WO2025226898A1 - Compositions and methods for the treatment of epidermolysis bullosa - Google Patents

Abstract

Described herein are methods of treating a dermatological lesion resulting from epidermolysis bullosa (EB) in a patient by administering a topical or transdermal composition to the dermatological lesion. The topical or transdermal composition comprises a beta blocker which has a plasma half-life of less than 1 hour to the dermatological lesion such as esmolol. In an aspect, the patient is an adult, an infant or a child.

Description

COMPOSITIONS AND METHODS FOR THE TREATMENT OF EPIDERMOLYSIS

BULLOSA

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims priority to U.S. Provisional Application 63/637,946 filed on April 24, 2024, which is incorporated herein by reference in its entirety.

FIELD OF THE DISCLOSURE

[0001] The present disclosure is related to the treatment of epidermolysis bullosa using topical beta blocker compositions.

BACKGROUND

[0002] Epidermolysis bullosa (EB) is a group of rare genetic conditions that affect the skin, making it fragile, causing numerous blisters and negatively impacting patients’ quality of life. EB has a wide range of severity, from mild disease with blistering of the palms and feet, to generalized forms with severe blistering resulting in chronic non-healing wounds. EB can be complicated by infection, pain, and fluid and electrolyte imbalance that can be lifethreatening, especially in infants and children. There is a large unmet need for the prevention and treatment of large blisters, erosions, keratoderma, and nonhealing wounds in this disease, particularly in infants and children.

BRIEF SUMMARY

[0003] In one aspect, a method of treating a dermatological lesion resulting from epidermolysis bullosa (EB) in a patient comprises administering a topical or transdermal composition comprising a beta blocker which has a plasma half-life of less than 1 hour to the dermatological lesion. In an aspect, the beta blocker is esmolol, landiolol, a racemic mixture of R and S isomers thereof, an R- or S-isomer thereof, or pharmaceutically acceptable salt thereof.

[0004] In specific aspects, the patient is an adult, an infant, or a child.

[0005] The above-described and other features will be appreciated and understood by those skilled in the art from the following detailed description and appended claims.

BRIEF DESCRIPTION OF THE DRAWINGS

[0006] FIG. 1 is a picture of the trunk of an infant with EB. [0007] FIG. 2 shows data for a scratch assay with skin keratinocytes derived from a patient with EB and a COL7A1 p.G2073D/ p.R578X mutation.

DETAILED DESCRIPTION

[0008] Oral and intravenous beta blockers have emerged as important adjunct therapy for patients with large wounds as a result of thermal injury (e g., bums). However, these oral and topical therapies pose significant risks for patients with EB, especially infants and children with the large chronic wounds caused by EB. Further, EB patients are at increased risk of adverse events related to systemic beta blockade due to their existing fluid, cardiovascular, electrolyte, and metabolic abnormalities. Topical beta blockers such as propranolol or timolol will be readily absorbed into the systemic circulation when applied to skin wounds observed in EB, particularly wounds that lack the stratum cornea and epidermis of the skin. Given the half-life of most beta blockers, topically administered beta blockers can accumulate in the circulation and reach steady state plasma concentrations similar to or greater than those achieved by orally or intravenously administered beta blockers. This problem is exacerbated in EB patients as they have large areas of eroded skin, which lacks the stratum cornea, facilitates absorption due to exposure of dermal capillaries. There is an unmet clinical need to develop safe topical formulations for the treatment of EB wounds, particularly in infants, that will not accumulate in systemic circulation.

[0009] Described herein is the treatment of EB by delivering an agent topically /transdermally, directly into the targeted tissue of the skin, with much less active drug in systemic circulation, minimizing or eliminating active drug exposure and subsequent systemic beta blockade in which side effects are known to occur.

[0010] In an aspect, a method of treating a dermatological lesion resulting from epidermolysis bullosa in a patient comprises administering a topical or transdermal composition comprising a beta blocker which has a plasma half-life of less than 1 hour to the dermatological lesion.

