HK1166278A

HK1166278A - Prophylactic or therapeutic agent for retinal diseases and method for preventing or treating retinal diseases, each comprising jnk (c-jun n-terminal kinase)-inhibiting peptide, and use of the peptide

Info

Publication number: HK1166278A
Application number: HK12107061.5A
Authority: HK
Inventors: 平井慎一郎; 松下登起义; 藤田由纪惠; 仓岛宏明; 大桥康司
Original assignee: 参天制药株式会社
Priority date: 2009-03-30
Filing date: 2010-03-25
Publication date: 2012-10-26

Description

Prophylactic or therapeutic agent for retinal diseases and method for preventing or treating retinal diseases using JNK (c-Jun amino terminal kinase) inhibitory peptide and use of the peptide

Technical Field

The present invention relates to a prophylactic or therapeutic agent for a retinal disease, which comprises a JNK inhibitory peptide comprising a specific amino acid sequence, which is less than 150 amino acids in length, and which comprises at least one dextrorotatory amino acid, as an active ingredient. The present invention also relates to a method for preventing or treating retinal diseases using such JNK inhibitory peptides. Furthermore, the present invention relates to the use of such JNK inhibitory peptides for the preparation of a prophylactic or therapeutic agent for retinal diseases.

Background

Retinal disease is a member of the most important family of diseases in the field of ophthalmology. Many retinal diseases are difficult to treat and severe symptoms that can cause blindness are also frequent. Representative examples of retinal diseases include age-related macular degeneration (hereinafter also referred to as "AMD"), diabetic retinopathy, central exudative chorioretinopathy, angioid streaks, retinal pigment epithelium detachment, multifocal choroiditis, retinopathy of prematurity, retinitis pigmentosa, leber's disease, retinal artery occlusion, retinal vein occlusion, central serous chorioretinopathy, giant retinal aneurysm, retinal detachment, proliferative vitreoretinopathy, recessive macular dystrophy, choroidal sclerosis, choroideremia, vitelliform macular dystrophy, ministomal disease, ichthyoid fundus oculi, ichthyoid retinal degeneration, and convoluted choroidal retinal atrophy. Neovascular maculopathy caused by high myopia, optic disc tilt syndrome, choroidal osteoma, and the like is also known as a retinal disease affecting vision.

Currently, there is a need to develop drugs effective in preventing or treating these retinal diseases. In particular, age-related macular degeneration and diabetic retinopathy are major causes of blindness from middle-aged to elderly in developed countries such as western countries and japan, and are thus considered as diseases of great importance both in ophthalmology and in society.

Age-related macular degeneration (also sometimes considered equivalent to age-related macular degeneration) is classified as: "atrophic AMD", which causes atrophy of the retinal pigment epithelium and choroidal capillaries; "exudative AMD" in which choroidal neovascularization progresses from the choroid to the macular region, causing hemorrhagic and exudative damage, and ultimately the formation of scar tissue. The rare type of exudative age-related macular degeneration known as "polypoidal choroidal vasculopathy" is also known. Polypoidal choroidal vasculopathy causes the choroidal vessels below the retina to dilate in the form of polyps, which can cause subretinal bleeding, resulting in the development of pathological conditions similar to those of age-related macular degeneration. The early stages of age-related macular degeneration, in which drusen and retinal pigment epithelium abnormalities are observed, are particularly referred to as "early age-related macular degeneration".

In addition, diabetic retinopathy is a retinal vascular disorder that is a complication of diabetes. Diabetic retinopathy is generally classified into the following three categories: "simple retinopathy" in which retinal macroaneurysm, retinal hemorrhage, retinal edema, and the like are observed; "proliferative retinopathy" accompanied by neovascularization, vitreous hemorrhage, tractional retinal detachment, and the like; and "pre-proliferative retinopathy", which lies between the two types. In the pathological condition of diabetic retinopathy, since macular edema caused by an increase in vascular permeability greatly affects vision, the pathological condition of diabetic retinopathy accompanied with macular edema is sometimes particularly referred to as "diabetic macular edema".

Retinal diseases other than age-related macular degeneration and diabetic retinopathy will be described further below.

With respect to central exudative chorioretinopathy, angioid streaks, retinal pigment epithelium detachment, and multifocal choroiditis, choroidal neovascularization is thought to be deeply involved in the pathological conditions of all these diseases, which are also known as the cause of neovascular maculopathy. Similarly, in ocular diseases such as high myopia, optic disc tilt syndrome and choroidal osteoma, choroidal neovascularization is sometimes observed, and these diseases sometimes progress to neovascular maculopathy. It is well known that abnormal vascular proliferation (neovascularization) is the cause of retinopathy of prematurity. That is, this choroidal neovascularization is thought to be involved in the visual deterioration observed in the above-mentioned diseases.

Retinitis pigmentosa and lyers disease are known to be diseases in which retinal pigment epithelial cells and photoreceptors are damaged, and blindness initially occurs, followed by progressive visual field narrowing. It is also known that, similar to retinal artery occlusion, photoreceptors are damaged by ischemia caused by occluded blood vessels.

Recessive macular dystrophy, choroidal sclerosis, choroideremia, vitelliform macular dystrophy, koilotoid disease, ichthyoid fundus oculi and ichthyoid retinal degeneration are all diseases which cause hypopsia caused by atrophy, degeneration and other damages of retinal pigment epithelium. That is, it has been pointed out that degeneration of the retinal pigment epithelium is the cause of latent macular dystrophy, and atrophy of the retinal pigment epithelium is one cause of the onset of choroidal sclerosis and choroideremia. On the other hand, although the pathological conditions of vitelliform macular dystrophy, microcutzfeldt disease, ichthyoid fundus and ichthyoid retinal degeneration have not been elucidated, damage to retinal pigment epithelium is still considered as one cause of these diseases.

Convoluted choroidal retinal atrophy is an autosomal recessive genetic disorder caused by a deficiency in ornithine metabolizing enzymes. Small ring-like atrophic lesions appear around the choroid and mid-retina, while visual disturbances such as hypopsia, blindness and a narrow field of vision are observed. Invest, ophthalmol. vis. sci., 48(1), 455-463(2007) (NPL 1) discloses that spermidine, one of the ornithine metabolites, damages retinal pigment epithelial cells, which reveals a correlation between spermidine-induced retinal pigment epithelial damage and convoluted choroidal retinal atrophy.

