Compositions comprising PEDF-derived short-chain peptides for the treatment of dry eye disease

Abstract

Provided is a composition comprising a PEDF-derived short-chain peptide for the treatment of dry eye disease. A pharmaceutical composition for use in the treatment of dry eye disease associated with cataract, the pharmaceutical composition comprising a peptide having an amino acid sequence selected from SEQ ID NOs: 1-7.

Description

【Technical Field】 【0001】 The present invention relates to a PEDF-derived short-chain peptide (PDSP) and its use in the treatment and / or amelioration of dry eye disease. Background of the Invention 【0002】 Dry eye (i.e., keratoconjunctivitis sicca) is a complex disease that causes symptoms such as discomfort, visual impairment, and instability of the tear film, and can cause damage to the ocular surface. Dry eye occurs when the eye's tears are not secreted sufficiently or when the tears evaporate rapidly. It is accompanied by an increase in the osmotic pressure of the tear film and inflammation of the ocular surface. The severity of the signs / symptoms of dry eye varies greatly among patients. Some patients experience only mild irritation, while others experience serious complications leading to severe corneal damage and visual impairment. 【0003】 Dry eye disease (DED) can occur from various causes that affect the production of tear components (lipids, aqueous, and mucin) or the stability of the tear film (e.g., rapid evaporation of tears), resulting in high osmotic pressure of the tears, instability of the tear film, and insufficient support for the integrity of the ocular surface epithelium. The high osmotic pressure state of the tears can damage and stimulate the inflammatory cascade of ocular epithelial cells, leading to loss of surface epithelial cells including conjunctival goblet cells. The loss of goblet cells reduces mucin secretion, resulting in loss of protection of the surface epithelium, instability of the tear film, and leading to the onset of dry eye disease and damage to corneal epithelial cells. The instability of the tear film often leads to a chronic cycle of inflammation and damage to the ocular surface that causes DED. 【0004】 Currently, there are few treatment methods available for DED patients, including artificial tears, anti-inflammatory drugs, and analgesics. Although these treatments may relieve the symptoms of some patients, better treatment and prevention means for DED are still needed. 【Summary of the Invention】 【0005】 One aspect of the present invention relates to a pharmaceutical composition for use in the treatment of dry eye disease (DED). A pharmaceutical composition for use in the treatment of dry eye disease (DED) according to one embodiment of the present invention comprises a peptide having an amino acid sequence selected from SEQ ID NOs: 1-7. According to an embodiment of the present invention, the subject has DED and cataracts. According to some embodiments of the present invention, the subject has cataracts treated by surgery. 【0006】 One aspect of the present invention relates to a method for treating dry eye disease (DED) in a subject. A method for treating dry eye disease (DED) according to one embodiment of the present invention comprises administering to a subject in need thereof a composition comprising a peptide having an amino acid sequence selected from SEQ ID NOs: 1-7. According to some embodiments of the present invention, the subject has DED and cataracts. According to some embodiments of the present invention, the subject has cataracts treated by surgery. 【0007】 Other aspects of the present invention will become apparent from the following description and the accompanying drawings. 【Brief Description of the Drawings】 【0008】 Figure 1 shows a schematic diagram of a treatment plan according to an embodiment of the present invention. 【0009】 Figure 2A shows the treatment effect of BRM421 on VAS dryness, VAS burning / stinging, and VAS photophobia. Figure 2B shows the treatment effect of BRM421 on VAS dryness and VAS burning / stinging analyzed with respect to the evaluations before and after CAE®. 【0010】 Figure 3A shows the treatment effect of BRM421 on diary dryness and diary burning. Figure 3B shows the treatment effect of BRM421 on diary (ODS) dryness, ODS burning, and ODS stinging analyzed with respect to the evaluations before and after CAE®. 