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Review
. 2024 Jan 15;25(2):1050.
doi: 10.3390/ijms25021050.

Delivery of Adeno-Associated Virus Vectors to the Central Nervous System for Correction of Single Gene Disorders

Rrita Daci  1   2 , Terence R Flotte  2   3
Affiliations
Review

Delivery of Adeno-Associated Virus Vectors to the Central Nervous System for Correction of Single Gene Disorders

Rrita Daci et al. Int J Mol Sci. .

Abstract

Genetic disorders of the central nervous system (CNS) comprise a significant portion of disability in both children and adults. Several preclinical animal models have shown effective adeno-associated virus (AAV) mediated gene transfer for either treatment or prevention of autosomal recessive genetic disorders. Owing to the intricacy of the human CNS and the blood-brain barrier, it is difficult to deliver genes, particularly since the expression of any given gene may be required in a particular CNS structure or cell type at a specific time during development. In this review, we analyzed delivery methods for AAV-mediated gene therapy in past and current clinical trials. The delivery routes analyzed were direct intraparenchymal (IP), intracerebroventricular (ICV), intra-cisterna magna (CM), lumbar intrathecal (IT), and intravenous (IV). The results demonstrated that the dose used in these routes varies dramatically. The average total doses used were calculated and were 1.03 × 1013 for IP, 5.00 × 1013 for ICV, 1.26 × 1014 for CM, and 3.14 × 1014 for IT delivery. The dose for IV delivery varies by patient weight and is 1.13 × 1015 IV for a 10 kg infant. Ultimately, the choice of intervention must weigh the risk of an invasive surgical procedure to the toxicity and immune response associated with a high dose vector.

Keywords: AAV; adeno-associated virus vector; gene delivery; gene therapy; inherited disorders.

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Conflict of interest statement

The authors declare no conflicts of interest.

Figures

Figure 1
Figure 1
Modes of delivery for AAV-mediated gene therapy to the nervous system used in clinical trials. Direct needle trajectory is not represented anatomically and varies by patient. Created utilizing Biorender.
Figure 2
Figure 2
Bar graph depicting average doses used in various delivery routes for AAV-mediated gene therapy to the central nervous system. IP = intraparenchymal; ICV = intracerebroventricular; CM = intra-cisterna magna; IT = lumbar intrathecal; IV = intravenous. For IP, ICV, CM and IT, the dose is a constant vector genome amount (vg). * For IV dosing, the dose is vg/kg. The dose in this graph demonstrates the total dose for a 10 kg infant. Adult IV dosing is much higher. For more information, see Table 1.
See this image and copyright information in PMC

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