Wnt signaling agonist molecules

Abstract

Therapeutic agents are capable of activating (GPR)124/RECK/Frizzled/lipoprotein receptor-related protein (LRP)-mediated Wnt signaling. The agents do not activate Frizzled/LRP-mediated Wnt signaling in the absence of RECK and/or GPR124. The agents are particularly useful for the prevention or treatment of neurovascular disorders or central nervous system (CNS) disorders that include neurovascular dysfunction.

What is claimed is: 
     
         1 . A pharmaceutical composition comprising a therapeutically effective amount of a polypeptide or a nucleic acid encoding said polypeptide, wherein said polypeptide consists of an N-terminal domain (NTD) of a Wnt7a or Wnt7b polypeptide,
 said NTD having at least 80% sequence identity to an amino acid sequence according to SEQ ID No. 24 or SEQ ID No. 25, or wherein   said polypeptide is a fragment of an NTD of a Wnt7a or Wnt7b polypeptide, said fragment comprising at least 225 contiguous amino acids of an amino acid sequence according to SEQ ID No. 24 or SEQ ID No. 25.   
     
     
         2 . The pharmaceutical composition according to  claim 1 , wherein said polypeptide has an amino acid sequence according to SEQ ID No. 24 or SEQ ID No. 25. 
     
     
         3 . The pharmaceutical composition according to  claim 1 , wherein said polypeptide is preceded N-terminally by a signal peptide having an amino acid sequence according to SEQ ID No. 26 or SEQ ID No. 27. 
     
     
         4 . The pharmaceutical composition according to  claim 1 , for use as a medicament. 
     
     
         5 . The pharmaceutical composition according  claim 1 , for use in the prevention or treatment of a neurovascular disorder or a central nervous system (CNS) disorder. 
     
     
         6 . The pharmaceutical composition for use according to  claim 5 , wherein said neurovascular disorder is selected from the group consisting of ischemic stroke, hemorrhagic stroke, ischemia/reperfusion injury, brain aneurysms, arteriovenous malformations (AVMs), cavernous malformations, vasculitis, cerebral hemorrhage, subarachnoid hemorrhage, spinal vascular malformations, carotid artery stenosis, Moyamoya disease and intracranial atherosclerosis and combinations thereof, or said CNS disorder is selected from the group consisting of multiple sclerosis, ischemic stroke, brain cancer, epilepsy, dementia, vascular dementia, HIV-1-associated dementia, Alzheimer's disease, Parkinson's disease, Huntington disease, amyotrophic lateral sclerosis, infectious brain diseases, traumatic brain injuries, migraine and chronic traumatic encephalopathy and combinations thereof.