[0011] As used herein, the term dermatological lesion includes blisters, erosions, ulcerations, keratoderma, and chronic wounds associated with EB. Excluded from this term are cutaneous carcinomas such as squamous cell carcinomas that occur particularly in patients with severe recessive dystrophic EB. Also, the term dermatological lesion includes both skin lesions and mucosal lesions. Mucosal lesions occur in the genitalia as well as the mouth and lips of EB patients and include orogenital lesions. [0012] A specific agent is a beta blocker which has a plasma half-life of less than 1 hour such as esmolol, landiolol, a racemic mixture of R and S isomers thereof, an R-or S- isomer thereof, or a pharmaceutically acceptable salt thereof.

[0013] In an aspect, the beta blocker is in racemic (i.e., a mixture of S and R isomers in any amounts but generally comprising >10% of more than one isomer), a resolved R- stereoisomer form (i.e., generally >90% R isomer), or a resolved S -stereoisomer form (i.e., generally >90% S isomer). In an aspect, the beta blocker has little or no beta adrenergic antagonist activity in its resolved R-stereoisomer form.

[0014] Esmolol (methyl 3-[4-[2-hydroxy-3-(propan-2-ylamino)propoxy] phenyl] propanoate) has the following formula:

[0015] R-esmolol has the PubChem ID CID 25271656, and S-esmolol has the PubChem ID CID 28125476. The chiral center in esmolol is at the carbon with the hydroxyl (-OH) and isopropylamino groups in the side chain. In R-esmolol the hydroxyl and isopropylamino groups are arranged in the R configuration (clockwise order). In S-esmolol: the hydroxyl and isopropylamino groups are arranged in the S configuration (counterclockwise order).

[0016] Landiolol ([(4S)-2,2-dimethyl-l,3-dioxolan-4-yl]methyl 3-[4-[(2S)-2-hydroxy- 3-[2-(morpholine-4-carbonylamino)ethylamino]propoxy]phenyl] propanoate) has the following formula: [0017] Esmolol alone has a combination of relatively high skin flux for local delivery of the drug into the skin and subcutaneous tissue plus a very short half-life for rapid clearance after entering systemic circulation, and hence minimal systemic exposure and accumulation. Landiolol was developed by modifying the chemical structure of esmolol. Because of its molecular weight, landiolol has an estimated lower skin permeation rate than esmolol. Also, it is believed that landiolol has a higher rate of cardiovascular (beta-1) selectivity, greater potency, and shorter duration of action.

[0018] The rapid clearance of esmolol and landiolol derive from their metabolic properties. For example, once introduced into the systemic circulation, esmolol is taken up into the cytosol of red blood cells where carboxylesterases cleave the phenylpropionate moiety, releasing methanol and an inactive metabolite with 1/1500 the potency of esmolol. This non-active metabolite is significantly more hydrophilic than esmolol, and hence, will not partition significantly across the blood brain barrier. Similarly, landiolol is metabolized via hydrolysis of the ester moiety. It is rapidly hydrolyzed to an inactive form by both carboxylesterases in the liver and pseudocholinesterases in the plasma, resulting in a very short elimination half-life of about 4 minutes.

[0019] As described herein, the beta blocker acts locally, i.e., at the site of the dermatological lesion, e.g., wound. Therefore, the drug needs to penetrate into, and preferably through, the epidermis and dermis for local activity’ and systemic delivery, i.e., delivery into the circulatory system, is not required. The present disclosure does not, however, exclude delivery through the skin and into the circulatory system, particularly in view of the relatively short half-lives of the beta blockers described herein.

[0020] As described in US 2022/0218716, topical esmolol has been proposed to treat infantile hemangioma (IH), a common benign vascular tumor in children. While the mechanism of beta blockers in the treatment of IH is not completely understood, vasoconstriction, inhibition of angiogenesis, and/or promotion of apoptosis are proposed mechanisms.