In retinal vein occlusion, damage to vascular endothelial cells caused by vein occlusion increases the permeability of the vessel wall, which causes severe retinal edema in the area of occlusion, which leads to long-term (1-2 years) neovascularization. An increase in choroidal vascular permeability is also thought to be the cause of central serous chorioretinopathy. In addition, retinal edema is also known to be found in giant retinal aneurysms.

Retinal detachment is also known to be associated with the above-mentioned ocular diseases such as diabetic retinopathy and retinopathy of prematurity. A great correlation was also observed between proliferative vitreoretinopathy and retinal degeneration.

On the other hand, JNK (c-Jun amino terminal kinase; c-Jun N terminal kinase), which is a member of the stress activation group in mitogen-activated protein (MAP) kinases, phosphorylates c-Jun. Japanese national patent publication No. 2008-518922(PTL 1) discloses that intraperitoneal administration of SP600125, a non-peptide JNK inhibitor, can protect rats from ischemia/reperfusion-induced ocular neuropathy. PTL1 also discloses that SP600125 can inhibit serum starvation and glutamate-induced death of cultured rat retinal ganglion cells. Based on these findings, PTL describes that JNK inhibitors (such as SP600125) can act as therapeutic agents for ocular diseases (such as glaucoma, ischemic neuropathy, ischemic retinopathy, pigmented retinopathy, and retinal detachment).

However, invest, ophthalmol, vis, sci, 44(12), 5383-5395(2003) (NPL 2) indicate that intravitreal administration of SP600125 does not protect against ischemic retinopathy, but rather tends to exacerbate the ischemic condition. That is, SP600125 may not be able to treat or prevent retinal disease when applied topically to the eye. Generally, the route of administration of therapeutic agents for retinal diseases is topical administration to the eye, such as intravitreal administration. Topical administration to the eye is also preferred from the standpoint of preventing systemic side effects.

Peptide JNK inhibitors are also known as JNK inhibitors other than SP600125 (NPL 2, Japanese patent laid-open No. 2003-507502 (PTL 2), Japanese patent laid-open No. 2009-507502(PTL 3), etc.). However, NPL2 suggests that intravitreal administration of peptidic JNK inhibitors also does not protect against ischemic retinopathy and tends to exacerbate the condition.

As described above, none of the prior art documents discloses a JNK inhibitor capable of treating or preventing retinal diseases when administered locally to the eye. In addition, no report has shown that JNK inhibitors other than SP600125 are effective for the treatment or prevention of retinal diseases.

Reference list

Patent document

PTL 1: japanese national patent publication No. 2008-518922

PTL 2: japanese national patent publication No. 2003-511071

PTL 3: japanese national patent publication No. 2009-507502

Non-patent document

NPL 1：Invest.Ophthalmol.Vis.Sci.，48(1)，455-463(2007)

NPL 2：Invest.Ophthalmol.Vis.Sci.，44(12)，5383-5395(2003)

Summary of The Invention

Technical problem

The present invention is designed to solve the various problems described above. It is an object of the present invention to provide a medicament and a method comprising a JNK inhibitory peptide as an active ingredient, which is capable of preventing or treating retinal diseases (even by ocular topical administration).

Problem solving scheme

The present inventors have conducted extensive studies concerning JNK inhibitors capable of treating or preventing retinal diseases, and thus have found that intravitreal administration of a JNK inhibitory peptide comprising a specific amino acid sequence, which is less than 150 amino acids in length and comprises at least one dextrorotatory amino acid can inhibit spermidine-induced retinal pigment epithelium damage, laser-induced choroidal neovascularization, and tunicamycin-induced photoreceptor cell damage, thereby arriving at the present invention. This is an unexpected result considering that the representative JNK inhibitor SP600125 did not prove to have similar effects. As described in the background section, retinal pigment epithelium damage, choroidal neovascularization, and photoreceptor cell damage are deeply involved in the occurrence and/or progression of many retinal diseases, and therefore, a drug for inhibiting retinal pigment epithelium damage, choroidal neovascularization, and photoreceptor cell damage is effective in preventing or treating retinal diseases.

In general, the present invention is a prophylactic or therapeutic agent for a retinal disease, comprising a JNK inhibitory peptide having a length of less than 150 amino acids, which comprises at least one dextrorotatory amino acid, and has (a) a JNK inhibitory sequence that is a sequence of SEQ ID NO: 1 and SEQ ID NO: 2, and (b) a transport sequence which is SEQ ID NO: 3 and SEQ ID NO: 4.

The present invention also provides a prophylactic or therapeutic agent for a retinal disease, which comprises a JNK inhibitory peptide having a length of less than 150 amino acids, which comprises at least one dextrorotatory amino acid and has a sequence represented by SEQ ID NO: 5 and SEQ ID NO: 6.

Further, the present invention provides a prophylactic or therapeutic agent for a retinal disease, comprising a JNK inhibitory peptide consisting of seq id NO: 5 or SEQ ID NO: 6 and comprises at least one dextrorotatory amino acid. In this case, all amino acids in the JNK inhibitory peptide are preferably dextrorotatory amino acids.

The retinal disease in the present invention is preferably at least one selected from the group consisting of: age-related macular degeneration (age-related macular degeneration), diabetic macular edema (diabetic retinopathy), diabetic retinopathy (diabetic retinopathy) (except diabetic macular edema), central exudative chorioretinopathy (central exudative retinopathy), angioid streaks (angioid streaks), retinal pigment epithelium detachment (endothelial retinal pigment detachment, atrial streak), multifocal choroidopathy (multifocal choroidal streaks), neovascular occlusive maculopathy (neovascular occlusive retinopathy) (conditions limited only to high myopia, oblique retinal syndrome, or choroidal papilloma), retinal vein retinopathy (retinal vein), retinal vein occlusion, central retinal vein occlusion, retinal vein occlusion, Giant retinal aneurysm (retinomacroaneurysm), retinal detachment (retino-detachment), proliferative vitreoretinopathy (proliferative vitreoretinopathy), recessive macular dystrophy (Stargardt's disease), choroidal sclerosis (choroid sclerosis), choroideremia (chorodieremia), vitelliform macular dystrophy (viroplasmic dystrophy), small-mouth disease (Oguchi's disease), ichthyoid lentigines (fundus albicans), ichthyoid retinal degeneration (retinitis pigmentosa), and gyroid choroidal retinal atrophy (gyroid atrophies of choroid and retinitis).

The route of administration of the prophylactic or therapeutic agent for a retinal disease of the present invention is preferably intravitreal (intravitreal) administration, conjunctival sac (conjectionsal) administration, subconjunctival (subconjunctival) administration, or subconjunctival (sub-ten) administration.

