Methods of delivering transgenes to the eye
Provided herein are methods of delivering transgenes to an eye of a subject comprising the use of pharmaceutical compositions having one or more polynucleotides suitable for enhancing, increasing, augmenting, and/or supplementing the levels of the transgene in the eye. Also provided herein are methods of correcting vision loss in a subject in need thereof comprising the use of the pharmaceutical compositions described herein.
1. A method of delivering a human transgene to an eye of a subject, the method comprising administering to the eye of the subject a pharmaceutical composition comprising:
a) a replication-defective herpes simplex virus type-1 (HSV-1) comprising a recombinant HSV-1 genome, wherein the recombinant HSV-1 genome comprises one or more polynucleotides comprising the human transgene; and
b) a pharmaceutically acceptable carrier,
wherein the pharmaceutical composition is administered topically or via injection to the eye of the subject,
wherein the one or more polynucleotides comprising the human transgene are operably linked to a promoter suitable for transcription in a mammalian cell,
wherein the subject has a disorder or disease of the eye associated with vision loss,
wherein the recombinant HSV-1 genome comprises an inactivating mutation in one or both copies of the ICP4 HSV-1 gene, and
wherein the recombinant HSV-1 genome comprises an inactivating mutation in the ICP22 HSV-1 gene.
2. The method of claim 1 , wherein the injection is intravitreal injection.
3. The method of claim 1 , wherein the replication-defective HSV-1 is suitable for delivering the one or more polynucleotides comprising the human transgene to one or more target cells of the eye of the subject.
4. The method of claim 1 , wherein the inactivating mutation in one or both copies of the ICP4 HSV-1 gene is a deletion of at least a portion of the coding sequence of the ICP4 HSV-1 gene.
5. The method of claim 1 , wherein the one or more polynucleotides comprising the human transgene is in one or both of the ICP4 viral gene loci.
6. The method of claim 1 , wherein the inactivating mutation in the ICP22 HSV-1 gene is a deletion of at least a portion of the coding sequence of the ICP22 HSV-1 gene.
7. The method of claim 1 , wherein the recombinant HSV-1 genome comprises an inactivating mutation in one or both copies of an ICP0 HSV-1 gene, an ICP27 HSV-1 gene, an ICP47 HSV-1 gene, a tk HSV-1 gene, an UL41 HSV-1 gene, or an UL55 HSV-1 gene.
8. The method of claim 1 , wherein the subject is a human.
9. The method of claim 1 , wherein the replication-defective HSV-1 has reduced cytotoxicity when compared to its wild-type counterpart.
10. The method of claim 1 , wherein the inactivating mutation in the ICP22 HSV-1 gene is a deletion of at least a portion of the promoter region of the ICP22 HSV-1 gene.
11. A method of delivering a human transgene to an eye of a subject, the method comprising:
providing a pharmaceutical composition comprising:
a) a replication-defective HSV-1 comprising a recombinant HSV-1 genome, wherein the recombinant HSV-1 genome comprises one or more polynucleotides comprising the human transgene, wherein the one or more polynucleotides comprising the human transgene are operably linked to a promoter suitable for transcription in a mammalian cell,
wherein the recombinant HSV-1 genome comprises an inactivating mutation in one or both copies of the ICP4 HSV-1 gene,
wherein the replication-defective HSV-1 is suitable for delivering the one or more polynucleotides comprising the human transgene to the epidermis and/or dermis of the subject; and
b) a pharmaceutically acceptable carrier; and
administering the pharmaceutical composition topically or via injection to the eye of the subject that has a disorder or disease of the eye associated with vision loss.
12. The method of claim 11 , wherein the injection is intravitreal injection.
13. The method of claim 11 , wherein the replication-defective HSV-1 is suitable for delivering the one or more polynucleotides comprising the human transgene to one or more target cells of the eye of the subject.
14. The method of claim 11 , wherein the inactivating mutation in one or both copies of the ICP4 HSV-1 gene is a deletion of at least a portion of the coding sequence of the ICP4 HSV-1 gene.
15. The method of claim 11 , wherein the one or more polynucleotides comprising the human transgene is in one or both of the ICP4 viral gene loci.
16. The method of claim 11 , wherein the recombinant HSV-1 genome comprises an inactivating mutation in the ICP22 HSV-1 gene.
17. The method of claim 16 , wherein the inactivating mutation in the ICP22 HSV-1 gene is a deletion of at least a portion of the coding sequence of the ICP22 HSV-1 gene.
18. The method of claim 16 , wherein the inactivating mutation in the ICP22 HSV-1 gene is a deletion of at least a portion of the promoter region of the ICP22 HSV-1 gene.
19. The method of claim 11 , wherein the recombinant HSV-1 genome comprises an inactivating mutation in one or both copies of an ICP0 HSV-1 gene, an ICP22 HSV-1 gene, an ICP27 HSV-1 gene, an ICP47 HSV-1 gene, a tk HSV-1 gene, an UL41 HSV-1 gene, or an UL55 HSV-1 gene.
20. The method of claim 11 , wherein the subject is a human.
21. The method of claim 11 , wherein the replication-defective HSV-1 has reduced cytotoxicity when compared to its wild-type counterpart.