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. 2022 Dec 7;30(12):3632-3638.
doi: 10.1016/j.ymthe.2022.08.003. Epub 2022 Aug 10.

Long-term safety of MRI-guided administration of AAV2-GDNF and gadoteridol in the putamen of individuals with Parkinson's disease

Matthew T Rocco  1 , Asad S Akhter  1 , Debra J Ehrlich  2 , Gretchen C Scott  3 , Codrin Lungu  4 , Vikas Munjal  1 , Anthony Aquino  5 , Russell R Lonser  1 , Massimo S Fiandaca  6 , Mark Hallett  7 , John D Heiss  3 , Krystof S Bankiewicz  8
Affiliations

Long-term safety of MRI-guided administration of AAV2-GDNF and gadoteridol in the putamen of individuals with Parkinson's disease

Matthew T Rocco et al. Mol Ther. .

Erratum in

Abstract

Direct putaminal infusion of adeno-associated virus vector (serotype 2) (AAV2) containing the human glial cell line-derived neurotrophic factor (GDNF) transgene was studied in a phase I clinical trial of participants with advanced Parkinson's disease (PD). Convection-enhanced delivery of AAV2-GDNF with a surrogate imaging tracer (gadoteridol) was used to track infusate distribution during real-time intraoperative magnetic resonance imaging (iMRI). Pre-, intra-, and serial postoperative (up to 5 years after infusion) MRI were analyzed in 13 participants with PD treated with bilateral putaminal co-infusions (52 infusions in total) of AAV2-GDNF and gadoteridol (infusion volume, 450 mL per putamen). Real-time iMRI confirmed infusion cannula placement, anatomic quantification of volumetric perfusion within the putamen, and direct visualization of off-target leakage or cannula reflux (which permitted corresponding infusion rate/cannula adjustments). Serial post-treatment MRI assessment (n = 13) demonstrated no evidence of cerebral parenchyma toxicity in the corresponding regions of AAV2-GDNF and gadoteridol co-infusion or surrounding regions over long-term follow-up. Direct confirmation of key intraoperative safety and efficacy parameters underscores the safety and tissue targeting value of real-time imaging with co-infused gadoteridol and putative therapeutic agents (i.e., AAV2-GDNF). This delivery-imaging platform enhances safety, permits delivery personalization, improves therapeutic distribution, and facilitates assessment of efficacy and dosing effect.

Keywords: AAV; GDNF; MRI-guided; Parkinson's disease; convection-enhanced delivery; gadoteridol; gene therapy; putamen; safety.

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Conflict of interest statement

Declaration of interests M.S.F. is an employee of Asklepios BioPharmaceutical, Inc. (AskBio). C.L. reports honoraria for editorial work from Elsevier, Inc. The work submitted here was conducted in the course of employment for the National Institute of Neurological Disorders and Stroke, an agency of the US Government. K.S.B. is a consultant to AskBio, Aviado Bio, and Scribe Tx and a patent holder on relevant technologies utilized in this study. K.S.B. was a co-founder of Voyager Therapeutics, has not been associated with the company for over 3 years, and reports no current financial interests in that company.

Figures

None
Graphical abstract
Figure 1
Figure 1
Intraoperative T1-weighted axial MRI during putaminal convection-enhanced delivery (CED) Serial images depict the static putaminal volume (green) and serial enlargement of an anterior putaminal infusion volume (red). From left to right, the infusion volume delivered increases and is displayed under the respective image. Putaminal volume representation and contrast co-infusion volume of distribution are depicted using the BrainLab iPlan software package.
Figure 2
Figure 2
Intraoperative T1-weighted coronal MRI obtained during putaminal CED co-infusions Bilateral inserted cannulae are providing convective delivery in the anterior putamen bilaterally. Note the contrast reflux unilaterally along the cannula (yellow arrows) but not on the contralateral side. No significant perivascular leakage is noted in this imaging series.
Figure 3
Figure 3
A single participant’s representative set of T1-weighted coronal MRI images over time (A–E) Pre-operation day 0 (A), 6-month scans (B), 18-month scans (C), 36-month scans (D), 60-month scans (E). (F–J) Higher magnification of the images in the top row. Note visible cannula tracks (black arrows) in postoperative images.
Figure 4
Figure 4
Serial axial MRI images from the participant with new postoperative unilateral putaminal lesion (A and B) Pre-operative (A) and intraoperative (B) axial T1-weighted images. (C and D) 60-month (C) axial T1-weighted and (D) axial T2-weighted images showing persistence of the new finding (white arrow) initially noted by both neuroradiologists 6 months after the operation but not in pre-surgical and surgical images. Note the absence of significant abnormalities on the contralateral side.
Figure 5
Figure 5
Changes in postoperative MRI-visualized cannula track volumes over time Shown are bar graph representations of quantitative volumetric data (defined via the BrainLab iPlan software package) from left (n = 23) and right (n = 23) cannula track volumes determined from the first and last available postoperative scans (typically using coronal or sagittal views). Error bars represent the standard error of mean (SEM). Note the statistically significant reductions in cannula track volumes over time (up to 54 months between the first and last scans). Minus bars are not displayed.
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