- Document Number:
20240024392
- Appl. No:
18/265248
- Application Filed:
December 03, 2021
- نبذة مختصرة :
Disclosed herein is an oncolytic HSV-1 virus genetically engineered for treatment of brain tumors, which lacks both copies of gamma 34.5 gene and an internal inverted repeat region and is optionally incorporated with immunostimulatory and/or immunotherapeutic genes. The oncolytic HSV-1 virus exhibited superior anti-tumor activity specifically in brain tumors. A pharmaceutical composition comprising the oncolytic HSV-1 virus and a pharmaceutically acceptable carrier, and a method of treatment of a brain tumor using the same is also disclosed.
- Claim:
1. An oncolytic Herpes Simplex Virus type 1 (oHSV-1) comprising a modified genome, wherein the modification comprises a) an alternation of a copy of γ34.5 gene that is in a terminal repeat of the genome, rendering that copy of γ34.5 gene incapable of expressing functional ICP34.5 protein, and b) a deletion of an internal inverted repeat region of the genome, causing one copy of each of double-copy genes and one copy of duplicated non-coding sequences within the internal inverted repeat region deleted, wherein the double-copy genes comprise genes encoding ICP0, ICP4, ICP34.5, ORF P and ORF O, and wherein all single-copy genes in both UL and US components of the genome are intact such that they are capable of expressing respective functional proteins.
- Claim:
2. The oHSV-1 of claim 1, wherein the alternation comprises a deletion of all or part of the coding or regulatory region of the copy of γ34.5 gene.
- Claim:
3. The oHSV-1 of claim 1, wherein the duplicated non-coding sequences include introns of ICP0, LAT domain and “a” sequence.
- Claim:
4. The oHSV-1 of claim 1, wherein the all single-copy genes in both UL and US components include UL1 to UL56 genes in the UL component and US1 to US12 genes in the US component.
- Claim:
5. The oHSV-1 of claim 1, wherein the HSV-1 is selected from the group consisting of strains F, KOS, and 17.
- Claim:
6. The oHSV-1 of claim 1, wherein the HSV-1 has a genome isomer of prototype (P).
- Claim:
7. The oHSV-1 of claim 6, wherein the deletion of an internal inverted repeat region causes excision of nucleotide positions 117005 to 132096 in the genome of F strain.
- Claim:
8. The oHSV-1 of claim 6, wherein the deletion of an internal inverted repeat region starts from the stop codon of the last gene in the UL component to the promotor of the first gene in the US component.
- Claim:
9. The oHSV-1 of claim 8, wherein the last gene in the UL component is UL56 gene.
- Claim:
10. The oHSV-1 of claim 8, wherein the first gene in the US component is US1 gene.
- Claim:
11. The oHSV-1 of claim 1, wherein the oHSV-1 is incorporated with a heterologous nucleic acid sequence encoding an immunostimulatory and/or immunotherapeutic agent, wherein the incorporation does not interfere with the expression of native genes of the HSV-1 genome.
- Claim:
12. The oHSV-1 of claim 11, wherein the oHSV-1 is incorporated with a heterologous nucleic acid sequence encoding an immunostimulatory agent and an immunotherapeutic agent.
- Claim:
13. The oHSV-1 of claim 11, wherein the immunostimulatory agent is selected from a group consisting of GM-CSF, IL-2, IL-12, IL-15, IL-24 and IL-27.
- Claim:
14. The oHSV-1 of claim 13, wherein the immunostimulatory agent is IL-12.
- Claim:
15. The oHSV-1 of claim 11, wherein the immunotherapeutic agent is an anti-PD-1 agent, an anti-CTLA-4 agent or both.
- Claim:
16. The oHSV-1 of claim 15, wherein the immunotherapeutic agent is an anti-PD-1 agent.
- Claim:
17. The oHSV-1 of claim 11, wherein the heterologous nucleic acid sequence is incorporated into the internal inverted repeat region and/or between UL3 and UL4 genes in the UL component.
- Claim:
18. The oHSV-1 of claim 11, wherein the oHSV-1 is incorporated with a heterologous nucleic acid sequence encoding IL-12 and an anti-PD-1 agent.
- Claim:
19. The oHSV-1 of claim 18, wherein the heterologous nucleic acid sequence encoding IL-12 is incorporated into the internal inverted repeat region and the heterologous nucleic acid sequence encoding the anti-PD-1 agent is incorporated between UL3 and UL4 genes in the UL component.
- Claim:
20. A pharmaceutical composition, comprising an effective amount of the oHSV-1 of claim 1 and a pharmaceutically acceptable carrier.
- Claim:
21-27. (canceled)
- Claim:
28. A method for treating or alleviating a tumor in a subject, comprising administering to the subject in need thereof an effective amount of the oHSV-1 of claim 1, or a pharmaceutical composition comprising the oHSV-1.
- Claim:
29. The method of claim 28, wherein the tumor is a brain tumor.
- Claim:
30. The method of claim 29, wherein the brain tumor is selected from a group consisting of glioma, glioblastoma, oligodendroglioma, astrocytoma, ependymoma, primitive neuroectodermal tumor, atypical meningioma, malignant meningioma, and neuroblastoma.
- Claim:
31. The method of claim 30, wherein the brain tumor is glioblastoma multiform.
- Current International Class:
61; 07; 12; 07; 07; 61
- الرقم المعرف:
edspap.20240024392
Processing Request
No Comments.