Engineered Drug Receptors as a Parkinson's Disease Therapy

Objective/Rationale:
The purpose of this project is to determine whether insertion of an engineered drug receptor into the subthalamic nucleus of a parkinsonian rat can alleviate akinesia when the receptor is stimulated by administration of a drug-like ligand. If these experiments are successful, it may be possible to develop a gene therapy for PD that has the same effect as Deep Brain Stimulation but without the associated electrode implantation.
Project Description:
The drug receptor gene (iRASSL) will be cloned into a clinically used AAV-based gene therapy vector. The vector will then be infused into the subthalamic nucleus of a rat that has been made parkinsonian on one side of the brain. Over subsequent weeks, rats will be given the small molecule – CNO - that turns on the iRASSL. If the activated iRASSL inhibits the excessive firing of the STN, we should see an improvement in limb movement in the affected limbs of that animal. A number of other experiments, designed to demonstrate appropriate expression and signaling of the iRASSL will also be part of our studies.
Relevance to Diagnosis/Treatment of Parkinson’s Disease:
A major therapeutic option for PD patients is Deep Brain Stimulation (DBS). However the presence of permanent electrodes and external leads is not an attractive feature. The approach we are exploring is to achieve the same effect by inserting a molecular machine to achieve the same effect as DBS but without the hardware. The patient would be able to regulate the therapeutic effect by taking a pill rather than having to undergo testing and adjustment of the stimulator hardware.
Anticipated Outcome:
This project is directed at proof-of-principle. We plan to use the next year to show in simple pre-clinical models of PD that AAV2-iRASSL can do what DBS does now. If this turns out to be the case, then we will be able to go on to a more complicated program of pre-clinical development that would allow us to test this new kind of Symptoms & Side Effects gene therapy in humans.