Neurosurgical gene therapy for central nervous system diseases

Abstract

Viral vector mediated gene therapies for neurodegenerative and neurodevelopmental conditions that require neurosurgical administration continue to expand. We systematically reviewed the National Institutes of Health (NIH) ClinicalTrials.gov database to identify all clinical trials studying in-vivo viral vector mediated gene therapies targeted to the CNS for neurodegenerative and neurodevelopmental diseases. We isolated studies which delivered therapies using neurosurgical approaches: intracisternal, intraventricular, and/or intraparenchymal. Clinical trials primarily registered in international countries were included if they were referenced by an NIH registered clinical trial. We performed a scoping review to identify the preclinical studies that supported each human clinical trial. Key preclinical and clinical data were aggregated to characterize vector capsid design, delivery methods, gene expression profile, and clinical benefit. A total of 64 clinical trials were identified in active, completed, terminated, and long-term follow-up stages. A range of CNS conditions across pediatric and adult populations are being studied with CNS targeted viral vector gene therapy, including Alzheimer's disease, Parkinson's disease, AADC deficiency, sphingolipidoses, mucopolysaccharidoses, neuronal ceroid lipofuscinoses, spinal muscular atrophy, adrenoleukodystrophy, Canavan disease, frontotemporal dementia, Huntington's disease, Rett syndrome, Dravet syndrome, mesial temporal lobe epilepsy, and glutaric acidemia. Adeno-associated viral vectors (AAVs) were utilized by the majority of tested therapies, with vector serotypes, regulatory elements, delivery methods, and vector monitoring varying based on the disease being studied. Intraparenchymal delivery has evolved significantly, with MRI-guided convection-enhanced delivery established as a gold standard method for pioneering novel gene targets.

Keywords: Clinical trials; Gene therapy; Gene transfer; Neurological disorders; Viral vectors.

Fig. 1

Neurosurgical Gene Therapy Clinical Trials. A. Number of included clinical trials for neurodegenerative and neurodevelopmental conditions. B. Distribution of the number of patients enrolled across all included clinical trials. C. Timelines of included clinical trials by disease category.

Fig. 2

Neurosurgical Gene Therapy Targets. A. Delivery locations for therapeutic agents by disease. B. Summary of viral-vector serotypes used for gene transfer.

Fig. 3

Technique for Intraparenchymal Delivery. Serial MRI images (axial, left panels; sagittal right panels) demonstrate the technique of progressive advancement of the SmartFlow cannula (red arrow in A) through the putamen from a posterior approach. The blue arrow heads in A demonstrate the start of a new area of infusion after cannula advancement. Panels B–E show progressive time points of the infusion as the cannula is inserted further into the putamen. In B, the green arrowhead demarcates the step in the cannula that is 13 ​mm above the tip. Parking this step at the putaminal border allows the infusion to fill the posterior putamen as seen in C, after which the infusion remains confined to this boundary as the cannula is advanced further (green arrow in E).