The prophylactic or therapeutic agent for a retinal disease of the present invention comprises a JNK inhibitory peptide consisting of SEQ ID NO: 5 or SEQ ID NO: 6, wherein all amino acids are dextrorotatory amino acids, preferably said retinal disease is at least one selected from the group consisting of: age-related macular degeneration, diabetic macular edema, and diabetic retinopathy (except diabetic macular edema), and the route of administration is intravitreal administration.

The present invention also provides a method for preventing or treating a retinal disease, the method for preventing or treating comprising administering to a patient a pharmacologically effective amount of a JNK inhibitory peptide of less than 150 amino acids in length, the JNK inhibitory peptide comprising at least one dextrorotatory amino acid and having (a) a JNK inhibitory sequence that is SEQ ID NO: 1 and SEQ ID NO: 2, and (b) a transport sequence which is SEQ ID NO: 3 and SEQ ID NO: 4.

Furthermore, the present invention provides a method for preventing or treating a retinal disease, the method for preventing or treating comprising administering to a patient a pharmacologically effective amount of a JNK inhibitory peptide of less than 150 amino acids in length, the JNK inhibitory peptide comprising at least one dextrorotatory amino acid and having an amino acid sequence set forth as SEQ ID NO: 5 and SEQ ID NO: 6.

Furthermore, the present invention provides a method for preventing or treating a retinal disease, the method for preventing or treating comprising administering to a patient a pharmacologically effective amount of a JNK inhibitory peptide consisting of SEQ ID NO: 5 or SEQ ID NO: 6 and comprises at least one dextrorotatory amino acid.

In the method for prevention or treatment of the present invention, all amino acids in the JNK inhibitory peptide are preferably dextrorotatory amino acids.

The retinal disease in the present invention is preferably at least one selected from the group consisting of: age-related macular degeneration, diabetic macular edema, diabetic retinopathy (excluding diabetic macular edema), central exudative chorioretinopathy, angioid streaks, retinal pigment epithelium detachment, multifocal choroiditis, neovascular maculopathy (restricted to conditions caused by high myopia, optic disc slope syndrome or choroidal osteoma), retinopathy of prematurity, retinitis pigmentosa, Leber's disease, retinal artery occlusion, retinal vein occlusion, central serous chorioretinopathy, giant retinal aneurysm, retinal detachment, proliferative vitreoretinopathy, occult macular dystrophy, choroideresclerosis, choroideremia, vitelliform macular dystrophy, kohlrabi disease, ichthyoid fundus oculi, ichthyoid retinal degeneration, and convoluted choroidal retinal atrophy.

The route of administration in the method for the prophylaxis or treatment of a retinal disease of the present invention is preferably intravitreal administration, conjunctival intracapsular administration, subconjunctival administration, or fascia subcapsular administration.

In the method for the prevention or treatment of a retinal disease of the present invention, in the case where a pharmacologically effective amount of a JNK inhibitory peptide (the JNK inhibitory peptide consisting of the amino acid sequence of SEQ ID NO: 5 or SEQ ID NO: 6, wherein all the amino acids are dextrorotatory amino acids) is administered to a patient, it is preferable that the retinal disease is at least one selected from the group consisting of: age-related macular degeneration, diabetic macular edema, diabetic retinopathy (excluding diabetic macular edema), and the route of administration is intravitreal administration.

The present invention also provides a use of a JNK inhibitory peptide having a length of less than 150 amino acids, comprising at least one dextrorotatory amino acid, and having (a) a JNK inhibitory sequence which is SEQ ID NO: 1 and SEQ ID NO: 2, and (b) a transport sequence which is SEQ ID NO: 3 and SEQ ID NO: 4.

Further, the present invention provides a use of a JNK inhibitory peptide having a length of less than 150 amino acids, comprising at least one dextrorotatory amino acid, and having an amino acid sequence of SEQ ID NO: 5 and SEQ ID NO: 6.

Further, the present invention provides use of a JNK inhibitory peptide consisting of SEQ ID NO: 5 or SEQ ID NO: 6 and comprises at least one dextrorotatory amino acid.

In the use of the JNK inhibitory peptide of the present invention, all amino acids in the JNK inhibitory peptide are preferably dextrorotatory amino acids.

The retinal disease in the present invention is preferably at least one selected from the group consisting of: age-related macular degeneration, diabetic macular edema, diabetic retinopathy (excluding diabetic macular edema), central exudative chorioretinopathy, angioid streaks, retinal pigment epithelium detachment, multifocal choroiditis, neovascular macular degeneration (limited to conditions caused by high myopia, optic disc slope syndrome, or choroidal osteoma), retinopathy of prematurity, retinitis pigmentosa, Leber's disease, retinal artery occlusion, retinal vein occlusion, central serous chorioretinopathy, giant retinal aneurysm, retinal detachment, proliferative vitreoretinopathy, occult macular dystrophy, choroideresclerosis, choroideremia, vitelliform macular dystrophy, kohlrabi disease, ichthyoid fundus oculi, ichthyoid retinal degeneration, and convoluted choroidal retinal atrophy.

The route of administration in the use of the JNK inhibitory peptide of the present invention is preferably intravitreal administration, conjunctival intracapsular administration, subconjunctival administration, or meningeal subcapsular administration.

In the use of a JNK inhibitor peptide (the JNK inhibitor peptide consists of the amino acid sequence of SEQ ID NO: 5 or SEQ ID NO: 6, wherein all the amino acids are dextrorotatory amino acids) for the preparation of a prophylactic or therapeutic agent for a retinal disease, the retinal disease is preferably at least one selected from the group consisting of: age-related macular degeneration, diabetic macular edema, and diabetic retinopathy (except diabetic macular edema), and the route of administration is intravitreal administration.

Advantageous effects of the invention

As will be described later, intravitreal administration of JNK inhibitory peptides (which include specific amino acid sequences in which at least one amino acid is a d-amino acid) inhibits spermidine-induced retinal pigment epithelial damage, laser-induced choroidal neovascularization, and tunicamycin-induced photoreceptor cell damage. That is, JNK inhibitory peptides have the surprising effect of inhibiting retinal pigment epithelium damage, photoreceptor cell damage, and choroidal neovascularization, all of which are the causes of many retinal diseases. Therefore, by incorporating the JNK inhibitory peptide as an active ingredient, a medicament and a method capable of preventing or treating retinal diseases (even by ocular local administration) can be provided, and also the use of the JNK inhibitory peptide for the preparation of the above-mentioned medicament is provided.