[0021] The use of topical esmolol to treat diabetic foot ulcers has also been described (Rastogi et al. (1), "Topical Esmolol Hydrochlonde as a Novel treatment Modality for Diabetic Foot Ulcers: A Phase 3 Randomized Clinical Study”, JAMA Network Open. 2023;6(5):e2311509; doi:10.1001/jamanetworkopen.2023.11509; Rastogi et al., (2), “Novel topical esmolol hydrochloride (Galnobax) for Diabetic Foot Wound: Phase 1/2 Multicenter, Randomized, Double-Blind , Vehicle-Controlled Parallel Group Study”, Advances in Wound Care, 12(8), 429-438, 2023). The patients in Rostogi et al. (1), for example, were patients with type I or type II diabetes and diabetic foot ulcers of grade 1 A and 1C. Grade 1 diabetic foot ulcers are superficial wounds through the epidermis or epidermis and dermis, but which do not penetrate to tendon, capsule or bone. The target ulcers had an area of 2-15 cm² postdebridement and had been open for at least 6 weeks at the time of their screening visit. The typical ulcer age was 49.8 weeks. A topical 14% esmolol gel was applied to the ulcers for 12 weeks in addition to the standard of care (SoC). For this study, the SoC included wound cleaning with normal saline, maintenance of a moist wound environment and removal of infected and/or nonviable tissue. The primary endpoint was target ulcer closure at 12 weeks. As shown in Figure 2B of Rostogi et al. (1), for wounds greater than or equal to 5 cm², for example, adding esmolol to the SoC increased the percent closed per ulcer site from about 28% to about 48%. It was asserted that esmolol works for diabetic foot ulcers because it “inhibits Casp3, upregulates Bcl-2 and activates ERK.1/2 mitogen-activated protein kinase, thereby facilitating wound repair. ”

[0022] The patients treated in Rastogi (1) and (2) were specifically patients with diabetic foot ulcers and in particular ulcers that had been open for at least 6 weeks. Debridement is an important part of care to remove necrotic or unhealthy tissue as was done in the SoC of Rastogi. Also importantly, as is known in the art, diabetic foot ulcers often develop as a result of neuropathy and hypoglycemia-induced metabolic abnormalities. According to Kulkami et al., (“Novel topical esmolol hydrochloride improves wound healing in diabetes by inhibiting aldose reductase, generation of advanced glycation end products, and facilitating the migration of fibroblasts”, Front. Endocrinol, 13:926129, 2022), esmolol is useful for healing of wounds in the diabetic condition due to its direct inhibition of aldose reductase, the formation of sorbitol and advanced glycation end products (AGEs), and promoting the migration of human fibroblasts, endothelial cells and keratinocytes in a high glucose condition. Another important consideration is that diabetic foot ulcers are accompanied by hydrostatic effects (swelling). Thus, diabetic foot ulcers are complex chronic wounds complicated by hydrostatic effects, sugar dysregulation, and obesity.

[0023] Diabetic foot ulcers are a very particular type of injury having the following characteristics: peripheral neuropathy including nerve damage due to prolonged high blood sugar which reduces sensation in the feet; poor circulation (peripheral arterial disease caused by reduced blood flow (and along with it reduced oxygen and nutrients) in the hands and feet due to narrowed blood vessels, neuropathy (nerve damage) leading to loss of sensation in the feet; a weakened immune response due to reduced white blood cell function; chronic inflammation which disrupts would healing: and impaired collagen synthesis which weakens the wound closure process.

[0024] The dermatological lesions in patients with EB are very different from diabetic foot ulcers. EB is a subclass of rare genetic conditions that result in extreme fragility of the skin as illustrated in FIG 1. Patients with EB are continually developing blistered skin as a result of loss-of -function mutations in genes that encode proteins critical for skin adhesion and integrity. Because these proteins are dysfunctional or missing, there is severe skin fragility mild trauma to the skin such as heat or friction result in separation of the skin layers and skin blisters. Patients with EB also have impaired healing of their wounds and can develop chronic, non-healing wounds, particularly at sites of friction such as elbows, knees, lower legs, nails, hands, and face. The pathophysiology and treatment of impaired wound healing observed in EB patients is very diffident form that observed in diabetic foot ulcers. Cleaning and management of fresh and chronic wounds in these patients can be quite challenging due to the skin fragility in these patients. Unlike diabetic foot ulcers, debridement is contraindicated in EB patients. In an aspect, the dermatological lesion to be treated in an EB patient is a fresh area of blistered, eroded, ulcerated, or keratoderma skin. In another aspect, the dermatological lesion to be treated in an EB patient is a chronic wound.

