Wnt ligands for the development of diagnostics and treatments of CNS and BBB disorders
Diseases of the brain are the third leading cause of death after heart disease and cancer. The central nervous system (CNS) is protected from general circulation by specialized vasculature, the tightly-sealed blood-brain barrier. Disruption of central nervous system vasculature, either in excess or shortage, can create or abet disease states such as brain cancer and stroke. Controlling blood flow and barrier permeability has the potential to treat diseases of vascular destruction (stroke, ischemia, hypoxia), vascular excess (brain tumors, gliomas), and difficulties with CNS drug delivery. The identification of genes and signaling pathways that influence the development of the CNS vasculature and blood-brain barrier (BBB) may provide useful therapeutic targets for treating vascular disorders of the CNS and disorders of the blood-brain barrier.
Innovations and Advantages
Using mouse genetics, scientists in Harvard University show that Wnt7a and Wnt7b are required for vascularization and initiation of a BBB in the developing CNS. They also show that in the absence of these Wnts, the CNS displays reduced and abnormal vascular sprouting, severe vascular leakage, and lack of GLUT-1 expression in the developing blood vessels. In addition, their findings suggest that Wnt signaling may be perturbed in diseases that affect the embryonic as well as adult neurovasculatures, such as those in brain tumors. The Wnt7a and Wnt7b signaling pathways may harbor valuable drug targets for specifically manipulating the cerebral vasculature and brain function in several human diseases.
This discovery will allow the development of methods for treating and diagnosing vascular disorders of the CNS or disorders of the blood-brain barrier. For example, a patient with tumor angiogenesis would benefit from inhibitors of Wnt7a/b or Wnt signaling that suppress blood vessel formation at the site of the tumor. In another example, when used with nuclear medicine techniques such as Positron emission tomography (PET) or Single photon emission computed tomography (SPECT), specific radiolabels that interact with the Wnt ligands may provide a means for diagnosing and monitoring vascular disorders of the CNS or disorders of the blood-brain barrier in a non-invasive manner. The level of activity of the canonical Wnt signaling pathway in the vasculature of brain tumors may correlate to the severity of the disease; therefore, it may be used to provide valuable information for staging the cancer and for monitoring treatment responses.
Intellectual Property Status : Patent pending.
Stenman JM, Rajagopal J, Carroll TJ, Ishibashi M, McMahon J, McMahon AP. 2008. Canonical Wnt signaling regulates organ-specific assembly and differentiation of CNS vasculature. Science. 322(5905):1247-50.
McMahon, Andrew P.
Stenman, Jan Mikael
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Reference Harvard Case #2944