COMPOSITIONS AND METHODS FOR THE TREATMENT OF AUTOSOMAL RECESSIVE CONGENITAL ICHTHYOSIS
The present disclosure provides recombinant nucleic acids comprising one or more polynucleotides encoding a transglutaminase (TGM) polypeptide (e.g., a Transglutaminase-1 (TGM1) 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 .- 30 . (canceled)
31 . A pharmaceutical composition comprising:
(a) a replication defective herpes virus comprising a recombinant herpes virus genome, wherein the recombinant herpes virus genome comprises one or more polynucleotides encoding a transglutaminase (TGM) polypeptide; and
(b) a pharmaceutically acceptable excipient.
32 . The pharmaceutical composition of claim 31 , 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.
33 . The pharmaceutical composition of claim 31 , wherein the replication defective herpes virus is a replication defective herpes simplex virus type-1 (HSV-1).
34 . The pharmaceutical composition of claim 31 , wherein the TGM polypeptide is selected from the group consisting of a TGM1 polypeptide, a TGM2 polypeptide, a TGM3 polypeptide, a TGM4 polypeptide, a TGM5 polypeptide, a TGM6 polypeptide, and a TGM7 polypeptide.
35 . The pharmaceutical composition of claim 31 , wherein the TGM polypeptide is a human TGM polypeptide.
36 . The pharmaceutical composition of claim 31 , wherein the replication defective herpes virus has reduced cytotoxicity as compared to a corresponding wild-type herpes virus.
37 . The pharmaceutical composition of claim 31 , wherein the replication defective 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.
38 . The pharmaceutical composition of claim 31 , wherein the pharmaceutical composition is suitable for topical, transdermal, subcutaneous, intradermal, administration.
39 . The pharmaceutical composition of claim 31 , wherein the pharmaceutical composition is suitable for topical administration.
40 . A method of enhancing, increasing, augmenting, or supplementing expression of one or more polynucleotides encoding a transglutaminase (TGM) 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 virus comprising a recombinant herpes virus genome, wherein the recombinant herpes virus genome comprises the one or more polynucleotides encoding the TGM polypeptide; and
(b) a pharmaceutically acceptable excipient.
41 . The method of claim 40 , wherein the subject is a human.
42 . The method of claim 40 , wherein the pharmaceutical composition is administered topically, transdermally, subcutaneously, intradermally, or transmucosally to the subject.
43 . The method of claim 40 , wherein the pharmaceutical composition is administered topically to the subject.
44 . The method of claim 40 , 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.
45 . The method of claim 40 , wherein the replication defective herpes virus is a replication defective herpes simplex virus type-1 (HSV-1).
46 . The method of claim 40 , wherein the TGM polypeptide is selected from the group consisting of a TGM1 polypeptide, a TGM2 polypeptide, a TGM3 polypeptide, a TGM4 polypeptide, a TGM5 polypeptide, a TGM6 polypeptide, and a TGM7 polypeptide.
47 . The method of claim 40 , wherein the TGM polypeptide is a human TGM polypeptide.
48 . The method of claim 40 , wherein the replication defective herpes virus has reduced cytotoxicity as compared to a corresponding wild-type herpes virus.
49 . The method of claim 40 , wherein the replication defective 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.
50 . The method of claim 40 , wherein the one or more target cells are one or more cells of the skin.