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

Abstract

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.

Commentary: Current Status of Gene Therapy for Spinal Muscular Atrophy

“…Potential strategies for increasing CNS delivery and selectivity are outlined in Figure 1 . They include different methods of administering/delivering the virus to the target tissue (IV, ICV, ICM, IT) and the engineering of a new generation of AAV capsids with enhanced delivery across the blood-brain barrier (BBB) to the adult primate CNS, while detargeting liver and other peripheral organs (Fischell and Fishman, 2021 ). Selecting optimized promoters and other tissue and cell-type specific control elements such as miRNA target sequences can provide an additional level of selectivity for finetuning the expression in transduced cells (Hordeaux et al, 2020 ).…”

AAV-mediated neuronal expression of a scFv antibody selective for Aβ oligomers protects synapses and rescues memory in Alzheimer models

“…We found that this strategy led to protection against AβO-induced memory decline in wild-type mice and, significantly, to reversal of age-dependent memory impairment in APPswe/PS1ΔE9 mice. Potential advantages of the current approach include (i) the need for a single infusion of AAV-NUsc1 to achieve sustained brain expression of NUsc1, (ii) local brain expression and secretion of a single-chain antibody devoid of the Fc domain and, thus, less likely to induce aberrant immune/inflammatory responses, (iii) specific targeting of a particular subpopulation of AβOs that is highly toxic to synapses and neurons (15, 16), and (iv) being amenable to further development, including systemic administration of modified AAV vectors capable of effectively crossing the blood-brain barrier (36). Based on our current findings, we propose that development of AAV-NUsc1 represents a step towards reaching immuno-gene therapy for AD.…”

Molecular Neurosurgery: Introduction to Gene Therapy and Clinical Applications

“…In recent years, viral vectors have become a leading tool for gene therapy in humans. [5][6][7][8][9][10][11][12][13][14][15][16][17][18][19] The most commonly used viruses in pediatric clinical trials to date are adeno-associated viruses (AAVs), followed distantly by lentivirus and adenovirus. 20 Below, we explain the features that have made these vehicles the dominant vector in gene therapy research and development.…”