Gene Therapy for Neurodegenerative Diseases

Abstract

Gene therapy has the potential to provide therapeutic benefit to millions of people with neurodegenerative diseases through several means, including direct correction of pathogenic mechanisms, neuroprotection, neurorestoration, and symptom control. Therapeutic efficacy is therefore dependent on knowledge of the disease pathogenesis and the required temporal and spatial specificity of gene expression. An additional critical challenge is achieving the most complete transduction of the target structure while avoiding leakage into neighboring regions or perivascular spaces. The gene therapy field has recently entered a new technological era, in which interventional MRI-guided convection-enhanced delivery (iMRI-CED) is the gold standard for verifying accurate vector delivery in real time. The availability of this advanced neurosurgical technique may accelerate the translation of the promising preclinical therapeutics under development for neurodegenerative disorders, including Parkinson's, Huntington's, and Alzheimer's diseases.

Keywords: Alzheimer’s disease; Gene therapy; Huntington’s disease; Parkinson’s disease; intraoperative MRI.; viral vector.

Fig. 1

MRI-compatible infusion cannula for clinical CED. A two-step design cannula with a ceramic body and inner silica sleeve designed to allow low priming volumes. The ceramic body is encased with a protective outer polymer sleeve (MRI Interventions, Inc.)

Fig. 2

Initial position of infusion cannula. Orange arrows indicate the artifact from the infusion cannula and white arrows indicate the border of the putamen, in axial (left) and sagittal (right) views. The red circle indicates the location of the second step, which is ~8 mm from the putamen border, placing the tip ~5 mm into the target structure. Initial reflux up to the first step will confine the initial infusion volume within the putamen. Further insertion of the cannula such that the second step reaches the border of the putamen will allow for further spherical expansion of the infusion volume within the target

Fig. 3

Real-time visualization of simultaneous bilateral MRI-guided infusion of AAV2-AADC (1:1 admixture with gadoteridol) to the putamen (blue shading in panel a). (a) Infusions are expected to grow concentrically after reaching the first step. (b) The cannula is advanced in ~2–3 mm increments, with a goal of filling the structure from proximal to distal. (c) A second step acts as an additional temporary barrier to infusion volume growth along the cannula axis. (d) An axial view demonstrates appropriate coverage of the putamen, on each side, at the end of the drug delivery procedure