Genetically modified tyrosine hydroxylase and uses thereof
AssigneeNew York University
InventorsMenek Goldstein, Jing Wu, David Filer, Arnold J. Friedhoff
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Abstract
Modification of the DNA encoding the enzyme tyrosine hydroxylase (TH) resulting in amino acid substitution in one of the first fifty five N-terminal residues, in particular replacing Ser-40 with Tyr or Leu, produced TH variants having substantially increased enzymatic activity upon transfection of suitable host cells. Cells transfected with the variant TH having enhanced enzymatic activity are useful for treating neurological or psychiatric disorders associated with deficient TH or dopamine, in particular Parkinson's disease, by grafting such cells into the brain.
Claims5
A variant tyrosine hydroxylase protein moelcule having at least one amino acid substitution in the N-terminal fifty-five amino acid residues of the wild-type protein sequence, said at least one substitution corresponding to an amino acid selected from Ser-8, Ser-31, Arg-37, Arg-38, Gln-39, Ser-40, Leu-41, Ile-42, Glu-43, Asp-44, Ala-45, Arg-46 or Lys-47 of a rat or human tyrosine hydroxylase, wherein the tyrosine hydroxylase enzymatic activity of said variant protein is at least three fold greater than the enzymatic activity of the wild-type protein, and wehrein said substitution is a larger amino acid for a smaller amino acid, a smaller amino acid for a larger amino acid, or a hydrophilic amino acid for a hydrophobic amino acid or a hydrophobic amino aicd for a hydrophilic amino acid.
Dependencies are inferred from the claim text.