Glutamic acid decarboxylase (GAD) based delivery systems
The invention provide methods and compositions for localized delivery of a vector comprising a therapeutic agent to a specific region of the brain that is overstimulated in neurodegenerative diseases. In particular, the invention provides methods and compositions used to deliver an adeno-associated virus vector (AAV) comprising a nucleotide sequence encoding glutamic acid decarboxylase (GAD) to cells in the hippocampus, subthalamic nucleus of the basal ganglia, mesaphilia and thalamus.
1. A vector for expression of glutamic acid decarboxylase 65 (GAD65) in cells of the central nervous system of a mammal comprising:
an adeno-associated viral vector;
a tissue specific promoter operably linked to a nucleotide sequence encoding GAD65; and
a post-transcriptional regulatory element, wherein the post-transcriptional regulatory element is the woodchuck hepadnavirus post-transcriptional regulatory element.
2. The vector of claim 1 , wherein the promoter is the neuron specific enolase (NSE) promoter.
3. The vector of claim 1 , wherein the promoter is a cytomegalovirus enhancer/chicken β-actin (CBA) promoter.
4. The vector of claim 1 wherein the GAD65 is human GAD65.
5. A pharmaceutical composition comprising the vector of claim 1 , wherein the composition is formulated for in vivo administration capable of transducing cells of the central nervous system (CNS) of the mammal.
6. The pharmaceutical composition of claim 5 wherein the GAD65 is human GAD65.
7. The vector of claim 1 , wherein the vector is capable of transducing a primary mammalian neural cell.
8. The pharmaceutical composition of claim 5 wherein the mammal is a primate.