GDNF GENE THERAPY FOR PARKINSON'S DISEASE
In Parkinson’s disease, there is a primary loss of dopamine-producing neuronal cell bodies and their processes originating from a brain region known as the substantia nigra. Primary dopaminergic connections from the substantia nigra to another brain region, the striatum, are associated with modulation of muscle function.
Loss of dopaminergic input to the striatum, therefore, leads to progressive difficulties in initiating and carrying out normal movements of the limbs, trunk, head, and face, along with other clinical problems. Such dopaminergic limitations eventually result in the development of the cardinal signs of Parkinson’s disease, including bradykinesia, resting tremor, rigidity, and postural instability. GDNF is a neurotrophic factor naturally occurring within the brain, and was discovered to provide support for the growth and survival of dopaminergic neurons. Subsequent investigations indicate that the trophic influence provided by GDNF protein infusions and gene therapy, are able to limit neuronal dysfunction and degeneration in a variety of model systems, including parkinsonian rodents and non-human primates.
For long-term trophic influence of neural networks in human neurodegenerative disorders, such as Parkinson’s disease, however, it is expected that a continuous supply or frequent administration of the trophic factor will be necessary. For GDNF protein this would require permanently implanted delivery devices to allow intermittent extrinsic dosing. Gene therapy, however, allows for continuous intrinsic production and release of GDNF protein after a one-time surgical administration procedure, without the need for any indwelling brain catheters or other chronically-implanted devices.
For our Parkinson’s disease program, we have selected the AAV gene transfer technology to deliver the GDNF gene sequence. AAV has been extensively evaluated in clinical studies, emerging as the preeminent platform for directly administered gene therapy to the brain. Prior Parkinson’s disease gene therapy clinical studies, including a Phase 1 trial of GDNF (ClinicalTrials.gov Identifier: NCT01621581), have established a favorable safety profile for brain-targeted AAV gene therapy.