Compositions and methods for the treatment of netherton syndrome

Abstract

The present disclosure provides recombinant nucleic acids comprising one or more polynucleotides encoding a Serine Protease Inhibitor Kazal-type (SPINK) polypeptide (e.g., a SPINK5 polypeptide); viruses comprising the recombinant nucleic acids; compositions and formulations comprising the recombinant nucleic acids and/or viruses; methods of their use (e.g., for the treatment of Netherton Syndrome); and articles of manufacture or kits thereof.

What is claimed is: 
     
         1 . A pharmaceutical composition comprising:
 (a) a herpes virus comprising a recombinant herpes virus genome, wherein the recombinant herpes virus genome comprises one or more polynucleotides encoding a Serine Protease Inhibitor Kazal-type (SPINK) polypeptide; and   (b) a pharmaceutically acceptable excipient.   
     
     
         2 . The pharmaceutical composition of  claim 1 , wherein the recombinant herpes virus genome is replication competent. 
     
     
         3 . The pharmaceutical composition of  claim 1 , wherein the recombinant herpes virus genome is replication defective. 
     
     
         4 . The pharmaceutical composition of  claim 1 , wherein the recombinant herpes virus genome is selected from the group consisting of a recombinant herpes simplex virus genome, a recombinant varicella zoster virus genome, a recombinant human cytomegalovirus genome, a recombinant herpesvirus 6A genome, a recombinant herpesvirus 6B genome, a recombinant herpesvirus 7 genome, a recombinant Kaposi's sarcoma-associated herpesvirus genome, and any derivatives thereof. 
     
     
         5 . The pharmaceutical composition of  claim 1 , wherein the recombinant herpes virus genome is a recombinant herpes simplex virus type 1 (HSV-1) genome. 
     
     
         6 . The pharmaceutical composition of  claim 5 , wherein the recombinant HSV-1 genome comprises an inactivating mutation in a herpes simplex virus gene selected from the group consisting of Infected Cell Protein (ICP) 0, ICP4, ICP22, ICP27, ICP47, thymidine kinase (tk), Long Unique Region (UL) 41, and UL55. 
     
     
         7 . The pharmaceutical composition of  claim 1 , wherein the SPINK polypeptide is a human SPINK polypeptide. 
     
     
         8 . The pharmaceutical composition of  claim 1 , wherein the SPINK polypeptide is a Serine Protease Inhibitor Kazal-type 5 (SPINK5) polypeptide. 
     
     
         9 . The pharmaceutical composition of  claim 1 , wherein the SPINK polypeptide comprises a sequence having at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to an amino acid sequence selected from the group consisting of SEQ ID NOS: 7-25. 
     
     
         10 . The pharmaceutical composition of  claim 1 , wherein the herpes virus has reduced cytotoxicity as compared to a corresponding wild-type herpes virus. 
     
     
         11 . The pharmaceutical composition of  claim 1 , wherein the herpes virus is selected from the group consisting of a herpes simplex virus, a varicella zoster virus, a human cytomegalovirus, a herpesvirus 6A, a herpesvirus 6B, a herpesvirus 7, and a Kaposi's sarcoma-associated herpesvirus. 
     
     
         12 . The pharmaceutical composition of  claim 1 , wherein the herpes virus is a herpes simplex virus type 1 (HSV-1). 
     
     
         13 . The pharmaceutical composition of  claim 1 , wherein the pharmaceutical composition is suitable for topical, transdermal, subcutaneous, intradermal, oral, intranasal, intratracheal, sublingual, buccal, rectal, vaginal, inhaled, intravenous, intraarterial, intramuscular, intracardiac, intraosseous, intraperitoneal, transmucosal, intravitreal, subretinal, intraarticular, peri-articular, local, or epicutaneous administration. 
     
     
         14 . The pharmaceutical composition of  claim 1 , wherein the pharmaceutical composition is suitable for topical, transdermal, or intradermal administration. 
     
