Authors: Davis Palmer Argersinger, B.S.; Codrin Lungu, MD; Dima Hammoud, MD; Peter Herscovitch, MD; Debra Ehrlich, MD; Gretchen Scott; Krystof Bankiewicz, MD, PhD; Kareem Zaghloul, MD, PhD; Mark Hallett, MD; Russell Lonser, MD; John Heiss, MD (Washington, DC)

Introduction:

Parkinson’s disease is progressive and presently incurable.  GDNF is a neurotrophic factor that prevented the death of dopaminergic neurons in culture and animal models of Parkinson’s disease (PD). 

Methods:

In this Phase 1 clinical trial, 13 adult patients with advanced PD underwent convection-enhanced delivery (CED) of an adeno-associated virus, serotype 2 vector containing glial cell line-derived neurotrophic factor (AAV2-GDNF) to investigate the safety, tolerability, and potential clinical effects of CED of AAV2-GDNF and gadoteridol, a surrogate magnetic resonance imaging (MRI) tracer, into the bilateral putamina (450 µl per hemisphere).  Three escalating dose levels were evaluated: 1) 9 x 1010vg (6 patients); 2) 3 x 1011vg (6 patients); and 3) 9 x 1011vg (1 patient).  Intraoperative MRI was performed during infusions.  Pre-operatively, and at 6-12 month intervals post-operatively, Unified Parkinson’s Disease Rating Scale (UPDRS) Part 3 assessed motor function and positron emission tomography (PET) scanning with [18F]DOPA assessed F-DOPA uptake, a sign of presynaptic dopaminergic integrity.

Results:

The patients tolerated AAV2-GDNF infusion without short- or long-term clinical or radiographic toxicity.  MRI tracked AAV2-GDNF infusion within the bilateral putamina.  Average coverage of the putamina was 22%.  UPDRS Part 3 assessment scores remained stable throughout the study.  Increased [18F]DOPA uptake in the infused areas was seen bilaterally in 10/13 patients at 6 months (range: 5-274%, median: 36%), and in 12/13 patients at 18 months after infusion (range: 8-130%, median: 54%). 

Conclusion:

Patients with advanced PD tolerated bilateral CED of AAV2-GDNF without toxicity.  Gadoteridol in the infusion solution tracked putaminal AAV2-GDNF distribution.  PET findings of increased putaminal [18F]DOPA uptake suggest a neurotrophic effect on dopaminergic neurons.  Based on a satisfactory safety profile, a follow-up clinical trial is planned to increase putaminal coverage and possibly reverse PD progression and signs.

Authors: Davis Palmer Argersinger, B.S.; Codrin Lungu, MD; Dima Hammoud, MD; Peter Herscovitch, MD; Debra Ehrlich, MD; Gretchen Scott; Krystof Bankiewicz, MD, PhD; Kareem Zaghloul, MD, PhD; Mark Hallett, MD; Russell Lonser, MD; John Heiss, MD (Washington, DC)

Introduction:

Parkinson’s disease is progressive and presently incurable.  GDNF is a neurotrophic factor that prevented the death of dopaminergic neurons in culture and animal models of Parkinson’s disease (PD). 

Methods:

In this Phase 1 clinical trial, 13 adult patients with advanced PD underwent convection-enhanced delivery (CED) of an adeno-associated virus, serotype 2 vector containing glial cell line-derived neurotrophic factor (AAV2-GDNF) to investigate the safety, tolerability, and potential clinical effects of CED of AAV2-GDNF and gadoteridol, a surrogate magnetic resonance imaging (MRI) tracer, into the bilateral putamina (450 µl per hemisphere).  Three escalating dose levels were evaluated: 1) 9 x 1010vg (6 patients); 2) 3 x 1011vg (6 patients); and 3) 9 x 1011vg (1 patient).  Intraoperative MRI was performed during infusions.  Pre-operatively, and at 6-12 month intervals post-operatively, Unified Parkinson’s Disease Rating Scale (UPDRS) Part 3 assessed motor function and positron emission tomography (PET) scanning with [18F]DOPA assessed F-DOPA uptake, a sign of presynaptic dopaminergic integrity.

Results:

The patients tolerated AAV2-GDNF infusion without short- or long-term clinical or radiographic toxicity.  MRI tracked AAV2-GDNF infusion within the bilateral putamina.  Average coverage of the putamina was 22%.  UPDRS Part 3 assessment scores remained stable throughout the study.  Increased [18F]DOPA uptake in the infused areas was seen bilaterally in 10/13 patients at 6 months (range: 5-274%, median: 36%), and in 12/13 patients at 18 months after infusion (range: 8-130%, median: 54%). 

Conclusion:

Patients with advanced PD tolerated bilateral CED of AAV2-GDNF without toxicity.  Gadoteridol in the infusion solution tracked putaminal AAV2-GDNF distribution.  PET findings of increased putaminal [18F]DOPA uptake suggest a neurotrophic effect on dopaminergic neurons.  Based on a satisfactory safety profile, a follow-up clinical trial is planned to increase putaminal coverage and possibly reverse PD progression and signs.