Method of treating dopaminergic and gaba-nergic disorders
AssigneeCuris, Inc.
InventorsNINGNING MIAO, MONICA WANG, NAGESH K. MAHANTHAPPA, PING JIN, KEVIN PANG
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Abstract
It is shown here that hedgehog proteins possess novel activities beyond phenotype specification. Using cultures derived from the embryonic day 14.5 (E14.5) rat ventral mesencephalon, we show that hedgehog is also trophic for dopaminergic neurons. Interestingly, hedgehog not only promotes dopaminergic neuron survival, but also promotes the survival of midbrain GABA-immunoreactive (GABA-ir) neurons.
Claims46
A method for promoting survival of substantia nigra neuronal cells comprising contacting the cells with a trophic amount of a ptc therapeutic.
A method for promoting survival of dopaminergic cells comprising contacting the cells with a trophic amount of a ptc therapeutic.
A method for promoting survival of GABAergic cells comprising contacting the cells with a trophic amount of a ptc therapeutic.
A method for treating a disorder characterized by loss of dopaminergic and/or GABAergic neurons which comprises administering to a patient a therapeutically effective amount of a ptc therapeutic.
A method for treating or preventing Parkinson's disease comprising administering to a patient in need thereof a therapeutically effective amount of a ptc therapeutic.
A method for treating or preventing Huntington's disease comprising administering to a patient in need thereof a therapeutically effective amount of a ptc therapeutic.
A therapeutic preparation of a small molecule antagonist of patched, which patched antagonist is provided in a pharmaceutically acceptable carrier and in an amount sufficient to promote survival of dopaminergic cells in a mammal.
A therapeutic preparation of a small molecule antagonist of patched, which patched antagonist is provided in a pharmaceutically acceptable carrier and in an amount sufficient to promote survival of dopaminergic cells in an adult human.
A method for limiting damage to neuronal cells by Parkinsonian conditions, comprising administering to a patient a gene activation construct which recombines with a genomic hedgehog gene of the patient to provide a heterologous transcriptional regulatory sequence operatively linked to a coding sequence of the hedgehog gene.
29 An isolated and/or recombinantly produced polypeptide comprising an amino acid sequence which is at least 95 percent identical to a sequence represented by SEQ ID. NO. 16 or 17, or a bioactive extracellular fragment thereof.
An isolated and/or recombinantly produced polypeptide encoded by a nucleic acid which hybridizes under stringent conditions to a sequence selected from the group consisting of SEQ ID. NO. 16 and SEQ ID. NO. 17.
An isolated and/or recombinantly produced Dhh hedgehog polypeptide, or a bioactive extracellular fragment thereof, encoded by a human Dhh gene.
An isolated and/or recombinantly produced Ihh hedgehog polypeptide, or a bioactive extracellular fragment thereof, encoded by a human Ihh gene.
An isolated nucleic acid encoding a polypeptide comprising a hedgehog amino acid sequence which is at least 95 percent identical to a hedgehog protein selected from the group consisting of SEQ ID No:16 and SEQ ID No:17, and fragments thereof, which hedgehog amino acid sequence (i) binds to a patched protein, (ii) regulates differentiation of neuronal cells, (iii) regulates survival of differentiated neuronal cells, (iv) regulates proliferation of chondrocytes, (v) regulates proliferation of testicular germ line cells, or (vi) functionally replaces drosopholia hedgehog in transgenic drosophila fly, or a combination thereof.
An isolated nucleic acid encoding a polypeptide having a hedgehog amino acid sequence encoded by a nucleic acid which hybridizes under stringent conditions to a nucleic acid sequence selected from the group consisting of SEQ ID No:7 and SEQ ID No:8, which hedgehog amino acid sequence of the polypeptide corresponds to a natural proteolytic product of a hedgehog protein and (i) binds to a patched protein, (ii) regulates differentiation of neuronal cells, (iii) regulates survival of differentiated neuronal cells, (iv) regulates proliferation of chondrocytes, (v) regulates proliferation of testicular germ line cells, or (vi) functionally replaces drosopholia hedgehog in transgenic drosophila fly, or a combination thereof.
An isolated nucleic acid comprising a coding sequence of a human hedgehog gene, encoding a bioactive hedgehog protein.
A method of producing a recombinant hedgehog polypeptide comprising culturing the cell of 40 in a cell culture medium to express a hedgehog polypeptide and isolating said hedgehog polypeptide from said cell culture.
A probe/primer comprising a substantially purified oligonucleotide, said oligonucleotide containing a region of nucleotide sequence which hybridizes under stringent conditions to at least 10 consecutive nucleotides of sense or antisense sequence of SEQ ID No. 7 or 8, or naturally occuring mutants thereof.
A purified preparation of an antisense nucleic acid which specifically hybridizes to and inhibits expression of a gene encoding a human Ihh or Dhh hedgehog protein under physiological conditions, which nucleic acid is at least one of (i) a synthetic oligonucleotide, (ii) single-stranded, (iii) linear, (iv) 20 to 50 nucleotides in length, and (v) a DNA analog resistant to nuclease degradation.
Dependencies are inferred from the claim text.