A Multifaceted Approach to Optimizing AAV Delivery to the Brain for the Treatment of Neurodegenerative Diseases.

Authors: Fischell JM, Fishman PS

Despite major advancements in gene therapy technologies, there are no approved gene therapies for diseases which predominantly effect the brain. Adeno-associated virus (AAV) vectors have emerged as the most effective delivery vector for gene therapy owing to their simplicity, wide spread transduction and low immunogenicity. Unfortunately, the blood-brain barrier (BBB) makes IV delivery of AAVs, to the brain highly inefficient. At IV doses capable of widespread expression in the brain, there is a significant risk of severe immune-mediated toxicity. Direct intracerebral injection of vectors is being attempted. However, this method is invasive, and only provides localized delivery for diseases known to afflict the brain globally. More advanced methods for AAV delivery will likely be required for safe and effective gene therapy to the brain. Each step in AAV delivery, including delivery route, BBB transduction, cellular tropism and transgene expression provide opportunities for innovative solutions to optimize delivery efficiency. Intra-arterial delivery with mannitol, focused ultrasound, optimized AAV capsid evolution with machine learning algorithms, synthetic promotors are all examples of advanced strategies which have been developed in pre-clinical models, yet none are being investigated in clinical trials. This manuscript seeks to review these technological advancements, and others, to improve AAV delivery to the brain, and to propose novel strategies to build upon this research. Ultimately, it is hoped that the optimization of AAV delivery will allow for the human translation of many gene therapies for neurodegenerative and other neurologic diseases.

Introduction

Purpose Drug delivery with BBB opening

Study Objective To review recent technological advancements and propose novel strategies to optimize AAV delivery to the brain for safe and translatable gene therapies.

Cargo name and characteristics Adeno-associated virus (AAV) vectors — recombinant viral gene therapy vectors used to deliver transgenes to the brain; characterized by widespread transduction, relatively low immunogenicity, amenability to capsid engineering/optimization and synthetic promoters, deliverable IV, intra-arterially or intracerebrally but limited by immune-mediated toxicity at high systemic doses.

Route of administration Intravenous (IV); direct intracerebral (intracerebral injection); intra-arterial

Outcomes and Safety

Summary of Outcomes This review concludes that strategies such as intra-arterial delivery with mannitol, focused ultrasound, optimized AAV capsid evolution and synthetic promoters can improve AAV delivery to the brain to achieve global, neuron-preferring transduction while minimizing systemic exposure and immune activation; the manuscript is a review and does not report or test specific focused ultrasound parameters.

Safety-related matter The authors note significant safety concerns, stating that IV AAV at doses needed for widespread brain expression carries a significant risk of severe immune-mediated toxicity and that AAV vectors and transgenes pose significant risks to patients, especially at high doses. They emphasize minimizing systemic delivery and avoiding immune cells (e.g., APCs) to improve safety.

Brain Region

Visualization unavailable

Ultrasound Parameters

Focal Characteristics Focal depth: None; Focal length: None; Aperture size: None

We are open to feedback. If you see a mistake or have a suggestion, please contact us.