Compositions and methods for treatment of netherton syndrome

Abstract

The present disclosure provides recombinant nucleic acids comprising one or more polynucleotides encoding a polypeptide; viruses comprising the recombinant nucleic acids; compositions comprising the recombinant nucleic acids and/or viruses; methods of their use; and articles of manufacture or kits thereof.

1 - 6 . (canceled) 
     
     
         7 . A method of providing 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 replication defective herpes simplex virus comprising a recombinant herpes simplex virus genome, wherein the recombinant herpes simplex virus genome comprises one or more polynucleotides encoding a Serine Protease Inhibitor Kazal-type 5 (SPINK5) polypeptide; and   (b) a pharmaceutically acceptable excipient,   wherein the one or more polynucleotides encoding the SPINK5 polypeptide are operably linked to a promoter suitable for transcription in a mammalian cell, and   wherein the pharmaceutical composition is administered topically, transdermally, subcutaneously, intradermally, or transmucosally.   
     
     
         8 . The method of  claim 7 , wherein the subject is a human. 
     
     
         9 . The method of  claim 7 , 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. 
     
     
         10 . The method of  claim 7 , wherein the one or more signs or symptoms of AD 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. 
     
     
         11 . The method of  claim 7 , wherein the skin of the subject is abraded prior to administration. 
     
     
         12 . The method of  claim 7 , wherein the recombinant herpes simplex virus genome is a recombinant herpes simplex virus type 1 (HSV-1) genome. 
     
     
         13 . The method of  claim 12 , 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. 
     
     
         14 . The method of  claim 7 , wherein the recombinant herpes simplex virus genome comprises an inactivating mutation in one or both copies of an ICP4 herpes simplex virus gene. 
     
     
         15 . The method of  claim 7 , wherein the SPINK5 polypeptide is a human SPINK5 polypeptide. 
     
     
         16 . The method of  claim 7 , wherein the SPINK5 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. 
     
     
         17 . A method of enhancing, increasing, augmenting, and/or supplementing the levels of a Serine Protease Inhibitor Kazal (SPINK) polypeptide in one or more cells of a subject, the method comprising administering to the subject an effective amount of a pharmaceutical composition comprising:
 (a) a replication defective herpes simplex virus comprising a recombinant herpes simplex virus genome, wherein the recombinant herpes simplex virus genome comprises one or more polynucleotides encoding the SPINK polypeptide; and   (b) a pharmaceutically acceptable excipient.   
     
     
         18 . The method of  claim 17 , wherein the subject is a human. 
     
     
         19 . The method of  claim 17 , wherein the one or more cells are selected from the group consisting of keratinocytes, melanocytes, Langerhans cells, Merkel cells, mast cells, fibroblasts, and adipocytes. 
     
     
         20 . The method of  claim 17 , wherein the recombinant herpes simplex virus genome is a recombinant HSV-1 genome. 
     
     
         21 . The method of  claim 20 , wherein the recombinant HSV-1 genome comprises an inactivating mutation in a herpes simplex virus gene selected from the group consisting of ICP0, ICP4, ICP22, ICP27, ICP47, tk, UL41, and UL55. 
     
     
         22 . The method of  claim 17 , wherein the recombinant herpes simplex virus genome comprises an inactivating mutation in one or both copies of an ICP4 herpes simplex virus gene. 
     
     
         23 . The method of  claim 17 , wherein the SPINK polypeptide is selected from the group consisting of SPINK1, SPINK2, SPINK4, SPINK5, SPINK6, SPINK7, SPINK8, SPINK9, SPINK13, and SPINK14. 
     
     
         24 . The method of  claim 17 , wherein the SPINK polypeptide is a human SPINK polypeptide. 
     
     
         25 . The method of  claim 17 , wherein the one or more polynucleotides encoding the SPINK polypeptide are operably linked to a promoter suitable for transcription in a mammalian cell. 
     
     
         26 . The method of  claim 17 , 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. 
     
     
         27 . The method of  claim 17  wherein the pharmaceutical composition is administered topically, transdermally, subcutaneously, intradermally, or transmucosally to the subject. 
     
     
         28 . A pharmaceutical composition comprising:
 (a) a replication defective herpes simplex virus comprising a recombinant herpes simplex virus genome, wherein the recombinant herpes simplex virus genome comprises one or more polynucleotides encoding a SPINK polypeptide; and   (b) a pharmaceutically acceptable excipient.   
     
     
         29 . The pharmaceutical composition of  claim 28 , wherein the recombinant herpes simplex virus genome is a recombinant HSV-1 genome. 
     
     
         30 . The pharmaceutical composition of  claim 29 , wherein the recombinant HSV-1 genome comprises an inactivating mutation in a herpes simplex virus gene selected from the group consisting of ICP0, ICP4, ICP22, ICP27, ICP47, tk, UL41, and UL55. 
     
     
         31 . The pharmaceutical composition of  claim 28 , wherein the recombinant herpes simplex virus genome comprises an inactivating mutation in one or both copies of an ICP4 herpes simplex virus gene. 
     
     
         32 . The pharmaceutical composition of  claim 28 , wherein the SPINK polypeptide is selected from the group consisting of SPINK1, SPINK2, SPINK4, SPINK5, SPINK6, SPINK7, SPINK8, SPINK9, SPINK13, and SPINK14. 
     
     
         33 . The pharmaceutical composition of  claim 28 , wherein the SPINK polypeptide is a human SPINK polypeptide. 
     
     
         34 . The pharmaceutical composition of  claim 28 , wherein the one or more polynucleotides encoding a SPINK polypeptide are operably linked to a promoter suitable for transcription in a mammalian cell. 
     
     
         35 . The pharmaceutical composition of  claim 28 , wherein the pharmaceutically acceptable excipient is suitable for topical, transdermal, subcutaneously, epicutaneous, intradermal, oral, sublingual, buccal, rectal, vaginal, intravenous, intraarterial, intramuscular, intraosseous, intracardial, intraperitoneal, transmucosal, intravitreal, subretinal, intraarticular, peri-articular, local, or inhaled administration. 
     
     
         36 . The pharmaceutical composition of  claim 28 , wherein the pharmaceutically acceptable excipient is suitable for topical, transdermal, subcutaneous, intradermal, or transmucosal administration.