[0025] There are several different types of EB caused by different genetic mutations. EB simplex (EBS) is typically a localized form of EB in which skin is cleaved in the basal layer of the epidermis. Blisters in these patients are typically found at sites of friction and on the palms of the hands and soles of the feet and are worsened by heat or friction. EBS is typically an autosomal dominant disease wherein the genetic mutations lead to a defective keratin protein. Junctional EB (JEB) occurs in the basement membrane and is an autosomal recessive disease caused by mutations in the gene coding for collagen 17 or laminin 5 and others. Dystrophic EB (DEB) can be caused by a mutation in the collagen 7 gene and can be dominant or recessive. DEB involves cleavage beneath the lamina densa within the dermis. Patients with the autosomal dominant form are prone to blisters in areas prone to bumping and knocking such as toes, knees, fingers and elbows. Patients with the rare recessive form have more debilitating disease with lifelong chronic wounds and fusion of toes and fingers. Patients with DEB, tike patients with thermal bums, have a greatly increased risk of squamous cell carcinoma in their chronic wounds. Kindler syndrome is a rare form of EB caused by mutations in kindlin 1. In early childhood, patients experience blisters and later experience scarring, thickened palms and soles, and other effects. [0026] In a specific aspect, the patient is an adult, an infant, or a child. EB can be determined by a clinical diagnosis and/or genetic mutations related to skin fragility and/or genomic mutations in proteins critical for skin integrity. Mutations in identified and unidentified genes, variation in non-coding regions, deletions, insertions, mutations and copy number variation can be associated with skin fragility and EB.

[0027] Genes involved in EB include intermediate cytoskeleton proteins including keratins 5/14 (KRT5/KRT14), EXPH5 (Exophilin-5), TGM5 (Transglutaminase-5) genes, laminin 332, integrin a6|34, LAMA3, COLVII-A1 (Collagen-VII-Al), COL VII, and FERMT1 (Four point one Ezrin Radixin and Moesin - 1).

[0028] Genetic testing for patients with suspected dystrophic epidermolysis bullosa (DEB) can performed by Prevention Genetics and Krystal Biotech Inc, for example. In an aspect, the methods described herein can further comprising genetic testing for CD 151, CDSN, CHST8, COL17A1, COL7A1, CSTA, DSG1, DSP, DST, EXPH5, FERMT1, ITGA3, ITGA6, ITGB4, JUP, KLHL24, KRT1, KRT10, KRT14, KRT5, LAMA3, LAMB3, LAMC2, PKP1, PLEC, SERPINB8, and/or TGM5.

[0029] Additional diagnostic tests for EB include immunohistochemistry, and skin biopsy as well as visual observation of skin blisters.

[0030] Described herein is the topical delivery of a beta blocker to minimize the systemic effects of the beta blocker. The beta blocker can be delivered topically using, e.g. sprays, solutions dispersions, gels, creams, foams, or patches. Advantageously, the beta blocker has a very short plasma half-life, i.e., less than 1 hour, preferably less than 0.5 hour and more preferably less than 15 or even 10 minutes, which can minimize the potential of the beta blocker to cause side effects in other organ systems. In illustrative embodiments, the beta blocker has one or more of the following properties: it has a plasma half-life of less than 1 hour; it is metabolized to a hydrophilic form that will not significantly penetrate the bloodbrain barrier, it is highly selective for the beta-1 adrenoceptor, e.g., at least 25 times greater affinity for the beta-1 receptor than for the beta-2 receptor.

[0031] The beta blockers, e.g. esmolol or landiolol, are delivered to a dermatological lesion in the form of a topical or transdermal composition. The terms “topical’⁷ and “transdermal” both refer to delivery of an active agent to the surface of the skin and to delivery⁷ of active agent into the skin. They encompass both topical delivery in the form of, e.g., lotions, gels, foams, sprays, dispersions, and creams applied directly to the skin as well as transdermal delivery⁷ in the form of patches and wound dressings. Patches include both reservoir and matrix patches. An exemplary patch is a matrix patch yvhere the active agent is incorporated into a polymer layer and those that are called reservoir patches where the drug is a solution, a gel, or a cream, enclosed between two or more polymer layers. In topical formulations as well as in reservoir type patch systems, gels or creams may be formed by dissolving in the solutions small amounts of hydrophilic thickening polymers, such as hydroxypropyl cellulose (e.g., Klucel®), at, e.g., 0.1 to 5 wt. % or 0.1 to 1 wt. %. Both reservoir and matrix patch systems are well accepted with transdermal products of both types available in the marketplace.

