Image-guided convection-enhanced delivery of GDNF protein into monkey putamen

Abstract

Recently, we developed an MRI-based method that enables tracking of parenchymal infusions of therapeutic agents by inclusion of a contrast reagent in the infusate. We show that both liposomal Gadoteridol (GDL) and free Gadoteridol (Gd) can be used for MRI-monitored infusions into the non-human primate (NHP) putamen to predict the distribution of GDNF protein after convection-enhanced delivery (CED). GDNF and both MRI tracers showed good co-distribution within the putamen and other brain regions. Although the CED infusion technique can distribute GDNF protein over large brain regions, continuous administration of GDNF could cause undesired effects that could counteract the benefits of CED as demonstrated in this study when large volumes of GDNF were delivered that lead to GDNF leakage into CSF. These limitations can be addressed by employing an intermittent CED schedule that permits consistent target coverage without GDNF leakage into CSF or white matter. We present an approach intracranial GDNF infusions that can be optimized by means of real-time monitoring via MRI. Adoption of this new standard, along with advanced, reflux-resistant cannulae, may permit reconsideration of direct GDNF infusion into parenchyma as a clinical strategy, since previous clinical studies involving chronic infusion of recombinant glial cell line-derived neurotrophic factor (GDNF) to the putamen for the treatment of Parkinson's disease have yielded mixed results, a state of affairs that may in part be attributed to suboptimal infusion parameters.