Development of a Zinc Finger Protein Therapeutic for the Potential Treatment of Parkinson's Disease

Objective/Rationale:
Engineered zinc finger protein transcription factors (ZFP TFs) can be designed to specifically increase the level of a therapeutically important protein from its native gene in a patients’ own cells. This pre-clinical study aims to establish the therapeutic efficacy of a ZFP TF designed to increase the levels of the potent neuroprotectant GDNF (glial cell line derived neurotrophic factor) in a pre-clinical model of Parkinson’s disease (PD).

Project Description:
First, a lead ZFP TF GDNF activator will be identified for pre-clinical testing. This protein will be selected from a panel of engineered ZFP TFs based upon potency (i.e. achieving a marked yet physiologically relevant increase in the production of GDNF from the endogenous gene), and specificity (no measurable off-target activity) in both human and pre-clinical model cell lines. Second, the selected lead will be formulated for efficient delivery. Finally, the formulated lead ZFP TF will be tested in a pre-clinical model of PD. Administration of the ZFP TF to the brain will be performed using a state-of-art method that ensures efficient coverage of the relevant brain tissues. Efficacy will be determined by assessing behavioral changes as well as evidence of neuroprotection and/or neuroregeneration.

Relevance to Diagnosis/Treatment of Parkinson’s Disease:
Unlike medications addressing the symptoms of PD – a treatment which prevents and/or rescues the neuronal loss responsible for PD would address the underlying cause of disease. Increasing GDNF levels has this potential, yet must be balanced against the potential side-effects of over-expression. The ZFP TF approach achieves both goals by specifically increasing expression of GDNF from the native gene. The proposed study will investigate the efficacy of physiologically relevant doses of GDNF in the brain thought critical for sustained efficacy and safety.

Anticipated Outcome:
This pre-clinical study will determine whether a physiologically relevant increase in GDNF levels, driven by an engineered ZFP delivered into the brain, will result in protection and/or rescue from neuronal loss in the pre-clinical model of PD and lead to correction of motor defects.  Successful demonstration of efficacy will provoke additional experiments (including formal safety, toxicology and biodistribution studies testing) necessary for evaluation in the clinic.