[0032] Unlike topical compositions which are typically administered at least once daily, patches can be worn for intervals of days, such as 2, 3, 4, 5, 6, or 7 days, for example.

[0033] Patches can include multilayer patches, including, for example, a backing layer, an active agent layer which may itself be one or more layers, and an overlay.

[0034] A matrix patch can include a pressure sensitive adhesive (PSA) into which the active agent is dissolved or dispersed. Exemplary PSA adhesives include acrylic polymers and copolymers, silicones and polyisobuty lenes and they represent anywhere from 50 to 95% of the drug active matrix. Acrylate PSAs have great flexibility because of their ease in forming copolymers and allowing larger amounts of drugs to be incorporated within (e.g., U.S. Pat. No. 9,539,201). Because they are more hydrophilic than other PSAs, they are not commonly used for adhesion to skin for more than three and one half days. Polyisobutylene adhesives are the most hydrophobic and they are often used for the development of patches that adhere to the skin for seven days. These PSAs are however not easy to modify, so in many cases the active portion of the patch, where the drug is dissolved, is made of acrylate adhesive and there is a peripheral adhesive attached to the back side of the patch and extending in all direction beyond the active patch to provide for long term adhesion of over seven days (U.S. Pat. No. 8,246,978).

[0035] In some embodiments, the compositions can be formulated with one or more of skin permeation enhancers and thickening agents.

[0036] Chemical enhancers, i.e., skin permeation enhancers, can be used with topical formulations (e.g., U.S. Pat. No. 9,186,352) as well as with patch formulations (e.g., U.S. Pat. No. 10,675,240). Exemplary chemical enhancers include dimethyl sulfoxide (DMSO), ethyl alcohol, lauryl lactate, ethyl lactate, capric acid, oleic acid, oleyl alcohol, glycerol monooleate, levulinic acid, propylene glycol, polyethylene glycol, diethylene glycol monoethyl ether, and dipropylene glycol among others. An exemplary enhancer comprises 10-25% (preferably 15-20%) propylene glycol, 10-25% (preferably 15-20%) polyethylene glycol, e.g., PEG 400, 10-25% (preferably 15-20%) DMSO, 5-20% (preferably 5-15%) diethylene glycol monoethyl ether, e.g., Transcutol® P, and 1-10% (preferably 2-6%) oleyl alcohol, with all percentages being wt. %. The book Percutaneous Penetration Enhancers, CRC Press, 1995, describes dozens of chemical families that can be used as enhancers and over 100 individual chemicals.

[0037] The pharmaceutical compositions may further comprise excipients such as gelling agents, plasticizers, humectants, buffers, and the like. The composition can be formulated and applied to the skin, for instance, as a lotion, cream, ointment, gel, foam, liquid dispersion or solution, or aerosol that can be applied directly to the skin, or it can be contained within a transdermal delivery device, such as a patch, in which the composition is contained, for example, within a reservoir by a semi-permeable membrane or as a soft polymeric matrix such as a pressure sensitive adhesive that is in direct contact with the skin, i.e., that is firm enough that a permeable membrane is not required.

[0038] Humectants, for example, can be used in transdermal patches to absorb the transepidermal water loss and reduce irritation. Humectants are water soluble or swellable polymers and those more commonly used include polyvinyl pyrrolidone and polyvinyl pyrrolidone/vinyl acetate copolymers (e.g., U.S. Pat. Nos. 9,050,348; 9,539,201). Such humectants can also function as plasticizers.

[0039] Antioxidants can also be used, for example, in the active portion of the patch if the active agent is susceptible to oxidation. Oxidation can take place from oxygen permeating through the packaging film or from the inactive ingredients in the patch. For example, acrylate pressure sensitive adhesives as well as polyvinyl pyrrolidone are manufactured by free radical polymerization processes. Therefore, free radicals remaining within these polymers may degrade a susceptible drug when incorporated into these polymers (e.g., U.S. Pat. No. 9,364,487). Exemplary antioxidants include sodium bisulfite, sodium sulfite, isopropyl gallate, Vitamin C, Vitamin E, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), pentaerythritol tetrakis (3-(3,5-di-tert-butyl-4-hydroxyphenyl) propionate), or tris (2,4-di-tert-butylphenyl) phosphite.

