Compositions and methods for treating craniosynostosis
Provided herein are compositions and methods for treating craniosynostosis. In particular, provided herein are methods of treating and preventing craniosynostosis by administering an isolated TNAP polypeptide or a nucleic acid molecule that encodes a TNAP polypeptide.
1. A method of treating or preventing craniosynostosis, comprising administering an alkaline phosphatase polypeptide to a human subject selected from the group consisting of a neonatal human subject, a human fetus, and a human embryo, wherein said alkaline phosphatase polypeptide decreases coronal suture fusion in the human subject.
2. The method of claim 1 , wherein the alkaline phosphatase polypeptide is selected from the group consisting of: tissue non-specific alkaline phosphatase (TNALF), placental alkaline phosphatase (PALP), germ cell alkaline phosphatase (GCALP), intestinal alkaline phosphatase (IALP), asfotase alfa, and any functional fragment thereof.
3. The method of claim 1 , wherein the alkaline phosphatase polypeptide comprises a soluble alkaline phosphatase (sALP).
4. The method of claim 1 , wherein the alkaline phosphatase polypeptide comprises a bone-targeting moiety.
5. The method of claim 4 , wherein the alkaline phosphatase polypeptide comprises a polypeptide having the structure selected from the group consisting of: Z-sALP-Y-spacer-X-W n -V and Z-W n -X-sALP-Y-spacer-V,
wherein V is absent or is an amino acid sequence of at least one amino acid;
X is absent or is an amino acid sequence of at least one amino acid;
Y is absent or is an amino acid sequence of at least one amino acid;
Z is absent or is an amino acid sequence of at least one amino acid; and
W n is a polyaspartate or a polyglutamate wherein n is 3-20.
6. The method of claim 5 , wherein the spacer comprises a fragment crystallizable region (Fc).
7. The method of claim 6 , wherein the Fc is the Fc of an immunoglobulin selected from the group consisting of IgG-1, IgG-2, IgG-3, and IgG-4.
8. The method of claim 2 , wherein the TNALP comprises the amino acid sequence set forth by SEQ ID NO: 2.
9. The method of claim 5 , wherein the alkaline phosphatase polypeptide comprises the amino acid sequence set forth by SEQ ID NO: 6 or SEQ ID NO: 7.
10. The method of claim 9 , wherein the alkaline phosphatase polypeptide consists of the amino acid sequence set forth by SEQ ID NO: 7.
11. The method of claim 1 , wherein said administering is in utero is initiated within 1 day of birth, within 3 days of birth, within 1 week of birth, or within 2 weeks of birth.
12. The method of claim 1 , wherein said administering is repeated at least once.
13. The method of claim 1 , wherein said human subject has hypophosphatasia (HPP) or is at risk of developing HPP.