Description of the embodiments

The present invention provides a prophylactic or therapeutic agent for a retinal disease, which comprises a JNK inhibitory peptide having a length of less than 150 amino acids, which comprises at least one dextrorotatory amino acid, and has (a) a JNK inhibitory sequence that is a sequence represented by SEQ ID NO: 1 and SEQ ID NO: 2, and (b) a transport sequence which is SEQ ID NO: 3 and SEQ ID NO: 4. The present invention also provides a method for preventing or treating a retinal disease, which comprises administering a pharmacologically effective amount of this JNK inhibitory peptide to a patient. The present invention further provides use of the JNK inhibitory peptide for producing a prophylactic or therapeutic agent for a retinal disease.

As used herein, the term "JNK inhibitory peptide" refers to a peptide having an activity of inhibiting phosphorylation of a substrate such as c-Jun by JNK (hereinafter also referred to as "JNK inhibitory activity"). The JNK inhibitory activity can be easily measured by using a commercially available JNK activity assay Kit (manufactured by Cell Signaling Technology, SAPK/JNK assay Kit (SAPK/JNKAssay Kit) (catalog No.: 9810), etc.), and can also be measured according to the methods disclosed in Japanese patent laid-open No. 2003-511071(PTL 2) and Japanese patent laid-open No. 2009-507502(PTL 3).

As used herein, the phrase "JNK inhibitory sequence is seq id NO: 1 and SEQ ID NO: 2 "refers to the amino acid sequence NH₂-RPKRPTTLNLFPQVPRSQD-COOH (SEQ ID NO: 1) and NH₂-DQSRPVQPFLNLTTPRKPR-COOH (SEQ ID NO: 2) which binds to JNK and inhibits its activity. Here, the JNK inhibitory sequence may consist of a levorotatory amino acid, a dextrorotatory amino acid, or a combination of both. Preferably, however, at least one amino acid in the JNK inhibitory sequence is a dextrorotatory amino acid, and more preferably, all amino acids in the JNK inhibitory sequence are dextrorotatory amino acids.

As used herein, the phrase "transport sequence is SEQ ID NO: 3 and SEQ ID NO: 4 "refers to the amino acid sequence NH₂-GRKKRRQRRR-COOH (SEQ ID NO: 3) and NH₂RRRQRRKKRG-COOH (SEQ ID NO: 4), which induces the peptide in the desired cell. Here, the transport sequence may consist of l-amino acids, d-amino acids or a combination of both. Preferably, however, at least one amino acid in the transit sequence is a dextrorotatory amino acid, and more preferably, all amino acids in the transit sequence are dextrorotatory amino acids.

Preference is given toThe JN inhibitory peptide of the present invention has the amino acid sequence NH₂-GRKKRRQRRRPPRPKRPTTLNLFPQVPRSQD-COOH (SEQ ID NO: 5) and NH₂-GRKKRRQRRRPPRPKRPTTLNLFPQVPRSQDT-COOH (SEQ ID NO: 6), said JNK inhibitory peptide being less than 150 amino acids in length and comprising at least one dextrorotatory amino acid.

Furthermore, preferably, the JNK inhibitory peptide of the invention consists of the amino acid sequence NH₂-GRKKRRQRRRPPRPKRPTTLNLFPQVPRSQD-COOH (SEQ ID NO: 5) or NH₂-GRKKRRQRRRPPRPKRPTTLNLFPQVPRSQDT-COOH (SEQ ID NO: 6), wherein at least one amino acid is a dextrorotatory amino acid.

Furthermore, all amino acids in the JNK inhibitory peptide of the present invention are preferably dextrorotatory amino acids.

A particular embodiment of the most preferred JNK inhibitory peptides of the invention is represented by the amino acid sequence NH₂-GRKKRRQRRRPPRPKRPTTLNLFPQVPRSQD-COOH (SEQ ID NO: 5), wherein all amino acids are dextrorotatory amino acids (hereinafter also referred to as "A peptide (peptide A)").

Here, the SEQ ID NO: 1-SEQ ID NO: the sequence of 6 is shown in table 1.

[ Table 1]

The JNK inhibitory peptide of the present invention may be synthesized according to the solid phase chemical synthesis method using commercially available peptide synthesis equipment, or may be synthesized according to the method disclosed in japanese national patent publication No. 2009-507502(PTL 3). The A peptide is marketed by BIOMOL under the trade name "D-JNKi 1" (Cat. No.: EI-355).

Examples of retinal diseases in the present invention include age-related macular degeneration, diabetic macular edema, diabetic retinopathy (except diabetic macular edema), central exudative chorioretinopathy, angioid streaks, retinal pigment epithelium detachment, multifocal choroiditis, retinopathy of prematurity, retinitis pigmentosa, lyer's disease, retinal artery occlusion, retinal vein occlusion, central serous chorioretinopathy, giant retinal aneurysm, retinal detachment, proliferative vitreoretinopathy, recessive macular dystrophy, choroidal sclerosis, choroideremia, vitelliform macular dystrophy, small-oroid disease, ichthyoid fundus, ichthyoid retinal degeneration and convoluted choroidal retinal atrophy. Neovascular maculopathy caused by high myopia, optic disc inclination syndrome, choroidal osteoma, and the like is also included in the retinal diseases in the present invention. The prophylactic or therapeutic agent for a retinal disease of the present invention can be suitably applied to the prevention or treatment of at least one of these retinal diseases.

As described above, in the present invention, early age-related macular degeneration, atrophic AMD and exudative AMD are included in age-related macular degeneration, and polypoidal choroidal vasculopathy is also included in age-related macular degeneration. Simple diabetic retinopathy, pre-proliferative diabetic retinopathy and proliferative diabetic retinopathy are included in diabetic retinopathy (with the exception of diabetic macular edema).

Central retinal artery occlusion and branch retinal artery occlusion are included in retinal artery occlusion. Central retinal vein occlusion and branch retinal vein occlusion are included in retinal vein occlusion.

Among the above-mentioned retinal diseases, the JNK inhibitory peptide of the present invention is particularly effective for age-related macular degeneration, diabetic macular edema, and diabetic retinopathy (excluding diabetic macular edema).

The JNK inhibitory peptides of the present invention can be optionally mixed with pharmaceutically acceptable additives using widely used techniques and formulated into a single formulation or a combined formulation.

