AAV9: a potential blood-brain barrier buster

Manfredsson, Fredric P.; Rising, Aaron; Mandel, Ronald J.

doi:10.1038/mt.2009.15

Cited by 79 publications

(51 citation statements)

References 29 publications

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“…20 The ability of AAV serotype 9 to pass the blood-brain barrier and transduce the CNS in mice has been well documented. 19,[32][33][34] This study demonstrated partial correction of glycogen accumulation in the brain of Gbe1 ys/ys mice by the AAV-GBE treatment (Fig. 2).…”

Section: Discussionsupporting

confidence: 52%

Systemic Correction of Murine Glycogen Storage Disease Type IV by an AAV-Mediated Gene Therapy

Zhang

Brooks

et al. 2017

Human Gene Therapy

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Section: Discussionsupporting

confidence: 52%

Systemic Correction of Murine Glycogen Storage Disease Type IV by an AAV-Mediated Gene Therapy

Zhang

Brooks

et al. 2017

Human Gene Therapy

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“…1,9,38--41 Validation of systemic gene delivery in a large animal is the next step and it has been one of the major limitations of gene transfer to the central nervous system. Our study combines desirable features of intrathecal delivery with a viral vector capable of crossing the BBB 42 for widespread gene delivery throughout the spinal cord. The mechanism by which AAV9 transduces spinal cord MNs following systemic delivery has been previously discussed, and it is likely to happen across the BBB in the case of intravascular injections.…”

Section: Discussionmentioning

confidence: 99%

Robust spinal motor neuron transduction following intrathecal delivery of AAV9 in pigs

et al. 2011

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Adeno-associated viral vector 9 (AAV9) has recently been shown to penetrate the blood--brain barrier via intravascular administration, making it a good candidate for diffuse gene delivery. However, the potential side effects of systemic delivery are unknown. Intrathecal viral vector administration may be more invasive than intravenous injections, but it requires far less vector and it can be performed on an outpatient basis, making it an ideal route of delivery for clinical translation. A total of 12 domestic farm pigs (o20 kg) underwent a single-level lumbar laminectomy with intrathecal catheter placement for AAV9 delivery. Animals were perfused and the tissue was harvested 30 days after treatment. Gene expression was assessed by anti-green fluorescent protein immunohistochemistry. Although a single lumbar injection resulted in gene expression limited to the lumbar segment of the spinal cord, three consecutive boluses via a temporary catheter resulted in diffuse transduction of motor neurons (MNs) throughout the cervical, thoracic and lumbar spinal cords. We now present the first successful robust transduction of MNs in the spinal cord of a large animal via intrathecal gene delivery using a self-complementary AAV9. These promising results can be translated to many MN diseases requiring diffuse gene delivery.

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“…AAV9 is a serotype that effectively crosses the blood-brain barrier (Manfredsson et al, 2009) and can robustly infect motoneurons (Snyder et al, 2011). Intrathecal delivery of scAAV9-GFP (2.5 · 10 9 vector genomes [VG]) transduced approximately 700 motoneurons in adult mice, but this was not restricted to a given motor pool (Snyder et al, 2011).…”

mentioning

confidence: 99%

Retrograde Gene Delivery to Hypoglossal Motoneurons Using Adeno-Associated Virus Serotype 9

ElMallah

Falk

Lane

et al. 2012

Human Gene Therapy Methods

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Retrograde viral transport (i.e., muscle to motoneuron) enables targeted gene delivery to specific motor pools. Recombinant adeno-associated virus serotype 9 (AAV9) robustly infects motoneurons, but the retrograde transport capabilities of AAV9 have not been systematically evaluated. Accordingly, we evaluated the retrograde transduction efficiency of AAV9 after direct tongue injection in 129SVE mice as well as a mouse model that displays neuromuscular pathology (Gaa -/ -). Hypoglossal (XII) motoneurons were histologically evaluated 8 weeks after tongue injection with AAV9 encoding green fluorescent protein (GFP) with expression driven by the chicken b-actin promoter (1 · 10 11 vector genomes). On average, GFP expression was detected in 234 -43 XII motoneurons 8 weeks after AAV9-GFP tongue injection. In contrast, tongue injection with a highly efficient retrograde anatomical tracer (cholera toxin b subunit, CT-b) resulted in infection of 818 -88 XII motoneurons per mouse. The retrograde transduction efficiency of AAV9 was similar between the 129SVE mice and those with neuromuscular disease (Gaa -/ -). Routine hematoxylin and eosin staining and cluster of differentiation (CD) immunostaining for T cells (CD3) indicated no persistent inflammation within the tongue or XII nucleus after AAV9 injection. Additional experiments indicated no adverse effects of AAV9 on the pattern of breathing. We conclude that AAV9 can retrogradely infect a significant portion of a given motoneuron pool in normal and dystrophic mice, and that its transduction efficiency is approximately 30% of what can be achieved with CT-b.

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AAV9: a potential blood-brain barrier buster

Cited by 79 publications

References 29 publications

Systemic Correction of Murine Glycogen Storage Disease Type IV by an AAV-Mediated Gene Therapy

Systemic Correction of Murine Glycogen Storage Disease Type IV by an AAV-Mediated Gene Therapy

Robust spinal motor neuron transduction following intrathecal delivery of AAV9 in pigs

Retrograde Gene Delivery to Hypoglossal Motoneurons Using Adeno-Associated Virus Serotype 9

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