Gene Therapy of Midbrain Dopamine Circuits

Recombinant adeno-associated viral (rAAV) vectors are to be developed for transgene delivery to thenervous system (CNS). In particular, we are engineering rAAVs designed to transduce an expression cathe human gene for glial cell-derived neurotrophic factor (GDNF). GDNF is a novel member of the tranfactor-beta (TGF-beta) superfamily which displays potent trophic effects on dopamine neurons. Dopamiplays a key role in affective and regulatory behaviors and in human neuropsychiatric and neurodegenenumber of disorders, such as schizophrenia, attention deficit/hyperactivity disorder, and Parkinson'some dysfunction in dopaminergic pathways. Gene therapy employing rAAVs may provide a means of directhe physiology and gene expression of the affected cells within the CNS.