When the JNK inhibitory peptide of the present invention is used for preventing or treating the above-mentioned retinal diseases, the JNK inhibitory peptide may be administered to a patient orally or parenterally. Examples of administration forms include oral administration, intravenous administration, topical administration to the eye (e.g., instillation, conjunctival sac administration, intravitreal administration, subconjunctival administration, and submucosal sac administration), and dermal administration. Among the above modes of administration, intravitreal administration, conjunctival intracapsular administration, subconjunctival administration, or pleural subcapsular administration are preferable, and intravitreal administration is particularly preferable.

Particularly preferably, the prophylactic or therapeutic agent for a retinal disease of the present invention comprises a JNK inhibitory peptide consisting of SEQ ID NO: 5 or S SEQ ID NO: 6, wherein all amino acids are dextrorotatory amino acids, in which case the retinal disease is at least one selected from the group consisting of: age-related macular degeneration, diabetic macular edema, and diabetic retinopathy (except diabetic macular edema), and the route of administration is intravitreal administration. This also applies to the method for preventing or treating retinal diseases and the use of the JNK inhibitory peptide of the present invention.

The JNK inhibitory peptides of the invention are formulated in a dosage form suitable for administration, optionally together with pharmaceutically acceptable additives. Examples of dosage forms suitable for oral administration include tablets, capsules, granules, fine granules (fine granules), and powders; dosage forms suitable for parenteral administration include injections, eye drops, ophthalmic ointments, patches, gels and inserts. These dosage forms can be prepared using general techniques widely used in the art. In addition to these formulations, the JNK inhibitory peptide of the present invention may be formulated into a formulation for intraocular implant, or a formulation formulated as DDS (Drug Delivery Systems), such as microspheres.

For example, tablets may be prepared by using additives, which may be suitably selected from the following agents: for example, excipients such as lactose, glucose, d-mannitol, anhydrous dicalcium phosphate, starch, and sucrose; disintegrants such as carboxymethylcellulose, carboxymethylcellulose calcium, croscarmellose sodium, crospovidone, starch, partially pregelatinized starch and low substituted hydroxypropylcellulose; binders such as hydroxypropyl cellulose, ethyl cellulose, gum arabic, starch, partially pregelatinized starch, polyvinyl pyrrolidone, and polyvinyl alcohol; lubricants such as magnesium stearate, calcium stearate, talc, hydrated silicon dioxide, and hydrogenated oil; coating agents such as refined sucrose, hydroxypropylmethylcellulose, hydroxypropylcellulose, methylcellulose, ethylcellulose and polyvinylpyrrolidone; and flavoring agents such as citric acid, aspartame, ascorbic acid and menthol.

The injection may be prepared by optionally using an additive selected from the following agents: for example, isotonic agents such as sodium chloride; buffering agents such as sodium phosphate; surfactants such as polyoxyethylene sorbitan monooleate; and thickeners such as methylcellulose.

The eye drops can be prepared by optionally using an additive which can be selected from the following agents: for example, isotonic agents such as sodium chloride and concentrated glycerol; buffers such as sodium phosphate and sodium acetate; surfactants such as polyoxyethylene sorbitan monooleate, polyoxyl (40) stearate, and polyoxyethylene hydrogenated castor oil; stabilizers such as sodium citrate and sodium edetate; and preservatives such as benzalkonium chloride and parabens. The pH of the eye drops may be in a range acceptable to ocular physiology, but is generally preferably 4 to 8. Ophthalmic ointments can be prepared by using widely used bases such as white vaseline and liquid paraffin.

The intercalating agent can be prepared by grinding and mixing a biodegradable polymer (e.g., hydroxypropyl cellulose, hydroxypropyl methylcellulose, carbopol, and polyacrylic acid) with the compound of the present invention, followed by compression molding the resulting powder. Excipients, binders, stabilizers, and pH adjusters may optionally be used. Formulations for intraocular implants can be prepared by using biodegradable polymers (e.g., polylactic acid, polyglycolic acid, lactic-glycolic acid copolymers, and hydroxypropyl cellulose).

The administration amount of the JNK inhibitory peptide of the present invention may suitably vary depending on the dosage form, severity of symptoms, age, body weight of a patient to be administered the peptide, judgment of a doctor, and the like. However, in the case of oral administration, 0.01 to 5000mg (preferably 0.1 to 2500mg, more preferably 1 to 1000mg) of the JNK inhibitory peptide per day may be generally administered to an adult in a single dose or divided doses. In the case of intravenous administration, 0.01 to 5000mg (preferably 0.1 to 2500mg, more preferably 1 to 1000mg) of the JNK inhibitory peptide per day may be administered to an adult in a single dose or divided doses. In the case of ocular topical administration (except instillation), 0.00001 to 10mg (preferably 0.00005 to 5mg, more preferably 0.0001 to 1mg) of the JNK inhibitory peptide per day may be administered to an adult in a single dose or divided doses. In the case of eye drops or inserts, eye drops or inserts comprising the active ingredient at a concentration of 0.000001-10% (w/v), preferably 0.00001-1% (w/v), more preferably 0.0001-0.1% (w/v), may be administered in a single dose or divided doses per day. In the case of patches, patches having a content of 0.00001-1000mg may be suitable for adults; and in case of the formulation for an intraocular implant, the formulation for an intraocular implant having a content of 0.00001-1000mg may be implanted into an eye of an adult.

The results of pharmacological tests and preparation examples will be illustrated below, which are intended to provide a better understanding of the invention and do not limit the scope of the invention.

[ examples ]

[ pharmacological test 1]

As described in the background section, it has been revealed that spermidine induces damage to the retinal pigment epithelium leading to photoreceptor cell damage. Therefore, the spermidine-induced retinal degeneration model was used as a model for evaluating therapeutic agents for diseases involving retinal pigment epithelium damage, such as atrophic AMD (invest. Ophthalmol. Vis. Sci., 48(1), 455-463(2007) (NPL 1); invest. Ophthalmol. Vis. Sci.51, ARVO E-abstrate 3644(2010), etc.). Therefore, the effect of the JNK inhibitory peptide of the present invention on photoreceptor cell damage caused by retinal pigment epithelium damage was investigated using the above-described model, and then the effect was compared with that obtained using the representative JNK inhibitor SP 600125.