[0040] Esterase inhibitors can be used with topical or transdermal delivery systems to protect the active agent from metabolizing to a non-active metabolite during its passage through the skin. Quinones, diones, isatins, flavanoids, fatty acids, sterols, myristic acid, sodium benzyd sulfate, and castor oil are some esterase inhibitors among many others that can be used (Current Medicinal Chemistry, 2018, Vol. 25, No. 14, p 1627).

[0041] The formulation can also comprise one or more preservatives, e.g., benzododecinium bromide 0.012%, citric acid, ascorbic acid, potassium sorbate, and the like. [0042] Wound dressings include hydrocolloid dressing, foam dressings and hydrogel dressings. For example, hydrocolloid dressings are gelling systems with an elastic matrix including a hydrophilic polymer such as sodium carboxymethylcellulose, gelatin, pectin, and/or sodium alginate. Duoderm® is a commercially available hydrocolloid dressing. Foam dressing include polyurethane-based foams such as Betafoam and Medifoam.

[0043] Hydrogel dressings are typically based on alginate, chitosan or collagen and include Tegagel®, Algosteril®, Nu-Gel®, Sorbsan®, and Curasorb®¹ alginate.

[0044] The topical beta blockers can also be administered with other therapies for EB such as gene therapies and other topical therapies.

[0045] Beremagene geperpavec-svdt (VYJUVEH®) is an FDA approved suspension for topical administration to treat epidermolysis bullosa with mutation(s) in the collagen type VII alpha 1 chain (COL7A1) gene. Beremagene geperpavec-svdt is a K is a herpes-simplex virus type 1 (HSV-1) vector-based gene therapy described in U.S. Patent No. 9,877,990.

[0046] A birch triterpenes (FILSUVEZ®) topical gel (U.S. Patent Nos. 8,828,444; 9,352,041; 9,827,214; 11,083,733: 11,266,660) for treating partial thickness wounds associated with junctional epidermolysis bullosa (JEB) and dystrophic epidermolysis bullosa in patients aged 6 months and older.

[0047] The invention is illustrated by the following example

Methods

[0048] Media: Keratinocyte growth media 400 mL DMDM/F12 medium (300 mL DMEM : 100 ML Fl 2); 40 mL FBS (10%); 4 mL RM + supplement; 4 mL 100 X penicillinstreptomycin; 1 mL 400X fungizone. Transport media: 3: 1 DMEM : F12 medium; 40 mL FBS (10%); RM-supplement; 2X penicillin-streptomycin; 1 X fungizone.

[0049] Scratch assay: The scratch assay is an art-accepted in vitro method to study would healing by observing cell migration. In the assay, a scratch is created in a confluent cell monolayer which removes cells from the scratch area. The migration of surrounding cells as they fill the gap created by the scratch is monitored. In the experiment below, the scratch assay is used to determine the effect of esmolol on cells from a patient with EB. Assay details:

[0050] Prepare 12-well plates for scratch assay. Draw lines on the bottom of the plate going through the center part of the wells to back track the coordinates of the well for imaging. [0051] Trypsinize the keratinocytes and count the cells using an automatic cell counter.

[0052] Seed the cells at a densify of 5X10⁵ cells/well and incubate at 37°C and 5% CO₂

[0053] Monitor cell grow th until the keratinocytes reach a confluency of approximately 80%. Remove keratinocyte growth media and replace with transport media for 25 hr to reduce cell proliferation (optional; if seeded using RM+ media).

[0054] Scratch the monolayers uniformly. The simplest method for performing a scratch is by using a 100 pL pipette tip ad applying enough force to disrupt the cells without damaging the bottom of the well.

[0055] Wash the cell monolayer with 1 mL of IX PBS and add 1 mL of fresh transport media with different concentrations of esmolol (NC, 1, 10, 50, 100 and 500 pM) into the respective wells.

[0056] Immediately after the scratch, TO (0 hr), take images of the scratch in each well using a phase contrast microscope at 4X magnification. Return the plate to the incubator.

[0057] Repeat imaging at T6, T 24 and T48 hr.

