Engineered zinc finger protein transcription factors (ZFP TFs) are an emerging class of molecules with the potential for broad therapeutic impact in the treatment of human disease. ZFP TFs function by mimicking the natural process of gene regulation i.e. the mechanism by which all cells turn on, or turn off the production of proteins.
Since ZFP TFs can be designed to bind specifically to virtually any DNA sequence, this technology permits the turning on, or turning off of effectively any gene in the human genome and thus greatly expands the universe of potential drug targets for disease intervention. Moreover, while "subtractive therapies," e.g. drugs that block an activity or process, represent the majority of current approaches to disease intervention, ZFP TFs provide the capability to "add" or increase the production of potentially beneficial activities at an appropriate dose.
We propose to develop ZFP TFs for GDNF that may enhance expression of GDNF naturally found in the brain. This would allow for a more controlled and targeted therapy because it would simply enhance a process that the brain is already performing. We will seek to develop this therapy and test it in rodent models.
Dr. Zhang and colleagues have successfully engineered ZFP activators to upregulate the endogenous rat, human and rhesus macaque GDNF gene. In addition, intrastriatal infusion of an AAV vector encoding the rat GDNF activator led to increased GDNF production in the rat striatum, and prevented motor defects (forelimb akinesia, sensorimotor neglect and amphetamine-induced rotations ). These results therefore provide in vivo evidence to support further development of GDNF activators as a potential therapy for PD. Dr. Zhang has been continuing the work on further optimization and characterization of the ZFP activators for the human/rhesus GDNF gene.