(preparation and drug administration of spermidine-induced retinal degeneration model)

Rats were induced general anesthesia by intramuscular administration of 1mL/kg of a mixture of 5% (W/V) ketamine hydrochloride injection and 2% (W/V) xylazine hydrochloride in a ratio of 7: 1. An ophthalmic solution of 0.5% (W/V) tropicamide-0.5% (W/V) phenylephrine hydrochloride was instilled into the eyes of rats to dilate their pupils. A micro-syringe (25 μ L capacity, Hamilton) fitted with a 33G needle was used and inserted into the vitreous cavity under conditions visible to the fundus. To the control group, 10. mu.L of Dulbecco PBS was administered. To the vehicle administration group (vehicle-administered) was administered 10. mu.L of a 2mM solution of spermidine dissolved in Dulbecco PBS. In the group for administration of A peptide, a 4mM solution of spermidine dissolved in Dulbecco PBS and 0.6mg/mL of A peptide dissolved in Dulbecco PBS were mixed at a ratio of 1: 1 to obtain a mixture, and 10. mu.L of the solution was administered into the vitreous cavity. For the SP600125 administration group, spermidine was dissolved in 0.3mg/mL of SP600125 solution in Dulbecco PBS to reach a concentration of 2mM, and 10. mu.L of the above solution was administered into the vitreous cavity. "Spermidine, Trihydrochloride" (Cat. No. 56766) purchased from Calbiochem was used as Spermidine. "D-JNKi 1" (catalog number EI-355) purchased from BIOMOL was used as the A peptide. "SP 600125" (catalog number S5567-50MG) purchased from Sigma Aldrich was used as SP 600125.

(evaluation)

13 days after spermidine administration, general anesthesia was induced in rats in dark adaptation by intramuscular administration of 1mL/kg of a mixture of 5% (W/V) ketamine hydrochloride injection and 2% xylazine hydrochloride injection (ratio of 7: 1). An ophthalmic solution of 0.5% (W/V) tropicamide-0.5% (W/V) phenylephrine hydrochloride was instilled into the eyes of rats to dilate their pupils. ERG (a-wave) was then measured using an Electroretinogram (ERG) measuring device (manufactured by Tomey Corporation, Portable ERG & VEPLE-3000). Subsequently, the suppression ratio for the ERG amplitude reduction was calculated using formula 1 shown below. The calculation results are shown in table 2.

[ equation 1]

Percent (%) inhibition of reduction of ERG amplitude ((E)_x-E_v)/(E_c-E_v))×100，

Wherein:

E_c: amplitude value of a wave of the control group;

E_v: amplitude values of a-waves for vehicle administration groups; and

E_x: amplitude value of a-wave of drug administration group.

[ Table 2]

Amount of drug administered	Suppression ratio (%) of reduction in ERG (a-wave) amplitude
		A peptide 3. mu.g/eye	72.7％
SP 6001253. mu.g/eye	-17.6％

(results)

As shown in table 2, intravitreal administration of the a peptide inhibited the reduction in ERG amplitude by approximately 73% in the spermidine-induced model of retinal degeneration. On the other hand, intravitreal administration of SP600125 exacerbated the reduction in ERG amplitude by up to about 18%.

(discussion)

The foregoing results indicate that the JNK inhibitory peptide of the present invention comprising the a peptide inhibits spermidine-induced retinal pigment epithelial damage and resultant photoreceptor cell damage. As described in the background section, retinal pigment epithelium damage and resultant photoreceptor cell damage is thought to be involved in the development and/or progression of the following retinal diseases, such as: age-related macular degeneration (particularly, early age-related macular degeneration and atrophic AMD), retinitis pigmentosa, leber's disease, occult macular dystrophy, choroideresclerosis, choroideremia, vitelliform macular dystrophy, kohlrabi disease, ichthyoid fundus oculi, ichthyoid retinal degeneration, and convoluted choroidal retinal atrophy. Therefore, the JNK inhibitory peptide of the present invention is considered to be effective for the prevention or treatment of retinal diseases including age-related macular degeneration (in particular, early age-related macular degeneration and atrophic AMD).

On the other hand, the representative JNK inhibitor SP600125 did not show damage inhibition in this model, but instead, as described in the background section, SP600125 may exacerbate damage to the retina. It was surprising that the JNK inhibitory peptides of the present invention possessing JNK inhibitory activity had inhibitory effects on retinal pigment epithelium damage as well as on photoreceptor cell damage, both of which were not observed in the representative inhibitors.

[ pharmacological test 2]

As a pharmacological test model for studying the inhibitory effect on choroidal neovascularization, a laser-induced choroidal neovascularization model is widely used (Folia Ophthalmologica Japonica, 45, 853-. This model was therefore used to evaluate the effectiveness of the JNK inhibitory peptides of the invention.

(preparation of laser-induced rat choroidal neovascularization model)

General anesthesia was induced in rats by intramuscular administration of 1mL/kg of a mixture of 5% (W/V) ketamine hydrochloride injection and 2% xylazine hydrochloride injection (7: 1 ratio). An ophthalmic solution of 0.5% (W/V) tropicamide-0.5% phenylephrine hydrochloride was instilled into the eyes of rats to dilate their pupils. Photocoagulation was then performed using a krypton laser photocoagulator (manufactured by NIDEK, multicolor laser photocoagulator MC-7000). By focusing the laser beam on the deep layer of the retina, photocoagulation is performed at 8 sites of the posterior pole of the fundus of each eye while avoiding dense retinal blood vessels. After photocoagulation, fundus photography was performed to determine the laser irradiation site.

(drug administration)

Immediately after the model preparation, a micro-syringe (25 μ L capacity, Hamilton) equipped with a 33G needle was used and inserted into the vitreous cavity with the fundus visible, and 5 μ L of a solution for administration (the solution containing 0.6mg/mL of a peptide dissolved in physiological saline) was administered (drug administration group). "D-JNKi 1" (catalog number EI-355) purchased from BIOMOL was used as the A peptide. For the vehicle administration group, 5 μ L of physiological saline was administered.

(evaluation)

On day 7 after laser photocoagulation, rats were induced to undergo general anesthesia by intramuscular administration of 1mL/kg of a mixture of a 5% (W/V) ketamine hydrochloride injection and a 2% xylazine hydrochloride injection (ratio of 7: 1). An ophthalmic solution of 0.5% (W/V) tropicamide-0.5% phenylephrine hydrochloride was instilled into the eyes of rats to dilate their pupils. Subsequently, 0.1mL of a 10% fluorescein sodium solution was injected via the tail vein, and fluorescein fundus angiography (manufactured by Kowa, FundusCamera Kowa proaiii) was performed. In fluorescein fundus angiography, sites that were not exposed to fluorescence were determined to be negative (no neovascularization) and sites that were exposed to visible fluorescence were determined to be positive (neovascularization). In addition, when there were two photocoagulation sites exposed to visible weak fluorescence, these photocoagulation sites were determined to be positive (neovascularization). Next, the incidence (%) of choroidal neovascularization was calculated from the ratio of the number of positive sites to 8 laser irradiation sites according to formula 2 shown below, and the inhibition (%) of the drug to be evaluated was calculated according to formula 3 shown below. The calculation results are shown in table 3. In both the drug-administered group and the vehicle-administered group, the number of cases in each group was 8.