     
         15 . A method of providing prophylactic, palliative, or therapeutic relief to one or more signs or symptoms of Netherton Syndrome (NS) or atopic dermatitis (AD) in a subject in need thereof, the method comprising administering to the subject an effective amount of a pharmaceutical composition comprising:
 (a) a herpes virus comprising a recombinant herpes virus genome, wherein the recombinant herpes virus genome comprises one or more polynucleotides encoding a Serine Protease Inhibitor Kazal-type (SPINK) polypeptide; and   (b) a pharmaceutically acceptable excipient.   
     
     
         16 . The method of  claim 15 , wherein the subject is a human. 
     
     
         17 . The method of  claim 15 , wherein the one or more signs or symptoms of NS are selected from the group consisting of defective keratinization, a defective skin barrier, recurrent skin infections, congenital ichthyosiform erythroderma, ichthyosis linearis circumflexa, trichorrhexis invaginata, chronic skin inflammation, and any combinations thereof. 
     
     
         18 . The method of  claim 15 , wherein the one or more signs or symptoms of atopic dermatitis are selected from the group consisting of itchy skin, dry skin, red to brownish-grey patches on the skin, small raised bumps on the skin, thickened skin, cracked skin, scaly skin, swollen skin, weeping sores, skin infections, eyelid dermatitis, cataracts, and any combinations thereof. 
     
     
         19 . The method of  claim 15 , wherein the pharmaceutical composition is administered topically, transdermally, subcutaneously, epicutaneously, intradermally, orally, sublingually, buccally, rectally, vaginally, intravenously, intraarterially, intramuscularly, intraosseously, intracardially, intraperitoneally, transmucosally, intravitreally, subretinally, intraarticularly, peri-articularly, locally, or via inhalation to the subject. 
     
     
         20 . The method of  claim 15 , wherein the pharmaceutical composition is administered topically, transdermally, or intradermally to the subject. 
     
     
         21 . The method of  claim 20 , wherein the skin of the subject is abraded prior to administration. 
     
     
         22 . The method of  claim 15 , wherein the recombinant herpes virus genome is selected from the group consisting of a recombinant herpes simplex virus genome, a recombinant varicella zoster virus genome, a recombinant human cytomegalovirus genome, a recombinant herpesvirus 6A genome, a recombinant herpesvirus 6B genome, a recombinant herpesvirus 7 genome, a recombinant Kaposi's sarcoma-associated herpesvirus genome, and any derivatives thereof. 
     
     
         23 . The method of  claim 15 , wherein the recombinant herpes virus genome is a recombinant herpes simplex virus type 1 (HSV-1) genome. 
     
     
         24 . The method of  claim 23 , wherein the recombinant HSV-1 genome comprises an inactivating mutation in a herpes simplex virus gene selected from the group consisting of Infected Cell Protein (ICP) 0, ICP4, ICP22, ICP27, ICP47, thymidine kinase (tk), Long Unique Region (UL) 41, and UL55. 
     
     
         25 . The method of  claim 15 , wherein the SPINK polypeptide is a human SPINK polypeptide. 
     
     
         26 . The method of  claim 15 , wherein the wherein the SPINK polypeptide is a Serine Protease Inhibitor Kazal-type 5 (SPINK5) polypeptide. 
     
     
         27 . The method of  claim 15 , wherein the SPINK polypeptide comprises a sequence having at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to an amino acid sequence selected from the group consisting of SEQ ID NOS: 7-25. 
     
     
         28 . The method of  claim 15 , wherein the herpes virus has reduced cytotoxicity as compared to a corresponding wild-type herpes virus. 
     
     
         29 . The method of  claim 15 , wherein the herpes virus is selected from the group consisting of a herpes simplex virus, a varicella zoster virus, a human cytomegalovirus, a herpesvirus 6A, a herpesvirus 6B, a herpesvirus 7, and a Kaposi's sarcoma-associated herpesvirus. 
     
     
         30 . The method of  claim 15 , wherein the herpes virus is a herpes simplex virus type 1 (HSV-1).