Protozoan variant-specific surface proteins (VSP) as carriers for oral drug delivery
The invention provides compositions for oral delivery and methods of treatment using VSP carriers, such as Giardia sp. variable surface proteins (VSP), to deliver therapeutic agents. VSP drug carriers can be combined with bioactive peptides, e.g., insulin, glucagon, or hGH, and be administered orally or mucosally. VSP carriers are resistant to acidic pHs and to proteolytic degradation and protect therapeutic agents from degradation in the gastrointestinal tract.
1. A method of delivering peptide hormone to-mucosal epithelial cells in a subject in need thereof comprising orally administering a therapeutic composition comprising a peptide hormone and a Giardia VSP (Variant-specific Surface Protein) carrier to the subject, wherein(i) the VSP carrier is bound non-covalently to the peptide hormone;(ii) the VSP carrier-bound peptide hormone is therapeutically effective;(iii) the VSP carrier-bound peptide hormone is more resistant to pH- mediated or enzymatic degradation than the same peptide hormone not bound to the same VSP carrier; and,(iv) the VSP carrier has at least 70% amino acid sequence identity with the sequence of the extracellular domain of a VSP from Giardia selected from VSP1267 (SEQ ID NO:490), VSP9B10 (SEQ ID NO:572), and VSPH7 (SEQ ID NO:504).
2. The method according to claim 1 , wherein the peptide hormone: VSP carrier molecule to molecule ratio ranges from about 10:1 to about 1:10.
3. The method according to claim 2 , wherein the peptide hormone: VSP carrier molecule to molecule ratio is about 3:1.
4. The method according to claim 2 , wherein the peptide hormone: VSP carrier molecule to molecule ratio is about 1:1.
5. The method according to claim 1 , wherein the VSP from Giardia is VSP 1267.
6. The method according to claim 1 , wherein the VSP carrier comprises the amino acid sequence of SEQ ID NO:2.
7. The composition according to claim 1 , wherein the VSP carrier consisting of the sequence of SEQ ID NO: 1.
8. The method according to claim 1 , wherein the VSP carrier further comprises a heterologous moiety.
9. The method according to claim 1 , wherein the peptide hormone is selected from the group consisting of insulin, human growth hormone, and glucagon, and a combination of two or more of said peptide hormones.
10. The method according to claim 1 , wherein the peptide hormone is a natural insulin, a recombinant insulin, an insulin analog, or a combination thereof.
11. The method according to claim 10 , wherein the insulin analog is a fast-acting insulin, a long-acting insulin, or a combination thereof.
12. The method according to claim 10 , wherein the insulin analog is insulin aspart, insulin glargine, or a combination thereof.
13. The method according to claim 1 , wherein the subject suffers from a hormone deficiency.
14. The method according to claim 13 , wherein the hormone deficiency is diabetes.
15. The method according to claim 1 , wherein the VSP carrier having at least 70% amino acid sequence identity with the sequence of the extracellular domain of VSP1267 (SEQ ID NO: 490), VSP9B10 (SEQ ID NO: 572), or VSPH7 (SEQ ID NO: 504) is selected from SEQ ID NOS: 58, 143, 163, 166, 167, 308, and 486, or a fragment thereof.
16. The method according to claim 1 , wherein the mucosal epithelial cells are intestinal, gastric, or oral mucosal epithelial cells.