[ formula 2]

Incidence (%) of choroidal neovascularization ═ (number of positive sites/total number of photocoagulation sites) × 100

[ formula 3]

Inhibition ratio (%) ((a)₀-A_X)/A₀) X 100, wherein:

A₀: incidence of choroidal neovascularization in the vehicle administration group; while

A_X: incidence of choroidal neovascularization in the drug administration group.

[ Table 3]

Amount of drug administered	Inhibition ratio (%) of occurrence of choroidal neovascularization
		A peptide 3. mu.g/eye	14.3

(results)

As shown in table 3, intravitreal administration of the a peptide inhibited choroidal neovascularization by about 14% in the laser-induced rat choroidal neovascularization model.

(discussion)

As described in the background section, choroidal neovascularization is the major pathology found in exudative AMD. Neovascularization is also known as one of the major findings in diabetic retinopathy, particularly proliferative diabetic retinopathy. In addition, choroidal neovascularization is also thought to be involved in the development and/or progression of retinopathies such as: central exudative chorioretinopathy, angioid streaks, retinal pigment epithelium detachment, multifocal choroiditis, neovascular macular degeneration (limited to conditions caused by high myopia, optic disc tilt syndrome, or choroidal osteoma), and retinopathy of prematurity. Therefore, the JNK inhibitory peptide of the present invention is considered to be effective for the prevention or treatment of retinal diseases including age-related macular degeneration (particularly, exudative AMD) and diabetic retinopathy (particularly, proliferative retinopathy).

[ pharmacological test 3]

Endoplasmic reticulum stress has been shown to be involved in retinal diseases such as age-related macular degeneration and retinitis pigmentosa (Expert rev. ophthalmol.3(1), 29-42 (2008)). Intravitreal administration of tunicamycin, an inducer of endoplasmic reticulum stress, has also been reported to induce damage to photoreceptor cells (Nature) 311, 575-. This model was therefore used to evaluate the effectiveness of the JNK inhibitory peptides of the invention for damage to photoreceptor cells.

(preparation and drug administration of tunicamycin-induced rat photoreceptor cell damage model)

General anesthesia was induced in rats by intramuscular administration of 1mL/kg of a mixture of 5% (W/V) ketamine hydrochloride injection and 2% xylazine hydrochloride injection (7: 1 ratio). An ophthalmic solution of 0.5% (W/V) tropicamide-0.5% phenylephrine hydrochloride was instilled into the eyes of rats to dilate their pupils. A micro-syringe (25 μ L capacity, Hamilton) fitted with a 33G needle was used and inserted into the vitreous cavity under conditions visible to the fundus. To the control group, 5. mu.L of a mixture of dimethyl sulfoxide and physiological saline (ratio of 1: 9) was administered. To the vehicle administration group, 5. mu.L of a mixture of 200. mu.g/mL tunicamycin solution in dimethyl sulfoxide and physiological saline (ratio of 1: 9) was administered. For the group of A peptide administration, 5. mu.L of a mixture of 200. mu.g/mL tunicamycin in dimethyl sulfoxide and 0.6mg/mL A peptide in physiological saline (1: 9 ratio) was administered into the vitreous cavity. "tunicamycin from Streptomyces SP" (catalog number T7765) purchased from Sigma Aldrich was used as tunicamycin. "D-JNKi 1" (catalog number EI-355) purchased from BIOMOL was used as the A peptide.

(evaluation)

After 7 days of tunicamycin administration, general anesthesia was induced in rats in dark adaptation by intramuscular administration of 1mL/kg of a mixture of a 5% (W/V) ketamine hydrochloride injection and a 2% xylazine hydrochloride injection (ratio of 7: 1). An ophthalmic solution of 0.5% (W/V) tropicamide-0.5% phenylephrine hydrochloride was instilled into the eyes of rats to dilate their pupils. ERG (a-wave) was then measured using an Electroretinogram (ERG) measuring device (manufactured by Tomey Corporation, Portable ERG & VEP LE-3000). Subsequently, the suppression ratio for the ERG amplitude reduction was calculated using equation 4 shown below. The calculation results are shown in table 4.

[ formula 4]

Inhibition ratio (%) of reduction of ERG amplitude ((B)_x-B_v)/(B_c-B_v) X 100, wherein:

B_c: amplitude value of a wave of the control group;

B_v: amplitude values of a-waves for vehicle administration groups; and

B_x: amplitude value of a-wave of drug administration group.

[ Table 4]

Amount of drug administered	Suppression ratio (%) of reduction in ERG (a-wave) amplitude
		A peptide 2.7. mu.g/eye	50.0

(results)

As shown in table 4, a peptide inhibited ERG amplitude reduction by about 50% in the tunicamycin-induced photoreceptor cell damage model.

(discussion)

As described above, endoplasmic reticulum stress is deeply involved in pathological conditions of retinal diseases such as age-related macular degeneration (in particular, early age-related macular degeneration and atrophic AMD) and retinitis pigmentosa, and damage of photoreceptor cells by endoplasmic reticulum stress is a major cause of visual deterioration. Damage to photoreceptor cells is also known to be observed in retinal diseases such as lyers disease and retinal artery occlusion. Therefore, the JNK inhibitory peptide of the present invention is considered to be effective for the prevention or treatment of retinal diseases including age-related macular degeneration (in particular, early age-related macular degeneration and atrophic AMD).

[ preparation examples ]

The medicament of the present invention will be more specifically described with reference to the preparation examples; however, the present invention is not limited thereto.

(formulation example 1: injection)

10mL of a mixture of:

a peptide 10mg

90mg of sodium chloride

Appropriate amount of polysorbate 80

Proper amount of sterile purified water

The A peptide and other components listed above were dissolved in sterile purified water to make injections. By varying the amount of A peptide added, injections containing 0.1mg, 1mg or 50mg of A peptide in 10ml can be prepared.

