sample a thickness of 23.77 pm. Fig. 2 (D) shows Wnt5a staining of normal not imiquimod-treated skin. This sample has markedly less Wnt5A staining than that seen in imiquimod-treated skin as outlined in Fig. 2 (B). Also in this sample we determined the thickness of the epidermis, marked with a green line, showing in this sample a thickness of 19.82 pm.

Fig. 3 outlines the accumulated data of epidermic thickness and Wnt5A stain- ing of skin from control not-imiquimod-treated mice and imiquimod-treated mice, respectively.

Conclusion:

Animals treated with imiquimod have a much thicker epidermis, which is a characteristic of psoriasis lesions. The samples from these animals also revealed an increased Wnt5a staining - that is similar to previously pub- lished data from human psoriasis lesions (Romanowska M, Evans A, Kellock D, Bray SE, McLean K, Donandt S, Foerster J.“Wnt5a exhibits layer-specific expression in adult skin, is upregulated in psoriasis, and synergizes with type 1 interferon”, PLoS One. 2009;4(4):e5354. doi: 10.1371/journal. pone.0005354. Epub 2009 Apr 28). This suggest that in- creased expression and signaling of Wnt5a play an essential role in the path- ogenesis of psoriasis in both humans and in the imiquimod experimental pso- riasis model in mice, thus arguing for the use of a Wnt5a antagonist such as Box5 in the future treatment of psoriasis

Example 3: Box5 does not increase the thickness of epidermis in psoriasis-like lesions in Imiquimod treated mice.

Methods:

C57BL/6 mice were topically treated with an imiquimod solution daily for six days. The solutions were applied on the shaved and depilated backs of the animals. These lesions were then treated twice a day with Box5 (80 mg/100 mI dissolved in 5% methylcellulose and 2% PEG40) for 5 days. Skin samples from imiquimod-induced and Box5 treated skin were fixed and embedded in paraffin. These embedded samples were sectioned (3-4 pm) and stained with Hematoxylin & Eosin (H&E). The thickness of the epidermis layer was meas- ured at 15 different locations in each skin sample from imiquimod-induced lesions treated with Box5.

Results:

The average of Epidermic thickness of skin of 4 imiquimod and Box5 treated mice is shown in Fig. 4. Conclusion:

Animals (n=4) first treated with imiquimod followed by Box5 (seen in Fig. 4) appeared to have an average epidermis thickness which is closer to that of animals treated with vehicle (n=3) than that of animals treated with imiquimod (n=3), seen in Fig. 3.

Claims

C L A I M S

1. A Wnt5A peptide and derivatives thereof for use in the treatment of psoria sis,

the Wnt5A peptide comprising XADGXBEL (SEQ. ID. NO. 2), wherein XA is methionine (M) or norleucine,

XB is cysteine (C) or alanine (A),

wherein said Wnt5A peptide has a t-butoxycarbonyl protecting group in amino acid position 1 ,

wherein the amino acid residues of said Wnt5A peptide, except gly cine, are either in the L- or D-stereoisomeric form, and

wherein the total length of the peptide is equal to or less than 50 amino acids.

2. Wnt5A peptide and derivatives thereof for use in the treatment of psoriasis according to claim 1 , wherein the total length of the peptide is equal to or less than 20 amino acids.

3. A Wnt5A peptide and derivatives thereof for use in the treatment of psoria sis according to claim 1 or 2, wherein XA is M and XB is C.

