Use of nrf2 inducers to treat epidermolysis bullosa simplex and related diseases

Inactive Publication Date: 2011-01-06
THE JOHN HOPKINS UNIV SCHOOL OF MEDICINE
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  • Abstract
  • Description
  • Claims
  • Application Information

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Benefits of technology

[0011]In an additional embodiment, the present invention provides a method for treating or preventing skin blistering in a patient comprising administering to the patient a composition comprising a therapeutically effective amount of an Nrf2 inducer. In one aspect of the invention, the patient may be affected by Epidermolysis bullosa simplex. In a preferred embodiment of the invention, the patient suffers from Epidermolysis bullosa simplex-Weber-Cockayne type, Epidermolysis bullosa simplex-Koebner type, Epidermolysis bullosa simplex with mottled pigmentation, Epidermolysis bullosa simplex-Dowling-Meara type, or Epidermolysis bullosa simplex with muscular dystrophy.
[0012]In a further embodiment, the method for treating or preventing skin blistering comprises administering a phase II enzyme inducer. In one embodiment, the phase II inducer is an isothiocyanate. In a preferred embodiment the phase II enzyme inducer is sulforaphane. In another preferred embodiment, the phase II enzyme inducer is a sulforaphane synthetic analogue. In yet another embodiment, the Nrf2 inducer is keratinocyte growth factor. In an additional embodiment, the Nrf2 inducer is oltipraz. In a further embodiment, the Nrf2 inducer is ethacrynic acid. In a further embodiment, the Nrf2 inducer is a Michael reaction acceptor, such as triterpenoids or cyclic/acyclic bis-benzylidene-alkalones. In still another preferred embodiment, the Nrf2 inducer causes the selective induction of K6, K16 or K17 in the keratinocytes in the skin of the patient.
[0013]In yet another embodiment, the present invention provides a method for treating or preventing a keratin-based skin disease in a patient comprising administering to the patient a composition comprising a therapeutically effective amount of an Nrf2 inducer. The patient to be treated may be affected by an epidermolytic or non-epidermolytic keratin-based skin disease. Exemplary types of keratin-based skin diseases (Cassidy et al., 2002) to be treated include, but are not limited to, epidermolytic hyperkeratosis, ichtyosis bullosa of Siemens, pachyonychia congenita, epidermolytic or non-epidermolytic palmoplantar keratoderma (diffuse or focal) steatocystoma multiplex, Naegeli-Francesch

Problems solved by technology

The patient to be treated may

Method used

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  • Use of nrf2 inducers to treat epidermolysis bullosa simplex and related diseases
  • Use of nrf2 inducers to treat epidermolysis bullosa simplex and related diseases
  • Use of nrf2 inducers to treat epidermolysis bullosa simplex and related diseases

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example 1

K14 Null and K5 Null Mouse Strains as Models for Very Severe EBS Disease

[0051]Introduction of null mutations at the K14 locus (Lloyd et al., 1995) and K5 locus (Peters et al., 2001) in mice essentially abrogate the keratin filament network in basal keratinocytes in the epidermis, and renders the keratinocytes acutely fragile in the face of physiological levels of mechanical trauma. The presence of small amounts of K15, a type I keratin related to K14, leaves a residual but wispy keratin filament network in basal keratinocytes of K14 null epidermis. Accordingly, K5 null mice show more extensive skin blistering and die sooner (before P0.5) than K14 null mice (P2-P3 in K14 null mice). Thus, these two mouse models represent very severe forms of the disease.

[0052]The K14 null mouse strain (Lloyd et al., 1995) has proven to be the more useful model for these studies. The selective fragility of epidermal basal cells and the associated trauma-induced skin blistering seen in K14-null mice mi...

example 2

Ectopic Expression of Gli2 Rescues Skin Blistering in K14 Null Mice but not in K5 Null Mice

[0053]Keratin 17 is a direct target for the transcription factor Gli, a powerful terminal effector of hedgehog signaling pathways (Bianchi et al., 2005). In Gli2TG transgenic mice (Grachtchouk et al., 2000), expression of the Gli2 coding sequence is controlled by the K5 gene promoter, thereby causing its accumulation in the basal layer of epidermis. Gli2TG mice appear normal at birth and in the days thereafter, but they develop epidermal hyperplasia as young adults, which progresses to basal cell carcinoma by 2-3 months of age. Availability of Gli2TG transgenic mice provided an opportunity to conduct a “proof of principle” experiment, whereby constitutive expression of Gli2TG transgene in the setting of K14− / − mice should cause a stable upregulation of K17 in basal keratinocytes of epidermis, and hence, rescue their oral and skin blistering. Conversely, the Gli2TG transgene should not rescue t...

example 3

Sulforaphane Selectively Induces K16 and K17 in Skin Keratinocytes in Vitro and in Vivo

[0055]To evaluate the effect of sulforaphane (SF) on keratin gene transcription in vitro, a mouse keratinocyte line (308 cells) was exposed to 1 μM SF in acetonitrile vehicle, and mRNA levels were measured at 12, 24, and 48 hours after treatment. Relative to vehicle treatment, SF-treated keratinocytes showed a significant increase in the mRNA levels of NQO1, a well-established SF target, at all time points as expected (Dinkova-Kostova, et al., 2006). Similarly to NQO1, K17 and K16 mRNAs were each elevated ˜2.5 fold at 12 h after SF treatment, but their induction was shorter-lived and levels returned to baseline by 24 hours. No significant change was measured for K5, K6a, K6b, K14 and K15 mRNA levels. Indirect immunofluorescence revealed an obvious induction of K17, but not K14, at the protein level.

[0056]At higher doses and in some specific contexts, SF induces apoptosis, or programmed cell death ...

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Abstract

The present invention relates to methods and compositions for the prevention and treatment of keratin-based skin diseases. In particular, the application describes compositions and methods of treating a patient suffering from skin blistering comprising the use of phase II enzyme inducers.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS[0001]This application claims the benefit of U.S. Provisional Application No. 60 / 929,985.BACKGROUND OF THE INVENTION[0002]The skin is continuously exposed to changes in the external environment, including oxidative insults, heat, cold, UV radiation, injury, and mechanical stresses. The stratum corneum, composed of terminally differentiated keratinocytes, constitutes the natural barrier that prevents loss of water and prevents entry of infectious agents (e.g., bacteria, viruses), small objects (e.g., particles), and a broad variety of water-soluble chemicals.[0003]Intermediate filaments (IFs), microtubules (MTs) and microfilaments (MFs) constitute the cytoskeleton and play important roles in the organization and mechanical integrity of skin keratinocytes (Fuchs and Cleveland, 1998). Keratins are a large family of proteins that form the intermediate filament cytoskeleton in epithelial cells. Keratins are encoded by two groups of genes, type I and...

Claims

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Application Information

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IPC IPC(8): A61K31/26A61K38/18A61P17/00
CPCA61K31/00A61K38/1825A61K31/497A61K31/26A61K31/192A61P17/00A61K9/0014A61K31/275
Inventor COLOUMBE, PIERRE A.KERNS, MICHELLE L.
Owner THE JOHN HOPKINS UNIV SCHOOL OF MEDICINE
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