Data-driven evolution of neurosurgical gene therapy delivery in Parkinson's disease

Abstract

Loss of nigrostriatal dopaminergic projection neurons is a key pathology in Parkinson's disease, leading to abnormal function of basal ganglia motor circuits and the accompanying characteristic motor features. A number of intraparenchymally delivered gene therapies designed to modify underlying disease and/or improve clinical symptoms have shown promise in preclinical studies and subsequently were evaluated in clinical trials. Here we review the challenges with surgical delivery of gene therapy vectors that limited therapeutic outcomes in these trials, particularly the lack of real-time monitoring of vector administration. These challenges have recently been addressed during the evolution of novel techniques for vector delivery that include the use of intraoperative MRI. The preclinical development of these techniques are described in relation to recent clinical translation in an adeno-associated virus serotype 2-mediated human aromatic L-amino acid decarboxylase gene therapy development programme. This new paradigm allows visualisation of the accuracy and adequacy of viral vector delivery within target structures, enabling intertrial modifications in surgical approaches, cannula design, vector volumes and dosing. The rapid, data-driven evolution of these procedures is unique and has led to improved vector delivery.

Keywords: Parkinson's disease; neurosurgery.

Figure 1

Intraoperative monitoring of VY-AADC01 admixed with gadoteridol. Backflow up cannula track (A) and perivascular and off-target leakage (B) in PD-1101. Stacked infusions (C) and progressive cannula advancement (D). Posterior approach with progressive cannula advancement employed in PD-1102 (E).

Figure 2

Stepped-design cannulas. Cannulas with two-diameter steps were employed in PD-1101, with the second step known to resist backflow past the first step after target insertion. The cannula tip was shortened from 18 mm (A) to 13 mm (B) for use in cohorts 2 and 3 of PD-1101 and PD-1102.

Figure 3

Infusion volumes and durations, vector concentrations and putaminal coverage in PD-1101 and PD-1102 trials. vg, vector genome.

Figure 4

AADC enzyme activity as measured by ¹⁸F-DOPA PET in individual patients from PD-1101 (A), by cohorts (baseline and at 6-month measurements) in PD-1101 and PD-1102 (B), and correlation of the change in ¹⁸F-DOPA PET with putaminal coverage measured by MRI (C). PET imaging frames captured 65–75 min after ¹⁸F-DOPA administration. Box plot in panel B shows median (middle line), 25th–75th percentiles (box) and range (bars). ^aSORs were calculated using bilaterally averaged occipital time–activity curve (kBq/mL) region-of-interest values in each patient. ^bn=7; analysis of scan for one patient in PD-1102 was confounded by movement artefact, and data for this patient were excluded. ^cData were not available for one patient from PD-1101 cohort 1 and one patient from PD-1102. ^dTwo overlapping data points from PD-1101 cohort 1 and cohort 2. ^eTwo overlapping data points from PD-1102. AADC, L-amino acid decarboxylase; ¹⁸F-DOPA, [¹⁸F]-fluoro-L-dihydroxyphenylalanine; PET, positron emission tomography; SOR-1, striatal-to-occipital ratio-1; SUVR, standardised uptake value ratio; vg, vector genome.

Figure 5

Relationship between AAV2 gene therapy infusion volumes and putaminal coverage. Data are based on analysis of iMRI images progressively acquired during putaminal infusions of VY-AADC01 (PD-1101 and PD-1102 trials), AAV2-GDNF, and AAV2-NTRN in patients with PD. Putaminal coverage was measured at infusion volumes matching those used in earlier gene therapy trials, to infer volumes of distribution that would have been provided by those infusion volumes. Values do not represent actual coverage from trials that did not employ iMRI monitoring. AADC, aromatic L-amino acid decarboxylase; AAV2, AAV serotype 2; GDNF, glial cell line-derived neurotrophic factor; iMRI, intraoperative MRI; NRTN, neurturin; PD, Parkinson’s disease; Vd, volume of distribution; vg, vector genome; Vi, volume of infusion.