TATk-CDKL5 fusion proteins, compositions, formulations, and use thereof
View Patent ↗Disclosed herein are compositions and formulations containing a TATk-CDKL5 fusion protein. Also disclosed are methods of producing a TATk-CDKL5 fusion protein from vectors containing a TATk-CDKL5 cDNA and methods of transducing cells with the vectors containing a TATk-CDKL5 cDNA and the TATk-CDKL5 fusion protein.
1. A fusion protein comprising:
a CDKL5 polypeptide sequence, wherein the CDKL5 polypeptide sequence comprises SEQ ID NO:2 or SEQ ID NO: 16; and
a TATκ polypeptide sequence, wherein the TATκ polypeptide sequence has about 90% to about 100% sequence identity to SEQ ID NO: 4, wherein the TATκ polypeptide is operatively coupled to the CDKL5 polypeptide.
2. The fusion protein of claim 1 , further comprising an Igk-chain leader sequence polypeptide, wherein the Igk-chain leader sequence is operatively coupled to the CDKL5 polypeptide.
3. The fusion protein of claim 1 , further comprising a reporter protein polypeptide, wherein the reporter protein polypeptide is operatively coupled to the CDKL5 polypeptide.
4. The fusion protein of claim 1 , further comprising a protein tag polypeptide, wherein the protein tag polypeptide is operatively coupled to the CDKL5 polypeptide.
5. The fusion protein of claim 1 , wherein the fusion protein has a polypeptide sequence according to SEQ ID NO: 8, SEQ ID NO: 10, SEQ ID NO: 12, or SEQ ID NO: 14.
6. The fusion protein of claim 1 , wherein the fusion protein increases neurite growth, elongation, branch number, or branch density in a brain of a treated subject as compared to an untreated control subject.
7. The fusion protein of claim 1 , wherein the fusion protein reduces neuron apoptosis in the brain of a treated subject as compared to an untreated control subject.
8. A pharmaceutical formulation comprising:
a therapeutically effective amount of a fusion protein comprising:
a CDKL5 polypeptide sequence, wherein the CDKL5 polypeptide sequence comprises SEQ ID NO:2 or SEQ ID NO: 16; and
a TATκ polypeptide sequence, wherein the TATκ polypeptide sequence has about 90% to about 100% sequence identity to SEQ ID NO: 4, wherein the TATκ polypeptide is operatively coupled to the CDKL5 polypeptide; and
a pharmaceutically acceptable carrier.
9. The pharmaceutical formulation of claim 8 , wherein the fusion protein further comprises an Igk-chain leader sequence polypeptide, wherein the Igk-chain leader sequence is operatively coupled to the CDKL5 polypeptide.
10. The pharmaceutical formulation of claim 8 , wherein the fusion protein further comprises a reporter protein polypeptide, wherein the reporter protein polypeptide is operatively coupled to the CDKL5 polypeptide.
11. The pharmaceutical formulation of claim 8 , wherein the fusion protein further comprises a protein tag polypeptide, wherein the protein tag polypeptide is operatively coupled to the CDKL5 polypeptide.
12. The pharmaceutical formulation of claim 8 , wherein the fusion protein has a polypeptide sequence according to SEQ ID NO: 8, SEQ ID NO: 10, SEQ ID NO: 12, or SEQ ID NO: 14.
13. The pharmaceutical formulation of claim 8 , wherein the therapeutically effective amount of the fusion protein treats one or more symptoms of a CDKL5 deficiency, Rett syndrome, or Rett syndrome variant in a treated subject as compared to an untreated control subject.
14. The pharmaceutical formulation of claim 8 , wherein the therapeutically effective amount of the fusion protein increases neurite growth, elongation, branch number, or branch density in a brain of a treated subject as compared to an untreated control subject.
15. The pharmaceutical formulation of claim 8 , wherein the therapeutically effective amount of the fusion protein reduces neuron apoptosis in the brain of a treated subject as compared to an untreated control subject.
16. The pharmaceutical formulation of claim 8 , wherein the therapeutically effective amount of the fusion protein improves motor function in a treated subject as compared to an untreated control subject.
17. The pharmaceutical formulation of claim 8 , wherein the therapeutically effective amount of the fusion protein improves cognitive function in a treated subject as compared to an untreated control subject.
18. A method comprising:
administering to a subject in need thereof a therapeutically effective amount of a pharmaceutical formulation comprising:
an amount of a fusion protein comprising:
a CDKL5 polypeptide sequence, wherein the CDKL5 polypeptide sequence comprises SEQ ID NO:2 or SEQ ID NO: 16; and
a TATκ polypeptide sequence, wherein the TATκ polypeptide sequence has about 90% to about 100% sequence identity to SEQ ID NO: 4, wherein the TATκ polypeptide is operatively coupled to the CDKL5 polypeptide; and
a pharmaceutically acceptable carrier.
19. The method of claim 18 , wherein the subject in need thereof has or is suspected of having a CDKL5 deficiency, Rett syndrome, or a Rett syndrome variant.
20. The method of claim 18 , wherein the therapeutically effective amount of the fusion protein treats one or more symptoms of a CDKL5 deficiency, Rett syndrome, or Rett syndrome variant in a treated subject as compared to an untreated control subject.