Method of treating dopaminergic and GABA-nergic disorders

Patent Number: 7,138,492

It is known that hedgehog proteins are important in specifying what cells give rise to what tissues during development. Others have patented using hedgehog proteins for stimulating insulin production. In this patent the inventors found a new use for hedgehog proteins besides their known role in embryogenesis. Initially, the potential of hedgehog to function in other areas besides development was suggested by the finding that sonic hedgehog is expressed in the ventral neural tissue after tissue specification has occurred. In this patent, expression of various hedgehog family members is demonstrated naturally in the substantia nigra, the cells that are dysfunctional in Parkinson’s patients. The inventors demonstrate various examples of the use of hedgehog for neuroprotection. One particularly interesting example is that administration of sonic hedgehog protected dopaminergic neurons from 5-phenyl-1,2,3,6-tetrahydropterine (MPTP)-mediated toxicity better than glia-derived neurotrophic factor (GDNF) and brain-derived neurotrophic factor (BDNF).

The patent provides 4 independent claims. The first one covers a polypeptide that can be either isolated or expressed recombinantly. The sequence has a minimum of 98% homology to the sequence described as SEQ ID #17 or and N-terminal fragment of the same sequence. The first independent claim further defines the invention as having a molecular weight of about 19 kDa. The statement in the claim that the polypeptide either binds to a patched protein or promotes the proliferation of testicular germ line cells provides functional classification of the protein. The second independent claim is a variant of the first one in that instead of claiming “…polypeptide comprising a sequence at least 98 percent identical…” claims “…polypeptide consisting essentially of a sequence at least 98 percent identical…” The third independent claim covers a sequence “identical” to the sequence ID mentioned. The fourth independent claim covers “…polypeptide consisting essentially of a sequence identical…” The dependent claims depend on all four independent claims and cover that the polypeptide binds to patched and promotes hedgehog signal transduction, that the polypeptide upregulates patched and/or gli expression after binding to patched, the polypeptide formulated in a pharmaceutically acceptable carrier, and the polypeptide purified to at least 80% by dry weight.

This patent is useful not only for treatment of a wide variety of neurological diseases associated with neural cell death, but also potentially for combination with cellular therapies or stimulators of endogenous neural stem cell replication. Additionally, given the various similarities between neural and hematopoietic stem cells, it may be interesting to assess the effects of hedgehog proteins on the hematopoietic system (if this has not previously been done before).

View this patent on the USPTO website.