Compositions and methods for the treatment of wounds, disorders, and diseases of the skin
The present disclosure relates, in part, to pharmaceutical compositions comprising one or more polynucleotides suitable for enhancing, increasing, augmenting, and/or supplementing the levels of Collagen alpha-1 (VII) chain polypeptide and/or Lysyl hydroxylase 3 polypeptide and/or Keratin type I cytoskeletal 17 polypeptide in a subject. The present disclosure also relates, in part, to pharmaceutical compositions and methods of use for providing prophylactic, palliative, or therapeutic relief of a wound, disorder, or disease of the skin in a subject, including a subject having, or at risk of developing, one or more symptoms of epidermolysis bullosa.
1. A method of delivering a transgene to the skin of a subject, the method comprising administering to the subject a pharmaceutical composition comprising:
a) a replication-defective herpes simplex type 1 virus (HSV-1) comprising a recombinant herpes simplex type 1 virus genome, wherein the recombinant genome comprises one or more polynucleotides encoding the transgene; and
b) a pharmaceutically acceptable carrier;
wherein the recombinant genome comprises an inactivating mutation in the infected cell protein 22 (ICP22) herpes simplex virus gene;
wherein the pharmaceutical composition is administered topically, transdermally, or intradermally to the subject; and
wherein the replication-defective HSV-1 is suitable for delivering the one or more polynucleotides encoding the transgene to one or more target cells of the epidermis and/or dermis of the subject.
2. The method of claim 1 , wherein the recombinant genome further comprises an inactivating mutation in a herpes simplex virus gene selected from the group consisting of ICP0, ICP4, ICP27, ICP47, thymidine kinase (tk), long unique region (UL) 41, and UL55.
3. The method of claim 1 , wherein the recombinant genome further comprises an inactivating mutation in one or both copies of the ICP4 herpes simplex virus gene.
4. The method of claim 2 , wherein the inactivating mutation is a deletion of the coding sequence of the herpes simplex virus gene.
5. The method of claim 1 , wherein the HSV-1 has reduced cytotoxicity as compared to a wild-type herpes simplex type 1 virus.
6. The method of claim 1 , wherein the subject is a human.
7. The method of claim 1 , wherein the pharmaceutical composition is administered to one or more areas of the subject affected by a wound, disorder, or disease of the skin.
8. A pharmaceutical composition useful for delivery of a transgene to the skin of a subject, comprising:
a) a replication-defective herpes simplex type 1 virus (HSV-1) comprising a recombinant herpes simplex type 1 virus genome, wherein the recombinant genome comprises one or more polynucleotides encoding the transgene; and
b) a pharmaceutically acceptable carrier;
wherein the recombinant genome comprises an inactivating mutation in the infected cell protein 22 (ICP22) herpes simplex virus gene;
wherein the pharmaceutically acceptable carrier is suitable for topical, transdermal, or intradermal administration; and
wherein the replication-defective HSV-1 is suitable for delivering the one or more polynucleotides encoding the transgene to one or more target cells of the epidermis and/or dermis of the subject.
9. The pharmaceutical composition of claim 8 , wherein the recombinant genome further comprises an inactivating mutation in a herpes simplex virus gene selected from the group consisting of ICP0, ICP4, ICP27, ICP47, thymidine kinase (tk), long unique region (UL) 41, and UL55.
10. The pharmaceutical composition of claim 8 , wherein the recombinant genome further comprises an inactivating mutation in one or both copies of the ICP4 herpes simplex virus gene.
11. The pharmaceutical composition of claim 9 , wherein the inactivating mutation is a deletion of the coding sequence of the herpes simplex virus gene.
12. The pharmaceutical composition of claim 8 , wherein the HSV-1 has reduced cytotoxicity as compared to a wild-type herpes simplex type 1 virus.
13. The pharmaceutical composition of claim 8 , wherein the subject is a human.
14. The pharmaceutical composition of claim 8 , wherein the pharmaceutical composition is administered to one or more areas of the subject affected by a wound, disorder, or disease of the skin.
15. The method of claim 1 , wherein the one or more target cells are one or more keratinocytes and/or fibroblasts.
16. The method of claim 1 , wherein the HSV-1 has been engineered to reduce cytotoxicity in keratinocytes and/or fibroblasts as compared to a wild-type herpes simplex type 1 virus.
17. The method of claim 1 , wherein the pharmaceutical composition comprises at least 1×10 8 plaque forming units (PFU) of the replication-defective HSV-1.
18. The pharmaceutical composition of claim 8 , wherein the one or more target cells are one or more keratinocytes and/or fibroblasts.
19. The pharmaceutical composition of claim 8 , wherein the HSV-1 has been engineered to reduce cytotoxicity in keratinocytes and/or fibroblasts as compared to a wild-type herpes simplex type 1 virus.
20. The pharmaceutical composition of claim 8 , wherein the pharmaceutical composition comprises at least 1×10 8 plaque forming units (PFU) of the replication-defective HSV-1.
21. The method of claim 1 , wherein the pharmaceutically acceptable carrier is suitable for topical administration.
22. The pharmaceutical composition of claim 8 , wherein the pharmaceutically acceptable carrier is suitable for topical administration.