Gene delivery for cerebral neurodegenerative disorders - current advancements and limitations.

Authors

Kunal Dayma, Arun Upadhyay

Published in

Molecular therapy : the journal of the American Society of Gene Therapy. Jun 19, 2026. Epub Jun 19, 2026.

Abstract

Gene delivery for neurodegenerative cerebral disorders faces formidable structural and practical challenges. The blood-brain, blood- cerebrospinal fluid (CSF), and arachnoid barriers tightly regulate molecular traffic, restrict paracellular diffusion, and actively clear xenobiotics, limiting brain penetration and retention of large molecules and nucleic acid therapeutics. Additional barriers include heterogeneous and diffuse pathology, the need for precise anatomical targeting, vector dose-limiting toxicities, pre-existing and therapy-induced immunity to viral capsids, and procedural risks of neurosurgical or intrathecal administration. These constraints have slowed translation, reflected by the small number of approved central nervous system (CNS)-directed gene therapies. Against this backdrop, a diverse therapeutic landscape has emerged. In vivo strategies are dominated by adeno-associated virus (AAV)-9 and AAV2 vectors delivered intravenously, intrathecally (including intracisternal and intracerebroventricular routes), or via image-guided intraparenchymal and intraputaminal infusions, alongside intrathecal antisense oligonucleotides and RNA interference therapeutics. Concurrently, emerging approaches, including engineered AAV capsids, receptor- and transporter-mediated transcytosis, nanoparticle platforms, and focused ultrasound with microbubbles, have demonstrated compelling yet preclinical proof-of-concept. Future progress will likely depend on convergent advances in machine learning-guided capsid, more controllable blood-brain barrier modulation, rational route selection tailored to disease topology, and optimized ex vivo and cell-mediated delivery strategies. These innovations could enable a more predictable therapeutic paradigm for cerebral neurodegeneration.

PMID:
42322051
Bibliographic data and abstract were imported from PubMed on 20 Jun 2026.

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