4. A Wnt5A peptide and derivatives thereof for use in the treatment of psoria sis according to any of Claims 1 to 3, wherein at least one peptide is selected from the group consisting of:

MDGCEL (SEQ. ID. NO. 3),

GMDGCEL (SEQ. ID. NO. 4),

EGMDGCEL (SEQ. ID. NO. 5),

SEGMDGCEL (SEQ. ID. NO. 6),

TSEGMDGCEL (SEQ. ID. NO. 7),

KTSEGMDGCEL (SEQ. ID. NO. 8),

NKTSEGMDGCEL (SEQ. ID. NO. 9),

CNKTSEGMDGCEL (SEQ. ID. NO. 10),

LCNKTSEGMDGCEL (SEQ. ID. NO. 1 1 ), RLCNKTSEGMDGCEL (SEQ. ID. NO. 12),

GRLCNKTSEGMDGCEL (SEQ. ID. NO. 13),

QGRLCNKTSEGMDGCEL (SEQ. ID. NO. 14),

TQGRLCNKTSEGMDGCEL (SEQ. ID. NO. 15),

GTQGRLCNKTSEGMDGCEL (SEQ. ID. NO. 16), and

LGTQGRLCNKTSEGMDGCEL (SEQ. ID. NO. 17).

5. A Wnt5A peptide and derivatives thereof for use in the treatment of psoria sis according to any of Claims 1 to 4, wherein the peptide is hexapeptide MDGCEL (SEQ. ID. NO. 3).

6. A Wnt5A peptide and derivatives thereof for use in the treatment of psoria sis according to Claim 1 or 2, wherein XA is M and XB is A.

7. A Wnt5A peptide and derivatives thereof for use in the treatment of psoria sis according to Claim 1 or 2, wherein XA is norleucine and XB is C.

8. A Wnt5A peptide and derivatives thereof for use in the treatment of psoria sis according to Claim 1 or 2, wherein XA is norleucine and XB is A.

9. A Wnt5A peptide and derivatives thereof for use in the treatment of psoria sis according to any preceding claim, wherein the psoriasis is vulgaris/plaque, guttate, inverse, pustular, palmoplantar or erythrodermic psoriasis.

10. A composition comprising:

a therapeutically active amount of a Wnt5A peptide or derivatives thereof,

the Wnt5A peptide comprising XADGXBEL (SEQ. ID. NO. 1 ), wherein XA is M or norleucine,

XB is C or A, and

wherein XA has a t-butoxycarbonyl protecting group; and at least one carrier component, wherein the carrier component comprises one or more pharmaceutically acceptable excipients adapted for systemic or topical administration.

1 1. The composition according to Claim 10, wherein the amount of the Wnt5A peptide range from 100-3,200 pg/mL, preferably 800 pg/mL.

12. The composition according to Claims 10-1 1 , wherein the means of topical administration is selected from the group consisting of cream, ointment, lo tion, spray and roll-on formulations.

13. The composition according to Claims 10 to 12, wherein XA IS M and XB is C and, optionally, at least one peptide is selected from the group consisting of:

MDGCEL (SEQ. ID. NO. 3),

GMDGCEL (SEQ. ID. NO. 4),

EGMDGCEL (SEQ. ID. NO. 5),

SEGMDGCEL (SEQ. ID. NO. 6),

TSEGMDGCEL (SEQ. ID. NO. 7),

KTSEGMDGCEL (SEQ. ID. NO. 8),

NKTSEGMDGCEL (SEQ. ID. NO. 9),

CNKTSEGMDGCEL (SEQ. ID. NO. 10),

LCNKTSEGMDGCEL (SEQ. ID. NO. 1 1 ),

RLCNKTSEGMDGCEL (SEQ. ID. NO. 12),

GRLCNKTSEGMDGCEL (SEQ. ID. NO. 13),

QGRLCNKTSEGMDGCEL (SEQ. ID. NO. 14),

TQGRLCNKTSEGMDGCEL (SEQ. ID. NO. 15),

GTQGRLCNKTSEGMDGCEL (SEQ. ID. NO. 16), and

LGTQGRLCNKTSEGMDGCEL (SEQ. ID. NO. 17).

14. A composition according to any one of Claims 10 to 13, wherein:

XA is M and XB is A, or

XA is norleucine and XB is A, or XA is norleucine and XB is C.

15. A pad, patch, strip, or bandage comprising a composition according to any of Claims 10 to 14.