(formulation example 2: eye drops (0.01% (w/v)))

100ml of the solution:

the A peptide and other components listed above were added to sterile purified water and mixed thoroughly to prepare an ophthalmic solution. By varying the amount of the A peptide added, eye drops comprising the A peptide at a concentration of 0.05% (w/v), 0.1% (w/v), 0.5% (w/v), or 1% (w/v) can be prepared.

(formulation example 3: tablet)

100mg of the total weight:

peptide a and lactose were mixed in a mixer. Carboxymethylcellulose calcium and hydroxypropylcellulose are added to the mixture, and the mixture is granulated. The resulting granules are dried and size-adjusted, magnesium stearate is added to the size-adjusted granules and mixed, after which the mixture is compressed into tablets in a tablet press. By varying the amount of A peptide added, tablets containing 0.1mg, 10mg or 50mg of A peptide in 100mg can be prepared.

INDUSTRIAL APPLICABILITY

Intravitreal administration of the JNK inhibitory peptides of the invention inhibits spermidine-induced retinal pigment epithelial damage, tunicamycin-induced photoreceptor cell damage, and laser-induced choroidal neovascularization. That is, the JNK inhibitory peptide of the present invention has an unexpected effect of inhibiting all three of retinal pigment epithelium damage, photoreceptor cell damage, and choroidal neovascularization, which are causes of many retinal diseases.

Therefore, the JNK inhibitory peptide of the present invention is effective as a prophylactic or therapeutic agent for a retinal disease, and is effective in a method for the prevention or treatment of a retinal disease.

Claims

1. A prophylactic or therapeutic agent for a retinal disease, which comprises a JNK (c-Jun amino terminal kinase) inhibitory peptide having a length of less than 150 amino acids, which contains at least one dextrorotatory amino acid and has (a) a JNK inhibitory sequence that is a sequence represented by SEQ ID NO: 1 and SEQ ID NO: 2, and (b) a transport sequence which is SEQ ID NO: 3 and SEQ ID NO: 4.

2. A prophylactic or therapeutic agent for a retinal disease, which comprises a JNK inhibitory peptide having a length of less than 150 amino acids, which comprises at least one dextrorotatory amino acid and has an amino acid sequence of SEQ ID NO: 5 and SEQ ID NO: 6.

3. A prophylactic or therapeutic agent for a retinal disease, which comprises a JNK inhibitory peptide consisting of SEQ ID NO: 5 or SEQ ID NO: 6 and comprises at least one dextrorotatory amino acid.

4. A prophylactic or therapeutic agent according to claim 3, wherein

All amino acids in the JNK inhibitory peptides are dextrorotatory amino acids.

5. The prophylactic or therapeutic agent according to any one of claims 1 to 4, wherein

The retinal disease is at least one selected from the group consisting of: age-related macular degeneration, diabetic macular edema, diabetic retinopathy (excluding diabetic macular edema), central exudative chorioretinopathy, angioid streaks, retinal pigment epithelium detachment, multifocal choroiditis, neovascular maculopathy (restricted to conditions caused by high myopia, optic disc slope syndrome or choroidal osteoma), retinopathy of prematurity, retinitis pigmentosa, Leber's disease, retinal artery occlusion, retinal vein occlusion, central serous chorioretinopathy, giant retinal aneurysm, retinal detachment, proliferative vitreoretinopathy, occult macular dystrophy, choroideresclerosis, choroideremia, vitelliform macular dystrophy, kohlrabi disease, ichthyoid fundus oculi, ichthyoid retinal degeneration, and convoluted choroidal retinal atrophy.

6. The prophylactic or therapeutic agent according to any one of claims 1 to 4, wherein

The route of administration is intravitreal, intracutaneous, subconjunctival, or subconjunctival.

7. The prophylactic or therapeutic agent according to claim 4, wherein

The retinal disease is at least one selected from the group consisting of: age-related macular degeneration, diabetic macular edema, and diabetic retinopathy (excluding diabetic macular edema), and

the route of administration is intravitreal.

8. A method for preventing or treating a retinal disease, the method for preventing or treating comprising administering to a patient a pharmacologically effective amount of a JNK inhibitory peptide of less than 150 amino acids in length, the JNK inhibitory peptide comprising at least one dextrorotatory amino acid and having (a) a JNK inhibitory sequence that is SEQ ID NO: 1 and SEQ ID NO: 2, and (b) a transport sequence which is SEQ ID NO: 3 and SEQ ID NO: 4.

9. A method for preventing or treating a retinal disease, the method for preventing or treating comprising administering to a patient a pharmacologically effective amount of a JN inhibitory peptide of less than 150 amino acids in length, the JNK inhibitory peptide comprising at least one dextrorotatory amino acid and having an amino acid sequence set forth as SEQ ID NO: 5 and SEQ ID NO: 6.

10. A method for preventing or treating a retinal disease, the method for preventing or treating comprising administering to a patient a pharmacologically effective amount of a JNK inhibitory peptide consisting of SEQ ID NO: 5 or SEQ ID NO: 6 and comprises at least one dextrorotatory amino acid.

11. The method of prophylaxis or treatment according to claim 10, wherein

All amino acids in the JNK inhibitory peptides are dextrorotatory amino acids.

12. A method of prophylaxis or treatment according to any one of claims 8 to 11, wherein

13. A method of prophylaxis or treatment according to any one of claims 8 to 11, wherein

14. The method of prophylaxis or treatment according to claim 11, wherein

the route of administration is intravitreal.

Use of a JNK inhibitory peptide for the preparation of a prophylactic or therapeutic agent for a retinal disease,

the JNK inhibitory peptide is less than 150 amino acids in length, comprises at least one dextrorotatory amino acid, and has (a) a JNK inhibitory sequence that is SEQ ID NO: 1 and SEQ ID NO: 2, and (b) a transport sequence which is SEQ ID NO: 3 and SEQ ID NO: 4.

the JNK inhibitory peptide is less than 150 amino acids in length, comprises at least one dextrorotatory amino acid, and has the amino acid sequence shown as SEQ ID NO: 5 and SEQ ID NO: 6.

the JNK inhibitory peptide consists of SEQ ID NO: 5 or SEQ ID NO: 6 and comprises at least one dextrorotatory amino acid.

18. Use according to claim 17, wherein

All amino acids in the JNK inhibitory peptides are dextrorotatory amino acids.

19. Use according to any one of claims 15 to 18, wherein

20. Use according to any one of claims 15 to 18, wherein

21. Use according to claim 18, wherein

the route of administration is intravitreal.