Adeno-associated virus vector delivery to the brain: Technology advancements and clinical applications.

Authors: Ye D, Chukwu C, Yang Y, Hu Z, Chen H

Adeno-associated virus (AAV) vectors have emerged as a promising tool in the development of gene therapies for various neurological diseases, including Alzheimer's disease and Parkinson's disease. However, the blood-brain barrier (BBB) poses a significant challenge to successfully delivering AAV vectors to the brain. Strategies that can overcome the BBB to improve the AAV delivery efficiency to the brain are essential to successful brain-targeted gene therapy. This review provides an overview of existing strategies employed for AAV delivery to the brain, including direct intraparenchymal injection, intra-cerebral spinal fluid injection, intranasal delivery, and intravenous injection of BBB-permeable AAVs. Focused ultrasound has emerged as a promising technology for the noninvasive and spatially targeted delivery of AAV administered by intravenous injection. This review also summarizes each strategy's current preclinical and clinical applications in treating neurological diseases. Moreover, this review includes a detailed discussion of the recent advances in the emerging focused ultrasound-mediated AAV delivery. Understanding the state-of-the-art of these gene delivery approaches is critical for future technology development to fulfill the great promise of AAV in neurological disease treatment.

Introduction

Purpose Drug delivery with BBB opening

Study Objective To review and summarize strategies for delivering AAV vectors across the blood-brain barrier for brain-targeted gene therapy, with emphasis on focused ultrasound-mediated delivery.

Cargo name and characteristics Adeno-associated virus (AAV) vectors — viral gene therapy vectors used to deliver genetic cargo to the brain; includes BBB‑permeable AAV variants and AAVs administered via intraparenchymal, intracerebrospinal fluid, intranasal, or intravenous (focused ultrasound‑facilitated) routes.

Route of administration Direct intraparenchymal injection; intracerebrospinal fluid (intra-CSF) injection; intranasal delivery; intravenous injection

Outcomes and Safety

Summary of Outcomes Focused ultrasound-mediated, spatially targeted transient opening of the blood–brain barrier enhances intravenous AAV delivery to the brain, enabling noninvasive, region-specific gene transfer; the review also covers intraparenchymal, intracerebrospinal fluid, intranasal, and intravenously administered BBB-permeable AAV strategies. The paper does not report specific focused ultrasound parameter tests or list which parameters were successful.

Safety-related matter The text does not mention any safety concerns or adverse effects related to AAV delivery strategies; no adverse effects were reported in this excerpt.

Brain Region

Visualization unavailable

Ultrasound Parameters

Focal Characteristics focal depth: None; focal length: None; aperture size: None

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