Interventional MRI-guided putaminal delivery of AAV2-GDNF for a planned clinical trial in Parkinson's disease

Abstract

Clinical trials involving direct infusion of neurotrophic therapies for Parkinson's disease (PD) have suffered from poor coverage of the putamen. The planned use of a novel interventional-magnetic resonance imaging (iMRI) targeting system for achieving precise, real-time convection-enhanced delivery in a planned clinical trial of adeno-associated virus serotype 2 (AAV2)-glial-derived neurotrophic factor (GDNF) in PD patients was modeled in nonhuman primates (NHP). NHP received bilateral coinfusions of gadoteridol (Gd)/AAV2-GDNF into two sites in each putamen, and three NHP received larger infusion volumes in the thalamus. The average targeting error for cannula tip placement in the putamen was <1 mm, and adjacent putamenal infusions were distributed in a uniform manner. GDNF expression patterns in the putamen were highly correlated with areas of Gd distribution seen on MRI. The distribution volume to infusion volume ratio in the putamen was similar to that in the thalamus, where larger infusions were achieved. Modeling the placement of adjacent 150 and 300 µl thalamic infusions into the three-dimensional space of the human putamen demonstrated coverage of the postcommissural putamen, containment within the striatum and expected anterograde transport to globus pallidus and substantia nigra pars reticulata. The results elucidate the necessary parameters for achieving widespread GDNF expression in the putamenal motor area and afferent substantia nigra of PD patients.

Figures

Figure 1

Three-dimensional reconstructions of putamenal infusions. Reconstructions of anterior (yellow) and posterior (red) infusions into both the right (blue) and left (green) putamen in one animal are shown in relation to the MRI plane through the anterior commissure, in the (a) anterior to posterior, (b) posterior to anterior, (c) ventral to dorsal, and (d) dorsal to ventral views.

Figure 2

Correlation between gadoteridol (Gd) signal and glial-derived neurotrophic factor (GDNF) expression. (a–c) The center magnetic resonance imaging (MRI) slice through three separate putamenal infusions and the matching GDNF (brown) histology sections. The arrowhead in b denotes infusate distribution along a presumed lenticulostriate artery. The cross-sectional area values from six-matched MRI and histological slices are shown in d. c. put, commissural putamen; p.c., postcommissural putamen.

Figure 3

Anterograde transport of glial-derived neurotrophic factor (GDNF) from putamen to globus pallidus. GDNF (brown) distribution at the center of the infusion (a) is confined to the putamen (Pu). Anterograde transport into external globus pallidus (GPe) and internal globus pallidus (GPi) is evident at distances of (b) 200-µm and (c) 240-µm posterior to the infusion. Second order neurons are seen to express GDNF in GPi (d, ×10 magnification of the area indicated by the arrowhead in c).

Figure 4

Anterograde transport of glial-derived neurotrophic factor (GDNF) from putamen to substantia nigra. A representative histological section at the level of the midbrain is shown in an nonhuman primates (NHP) that received bilateral putamenal adeno-associated virus serotype 2 (AAV2)-GDNF. GDNF expression (brown) primarily occurs in the area of substantia nigra reticulata (SNr), with minimal overlap into substantia nigra compacta (SNc) identified by tyrosine hydroxylase expression (blue). The box in a is shown at greater magnification in b, and the box in b is shown at greater magnification in c. Arrowheads in c identify neurons in SNr that express GDNF. VTA, ventral tegmental area.

Figure 5

Rapid infusions of clinical volumes in the nonhuman primates (NHP) thalamus. (a) Real-time coronal magnetic resonance (MR) image obtained at the conclusion of a 300-µl volume infused at a rate of 5 µl/min. The MRI-visible trajectory guide is indicated by the arrowhead. (b) Three-dimensional reconstruction of the same infusion with cannula trajectory shown in blue.

Figure 6

Three-dimensional reconstructions of nonhuman primates (NHP) thalamic infusions merged into magnetic resonance imaging (MRI)-space of human putamen. (a) The outlines of a 300 µl infusion (red) and a 150 µl infusion (yellow) from NHP thalamus are shown superimposed onto the human putamen, in one representative axial plan of an MRI from a Parkinson's disease (PD) patient. The precommissural putamen is shown in blue, and the postcommissural putamen is shown in green. Volumetric reconstructions of these infusions and the putamen are shown in the (b) lateral to medial, (c) posterior to anterior, and (d) dorsal to ventral planes.

Figure 7

Diagram demonstrating the functional organization of striatal afferent projections. Colors denote functional distinctions in the organization of cortical and subcortical inputs to the striatum. Yellow, motor actions; green, premotor planning; blue, cognitive and associative functions (after Haber). Yellow regions also are most susceptible to dopaminergic degeneration in Parkinson's disease.