【0011】 Figure 4A shows the therapeutic effect of BRM421 on VAS burning / stinging in subjects without cataract. Figure 4B shows the therapeutic effect of BRM421 on VAS burning / stinging in subjects with cataract. Figure 4C shows the therapeutic effect of BRM421 on VAS burning / stinging in subjects with cataract who have not undergone surgery. Figure 4D shows the therapeutic effect of BRM421 on VAS burning / stinging in subjects with cataract who have undergone surgery. Figure 4E shows the therapeutic effect of BRM421 on VAS dryness in subjects without cataract. Figure 4F shows the therapeutic effect of BRM421 on VAS dryness in subjects with cataract. Figure 4G shows the therapeutic effect of BRM421 on VAS dryness in subjects with cataract who have not undergone surgery. Figure 4H shows the therapeutic effect of BRM421 on VAS dryness in subjects with cataract who have undergone surgery. 【0012】 Figure 5A shows corneal injury repair in subjects without cataract. Figure 5B shows a significant improvement in corneal injury repair in the BRM421 group compared to the placebo group. Figure 5C shows a significant improvement in corneal injury repair in the BRM421 group compared to the placebo group in patients with cataract who have not undergone surgery. Figure 5D shows a slight improvement in corneal injury repair in the BRM421 group compared to the placebo group in patients with cataract who have undergone surgery. DETAILED DESCRIPTION OF THE INVENTION 【0013】 Human pigment epithelium-derived factor (PEDF) is a secreted protein containing 418 amino acids and has a molecular weight of approximately 50 kDa. PEDF is a multifunctional protein with many biological functions. (See, for example, U.S. Patent Application Publication No. 2010 / 0047212). Different peptide regions of PEDF have been found to be responsible for different functions. For example, a 34-mer fragment (residues 44-77 of PEDF) has been confirmed to have anti-angiogenic activity, and a 44-mer fragment (residues 78-121 of PEDF) has been confirmed to have neurotrophic properties. 【0014】 U.S. Patent Application Publication No. 2010 / 0047212 discloses that PEDF can promote the self-renewal of stem cells. U.S. Patent Nos. 9,051,547 and 9,617,311 disclose that fragments of PEDF that are 20 to 39 amino acids in length (residues 93 to 121 of PEDF) can promote the proliferation of stem cells and wound healing. These short peptides derived from PEDF are referred to herein as PDSPs. The PDSPs used in the present invention are listed in Table 1 below. 【Table 1】 【0015】 Embodiments of the present invention relate to PDSPs and their use in the prevention and / or treatment of dry eye disease (DED). In preclinical studies, it has been found that all of the PDSPs listed in Table 1 are effective in the prevention and / or treatment of DED. In the following examples, the results of a clinical trial of 29-mer (SEQ ID NO: 3, hereinafter referred to as "BRM421") are used to illustrate embodiments of the present invention, but other PDSPs listed in Table 1 also have similar effects. Those skilled in the art will understand that the results of BRM421 are for illustrative purposes and do not limit the scope of the present invention. 【0016】 A multi-site, randomized, double-blind, placebo-controlled clinical trial was conducted using a Controlled Adverse Environment (CAE®) model (Ora, Inc., Andover, Massachusetts, USA) to evaluate the safety and efficacy of BRM421 ophthalmic solution (OS) in subjects with DED. CAE® uses controlled ocular surface stress to exacerbate the signs and symptoms of DED in a safe and controllable manner. 【0017】 Figure 1 shows a test schedule including four weekly visits. At the first visit (-7±1 days), the subjects were screened, evaluated before CAE®, exposed to CAE®, evaluated after CAE®, and a placebo lead-in period (7±1 days) was initiated. During the 7-day test lead-in period before randomization (for subject selection), all subjects were administered placebo OS three times a day (TID) in both eyes. During the second visit, the subjects were evaluated before CAE®, exposed to CAE®, and evaluated after CAE®. These evaluations formed the baseline measurements. Thereafter, the subjects were randomly divided into two groups and administered either BRM421 eye drops (OS) or placebo OS (vehicle) three times a day (TID) in both eyes for 14 days from visit 2 to visit 4. 【0018】 During these visits, the subjects were evaluated for symptom efficacy. Specifically, the subjects were asked to evaluate each eye symptom due to dry eyes and the visual analog scale (VAS) was measured. The evaluated symptoms included burning / stinging, itching, foreign body sensation, blurred vision, dry eyes, photophobia, and pain. 【0019】 Figure 2A shows the results of the VAS dryness, VAS burning / stinging, and VAS photophobia scales at the third and fourth visits compared to the pre-CAE® evaluation at the second visit as the baseline. As shown in Figure 2A, both the BRM421 OS group and the placebo group showed improvement compared to the baseline. Compared to the placebo group, the BRM421 OS group showed a significant difference in the mean change from the baseline in burning / stinging, dry eyes, and photophobia in the intention-to-treat (ITT) population at visit 3, but not at visit 4. There was no significant difference between the treatment group and the placebo group at visit 4 because the vehicle also has a sedative effect that can relieve / mitigate symptoms over time. The fact that a significant difference was observed between the treatment group and the placebo group at visit 3 suggests that the effect of BRM421 appears relatively early. 