Analysis and data interpretation:

[0058] Measure the area of the gap that has not been covered by the cells using ImageJ software. Calculate as:

Migrated area = Initial area (Ai) - area at a specific time point (At)

Percentage of gap closed (%): (100-Ai/At)*100

[0059] Or express the data as area uncovered and normalize all the data points to TO.

[0060] Perform 2-way ANOVA to determine statistical significance.

Results

[0061] The data in FIG. 2 labeled EB 13 is skin keratinocytes derived from a patient with EB and a COL7A1 p.G2073D/ p.R578X mutation. For EB13, lOOmM and 500mM migrated faster than no drug, although only no drug vs 500mM was statically significant.

[0062] The use of the terms “a” and “an” and “the” and similar referents (especially in the context of the following claims) are to be construed to cover both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context. The terms first, second etc. as used herein are not meant to denote any particular ordering, but simply for convenience to denote a plurality of, for example, layers. The terms ‘‘comprising”, “having”, “including”, and “containing” are to be construed as open-ended terms (i.e., meaning “including, but not limited to”) unless otherwise noted. Recitation of ranges of values are merely intended to serve as a shorthand method of referring individually to each separate value falling within the range, unless otherwise indicated herein, and each separate value is incorporated into the specification as if it were individually recited herein. The endpoints of all ranges are included within the range and independently combinable. All methods described herein can be performed in a suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. The use of any and all examples, or exemplary language (e.g., “such as”), is intended merely to better illustrate the invention and does not pose a limitation on the scope of the invention unless otherwise claimed. No language in the specification should be construed as indicating any non-claimed element as essential to the practice of the invention as used herein.

[0063] While the invention has been described with reference to an exemplary embodiment, it will be understood by those skilled in the art that various changes may be made and equivalents may be substituted for elements thereof without departing from the scope of the invention. In addition, many modifications may be made to adapt a particular situation or material to the teachings of the invention without departing from the essential scope thereof. Therefore, it is intended that the invention not be limited to the particular embodiment disclosed as the best mode contemplated for carrying out this invention, but that the invention will include all embodiments falling within the scope of the appended claims. Any combination of the above-described elements in all possible variations thereof is encompassed by the invention unless otherwise indicated herein or otherwise clearly contradicted by context.

Claims

Claims

1. A method of treating a dermatological lesion resulting from epidermolysis bullosa (EB) in a patient, comprising administering a topical or transdermal composition comprising a beta blocker which has a plasma half-life of less than 1 hour to the dermatological lesion.

2. The method of claim 1, wherein the beta blocker is esmolol, landiolol, a racemic mixture of R and S isomers thereof, an R-isomer thereof, or pharmaceutically acceptable salt thereof.

3. The method of claim 1, wherein the beta blocker is esmolol, a racemic mixture of R and S isomers thereof, an R-isomer thereof, or pharmaceutically acceptable salt thereof.

4. The method of claim 1, wherein the patient is an adult.

5. The method of claim 1, wherein the patient is an infant or child.

6. The method of any of the foregoing claims, wherein the dermatological lesion is a fresh area of blistered skin.

7. The method of any of the foregoing claims, wherein the dermatological lesion is a mucosal lesion.

8. The method of any of the foregoing claims, wherein the dermatological lesion is a skin lesion.

9. The method of any of the foregoing claims, wherein the dermatological lesion is a fresh area of blistered, eroded, ulcerated, or keratoderma skin.

10. The method of any of the foregoing claims, wherein the dermatological lesion is a chronic wound.

11. The method of any of the foregoing claims, wherein the EB is EB simplex, junctional EB, dystrophic EB, or Kindler syndrome.

12. The method of any of the foregoing claims, further comprising, prior to treating, genetic testing the patient for CD151, CDSN, CHST8, COL17A1, COL7A1, CSTA, DSG1, DSP, DST, EXPH5, FERMT1, ITGA3, ITGA6, ITGB4, JUP, KLHL24, KRT1, KRT10, KRT14, KRT5, LAMA3, LAMB3, LAMC2, PKP1, PLEC, SERPINB8, and/or TGM5.

13. The method of any of the foregoing claims, wherein the topical or transdermal composition is in the form of a lotion, gel, foam, spray, dispersion, cream, patch, wound dressing, or a combination thereof.