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 ( Identifier: NCT01621581), have established a favorable safety profile for brain-targeted AAV gene therapy.



Advancing gene therapies, methods, and technologies for Parkinson's Disease and other neurological disorders.

Fiandaca MS, Lonser RR, Elder JB, Zabek M, Bankiewicz KS. Neurol Neurochir Pol. 2020. Epub 2020/06/20.

GDNF and Parkinson's Disease: Where Next? A Summary from a Recent Workshop.

Barker RA, Bjorklund A, Gash DM, Whone A, Van Laar A, Kordower JH, Bankiewicz K, Kieburtz K, Saarma M, Booms S, Huttunen HJ, Kells A, Fiandaca MS, Stoessl AJ, Eidelberg D, Federoff H, Voutilainen M, Dexter DT, Eberling J, Brundin P, Isaacs L, Mursaleen L, Bresolin E, Carroll C, Coles A, Fiske B, Matthews H, Lungu C, Wyse RK, Stott S, Lang AE. J Parkinsons Dis. 2020. Epub 2020/06/09.

Gene therapy for Parkinson's disease: contemporary practice and emerging concepts.

Merola A, Van Laar A, Lonser R, Bankiewicz K. Expert Rev Neurother. 2020:1-14. Epub 2020/05/20.

Interventional MRI-guided Putaminal Delivery of AAV2-GDNF for a Planned Clinical Trial in Parkinson’s Disease.

Richardson RM, Kells AP, Rosenbluth KH, Salegio EA, Fiandaca MS, Larson PS, et al Mol Ther 19:1048-1057, 2011

Real-time MR imaging of adeno-associated viral vector delivery to the primate brain.

Fiandaca MS, Varenika V, Eberling J, McKnight T, Bringas J, Pivirotto P, et al Neuroimage 47 Suppl 2:T27-35, 2009

Image-guided convection-enhanced delivery platform in the treatment of neurological diseases.

Fiandaca MS, Forsayeth JR, Dickinson PJ, Bankiewicz KS Neurotherapeutics 5:123-127, 2008

Glial-derived neurotrophic factor gene transfer for Parkinson’s disease: anterograde distribution of AAV2 vectors in the primate brain.

Kells AP, Forsayeth J, Bankiewicz KS. Neurobiol Dis. 2012.

Anterograde axonal transport of AAV2-GDNF in rat basal ganglia.

Ciesielska A, Mittermeyer G, Hadaczek P, Kells AP, Forsayeth J, Bankiewicz KS. Mol Ther. 2011.

Clinically relevant effects of convection-enhanced delivery of AAV2-GDNF on the dopaminergic nigrostriatal pathway in aged rhesus monkeys.

Johnston LC, Eberling J, Pivirotto P, Hadaczek P, Federoff HJ, Forsayeth J, Bankiewicz KS. Hum Gene Ther. 2009.

Regeneration of the MPTP-lesioned dopaminergic system after convection-enhanced delivery of AAV2-GDNF.

Kells AP, Eberling J, Su X, Pivirotto P, Bringas J, Hadaczek P, Narrow WC, Bowers WJ, Federoff HJ, Forsayeth J, Bankiewicz KS. J Neurosci. 2010.

Safety evaluation of AAV2-GDNF gene transfer into the dopaminergic nigrostriatal pathway in aged and parkinsonian rhesus monkeys.

Su X, Kells AP, Huang EJ, Lee HS, Hadaczek P, Beyer J, Bringas J, Pivirotto P, Penticuff J, Eberling J, Federoff HJ, Forsayeth J, Bankiewicz KS. Hum Gene Ther. 2009.

Trial of magnetic resonance-guided putaminal gene therapy for advanced Parkinson’s disease.

Heiss JD, Lungu C, Hammoud DA, Herscovitch P, Ehrlich DJ, Argersinger DP, Sinharay S, Scott G, Wu T, Federoff HJ, Zaghloul KA, Hallett M, Lonser RR, Bankiewicz KS. Mov Disord. 2019.