Tissue-specific Wnt signal enhancing molecules and uses thereof

A tissue-specific Wnt (“Wingless-related integration site” or “Wingless and Int-I” or “Wingless-Int”) signal enhancing molecule, or a pharmaceutically acceptable salt thereof, comprising:

• (a) a first domain comprising two R-spondin 2 polypeptides, or fragments thereof comprising the furin I domain of the R-spondin 2 polypeptide, wherein the R-spondin 2 polypeptides comprise amino acid substitutions at amino acids corresponding to F105 and F109 of human R-spondin 2 of SEQ ID NO:2, and wherein the first domain specifically binds one or more-transmembrane E3 ubiquitin ligases, wherein the one or more transmembrane E3 ubiquitin ligases are Zinc and Ring Finger 3 (ZNRF3) and Ring Finger Protein 43 (RNF43);
• and
• (b) a second domain comprising an Immunoglobulin G (IgG) antibody;
• wherein the second domain specifically binds a tissue-specific cell surface molecule, wherein the tissue-specific cell surface molecule is an asialoglycoprotein receptor I (ASGRI), and wherein the IgG antibody comprises two heavy chain polypeptides and two light chain polypeptides, wherein each light chain polypeptide comprises SEQ ID NO:
• 72, and each heavy chain polypeptide comprises SEQ ID NO:
• 86,
• wherein the R-spondin 2 polypeptides are fused to the heavy chain polypeptides of the IgG antibody.