【0020】 Figure 2B shows the results of the VAS dryness and VAS burning / stinging scales at the third visit, using the CAE (registered trademark) pre - evaluation or CAE (registered trademark) post - evaluation at the second visit as the baseline. When the CAE (registered trademark) pre - evaluation was used as the baseline, significant improvement was seen in both VAS dryness and VAS burning / stinging in the BRM421 group compared to the placebo group. When the CAE (registered trademark) post - evaluation was used as the baseline, no improvement in VAS dryness was seen in the BRM421 group compared to the placebo group, but the VAS burning / stinging in the BRM421 group was significantly improved compared to the placebo group. 【0021】 The evaluation results of VAS dryness, burning / stinging, and photophobia are summarized in Table 2. 【Table 2 - 1】 【Table 2 - 2】 【Table 2 - 3】 【0022】 The subjects were further asked to record the severity of the symptoms of dry eye disease in the morning and evening records before instilling the test drug. Ocular discomfort and a 4 - symptom questionnaire (ODS questionnaire) were used, and the severity of 5 symptoms, namely ocular discomfort, burning, dryness, foreign body sensation, and stinging, was evaluated. The evaluation of each symptom was in the range of 0 to 5, where 0 = none and 5 = worst. 【0023】 Figure 3A shows the results of daily records regarding dryness and burning sensation. Compared with the placebo group, the BRM421OS group showed a significant improvement in dryness from the baseline (before CAE®) from day 1 to evening of day 7 (from the second visit to the third visit), but not significantly improved in the morning and from day 8 to day 15 (from the third visit to the fourth visit). It is considered that the lack of significant improvement in the morning is because the morning dryness after a long night's sleep (with eyes closed) was not severe. The fact that no improvement was seen in the BRM421OS group compared with the placebo group from day 8 to day 15 (from the third visit to the fourth visit) suggests that the effect of BRM421 appears relatively early and the mild sedative effect of the solvent finally caught up with the effect of BRM421. 【0024】 Regarding eye discomfort and burning sensation, the BRM421OS group showed a significantly better improvement from the baseline (before CAE®) during the morning from day 1 to day 7 (from the second visit to the third visit) compared with the placebo group. However, compared with the placebo group, the better improvement in the BRM421OS group was not significant in the evening and not significant from day 8 to day 15 (from the third visit to the fourth visit). The fact that no better improvement was seen in the BRM421OS group than in the placebo group from day 8 to day 15 (from the third visit to the fourth visit) suggests that the effect of BRM421 appears relatively early and the mild sedative effect of the solvent finally caught up with the effect of BRM421. 【0025】 Figure 3B shows the results of ODS dryness, ODS burning sensation, and ODS stinging pain at the third visit, compared with the pre-CAE® and post-CAE® evaluations at the second visit as the baseline. Regarding ODS dryness, there was no significant difference between the BRM421 group and the placebo group in both pre-CAE® and post-CAE® evaluations as the baseline. Regarding ODS burning sensation and ODS stinging pain, the BRM421 group showed a significant effect compared with the placebo group in the post-CAE® evaluation, but no effect was seen in the pre-CAE® evaluation. 【0026】 The results of eye discomfort and the 4 - symptom questionnaire (ODS) recording data are summarized in Table 3. 【Table 3 - 1】 【Table 3 - 2】 【Table 3 - 3】 【Table 3 - 4】 【0027】 Cataract is the clouding of the eye's lens. The prevalence rates of both dry eye and cataract increase with age. Therefore, it is not uncommon for patients to suffer from DED and cataract simultaneously. The subjects in the above - mentioned BRM421 group and placebo group are further analyzed into subgroups based on whether they have cataract. Unexpectedly, based on the evaluations before and after CAE (registered trademark), no significant improvement in VAS burning / stinging pain was seen in patients with only DED with BRM421 treatment (see Figure 4A). However, based on the evaluations before and after CAE (registered trademark), a very significant improvement in VAS burning / stinging pain was seen in patients with both DED and cataract with BRM421 treatment (see Figure 4B). 【0028】 Cataracts are typically treated surgically. DED can complicate cataract surgery or its postoperative effects. Furthermore, cataract surgery can worsen existing dry eye disease or cause dry eye in patients with healthy corneas. Postoperative dry eye can affect visual outcomes and visual recovery time. Therefore, subjects with both DED and cataracts were further analyzed based on whether they had received cataract surgery. As shown in FIGS. 4C and 4D, BRM421 treatment showed a significant improvement in VAS burning / stinging, regardless of cataract surgery, compared to the placebo group. Nevertheless, BRM421 treatment showed a more pronounced improvement in VAS burning / stinging in subjects who had received cataract surgery (see FIG. 4D) than in those who had not (see FIG. 4C). These results suggest that BRM421 treatment is particularly effective in treating DED in patients who have undergone cataract surgery. 【0029】 When analyzed with respect to VAS dryness, the same results were obtained. As shown in FIG. 4E, BRM421 treatment did not show a significant improvement (based on both pre- and post-CAE® evaluations) in subjects without cataracts compared to the placebo group. On the other hand, BRM421 treatment showed a significant improvement (based on both pre- and post-CAE® evaluations) in subjects with cataracts compared to the placebo group (see FIG. 4F). Furthermore, BRM421 treatment showed a significant improvement (based on both pre- and post-CAE® evaluations) in subjects with cataracts, regardless of surgical status (see FIGS. 4G and 4H). 【0030】 Severe dry eye cases can lead to corneal damage, which can be evaluated by fluorescein staining. The PDSPs of the present invention can treat DED. Furthermore, these PDSPs can also repair corneal damage. As shown in Figure 5A, BRM421 treatment did not show a significant improvement in corneal damage repair in subjects without cataracts. In contrast, Figure 5B shows that BRM421 treatment showed a significant improvement in corneal damage repair in subjects with cataracts. These improvements appear to be more significant in cataract subjects without surgery (Figure 5C) compared to cataract subjects with surgery (Figure 5D). The selective effectiveness of BRM421 treatment in cataract patients is unexpected. 【0031】 The above results clearly show that the PDSPs of the present invention are effective in the treatment of DED. In particular, it has been found that these PDSPs are unexpectedly very effective in the treatment or prevention of DED in subjects before or after cataract surgery. Embodiments of the present invention relate to pharmaceutical compositions and methods for preventing and / or treating dry eye in a subject. The subject according to embodiments of the present invention can be a human or an animal. The method according to embodiments of the present invention can include administering to a subject in need of prevention or treatment of dry eye a pharmaceutical composition comprising a peptide selected from any of the PDSPs listed in Table 1. According to an example of the present invention, the pharmaceutical composition can include a peptide of the present invention, or a salt of such a peptide, together with a pharmaceutically acceptable carrier or excipient such as distilled water, physiological saline, oil, or gel. 【0032】 The pharmaceutical composition of the present invention can be formulated in any suitable dosage form such as a solution, ointment, suspension, gel, or emulsion, and can be formulated at any suitable concentration such as 10 - 200 μM. A person skilled in the art would be able to formulate these at appropriate concentrations to deliver an effective dose without inventive effort. These dosage forms can be formulated for topical application to the eye or for other suitable routes of administration (e.g., oral or injection). 【0033】 Although the embodiments of the present invention have been described by way of limited examples, those skilled in the art will understand that other modifications or changes are possible without departing from the scope of the present invention. Therefore, the scope of protection should be limited by the appended claims.

Claims

[Claim 1] A pharmaceutical composition for use in the treatment of dry eye disease associated with cataracts, comprising a peptide consisting of an amino acid sequence selected from any of SEQ ID NOs: 1-7. [Claim 2] A pharmaceutical composition according to claim 1, comprising a peptide having the amino acid sequence of SEQ ID NO:

3. [Claim 3] A pharmaceutical composition according to claim 1 or 2, wherein the dry eye disease is a dry eye disease caused by cataract surgery.

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