Taking a Hint from Structural Biology: To Better Understand AAV Transport across the BBB

Wang, Dan; Gao, Guangping

doi:10.1016/j.ymthe.2018.01.005

Cited by 4 publications

(2 citation statements)

References 13 publications

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“…These data are consistent with previous reports for another Clade F virus, AAV9, which can effectively cross the BBB after IV administration in nonhuman primates [18, 19] supporting the claim that the ability to efficiently cross the BBB may be a feature of Clade F AAVs. A number of native and engineered recombinant AAVs from other clades have been shown to cross the BBB in mice following systemic delivery [25–28] for reviews and [29–32] with only a few of these vectors studied in larger animals to date [33]. In some cases moreover, translation of the biodistribution data observed in mice to nonhuman primates has been poor [21, 34, 35], emphasizing the importance of studying the tissue tropism of AAV in large animals that may more closely reflect the underlying biology in humans.…”

Section: Discussionmentioning

confidence: 99%

Clade F AAVHSCs cross the blood brain barrier and transduce the central nervous system in addition to peripheral tissues following intravenous administration in nonhuman primates

Ellsworth¹,

Gingras²,

Smith³

et al. 2019

PLoS ONE

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The biodistribution of AAVHSC7, AAVHSC15, and AAVHSC17 following systemic delivery was assessed in cynomolgus macaques (Macaca fascicularis). Animals received a single intravenous (IV) injection of a self-complementary AAVHSC-enhanced green fluorescent protein (eGFP) vector and tissues were harvested at two weeks post-dose for anti-eGFP immunohistochemistry and vector genome analyses. IV delivery of AAVHSC vectors produced widespread distribution of eGFP staining in glial cells throughout the central nervous system, with the highest levels seen in the pons and lateral geniculate nuclei (LGN). eGFP-positive neurons were also observed throughout the central and peripheral nervous systems for all three AAVHSC vectors including brain, spinal cord, and dorsal root ganglia (DRG) with staining evident in neuronal cell bodies, axons and dendritic arborizations. Co-labeling of sections from brain, spinal cord, and DRG with anti-eGFP antibodies and cell-specific markers confirmed eGFP-staining in neurons and glia, including protoplasmic and fibrous astrocytes and oligodendrocytes. For all capsids tested, 50 to 70% of glial cells (S100-β+) and on average 8% of neurons (NeuroTrace+) in the LGN were positive for eGFP expression. In the DRG, 45 to 62% of neurons and 8 to 12% of satellite cells were eGFP-positive for the capsids tested. eGFP staining was also observed in peripheral tissues with abundant staining in hepatocytes, skeletal- and cardio-myocytes and in acinar cells of the pancreas. Biodistribution of AAVHSC vector genomes in the central and peripheral organs generally correlated with eGFP staining and were highest in the liver for all AAVHSC vectors tested. These data demonstrate that AAVHSCs have broad tissue tropism and cross the blood-nerve and blood-brain-barriers following systemic delivery in nonhuman primates, making them suitable gene editing or gene transfer vectors for therapeutic application in human genetic diseases.

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Section: Discussionmentioning

confidence: 99%

Clade F AAVHSCs cross the blood brain barrier and transduce the central nervous system in addition to peripheral tissues following intravenous administration in nonhuman primates

Ellsworth¹,

Gingras²,

Smith³

et al. 2019

PLoS ONE

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show abstract

“…It is well known that AAV vectors are predominantly sequestered in the liver after systemic injection [39,62]. To minimize liver infection, it is possible to use AAV variant proteins containing liver-de-targeted mutations [63][64][65]. In addition, intramuscular injection can also be used to minimize off-target expression.…”

Section: Disscussionmentioning

confidence: 99%

An AAV Vector for Inducible Gene Expression Preferentially in Muscles

Zhou,

Le,

Jiang

et al. 2023

IJGMR

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Adeno associated viral (AAV) vectors has been used widely in gene therapy and efforts have been madeto improve their utility by adding genetic elements that would enable targeting transgene expression to particular cells or tissues of interest and permitting on/off regulation of expression. In this study, we designed a recombinant AAV9 variant PHP.eB vector with muscle creatine kinase (Mck)-derived enhancers, a synthetic muscle-expression promoter, in combination with a third-generation tetracycline-inducible promoter, to drive expression of reporter genes luciferase and GFP (PHP.eB-Pmus-TetOn-teLuc and PHP.eB-Pmus-TetOn-eGFP, respectively). This recombinant vector expresses genes at high levels preferentially in muscle cells, that can be controlled by doxycycline (Dox) exposure both in vitro and in vivo. To test inducibility of these vectors in vivo, adult SKH hairless mice were injected intravenously with 2x10 12 virus genomes. Dox-containing food (625 mg/kg) was given 1 day after virus injection to initiate expression. After one month, tissue luciferase activity was assayed. Luciferase expression level per viral genome in muscle tissues including biceps brachii, biceps femoris, and heart tissue were higher in Pmus-TetOn group. Long-term expression was also assessed for the PHP.eB-Pmus-TetOn-teLuc vector: two weeks after virus injection and Dox induction, Dox-containing food was replaced with conventional diet and luciferase expression was tracked biweekly using IVIS in vivo imaging. Following Dox removal, luciferase expression decreased and by 6 weeks had returned to basal levels. Re-exposure to Dox stimulated luciferase expression to levels similar to the first Dox-induced expression. Removal of the second Dox stimulus resulted in slow loss of luciferase activity, which could again be re-induced by Dox exposure. These experiments indicate that this inducible, tissue-selective expression could be maintained in vivo for at least 18 weeks.

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Emerging Therapies

Grabowski

Hughes

2022

Lysosomal Storage Disorders

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Taking a Hint from Structural Biology: To Better Understand AAV Transport across the BBB

Abstract: CRISPR-mediated modular RNA-guided regulation of transcription in eukaryotes. Cell 154, 442-451.

Cited by 4 publications

References 13 publications

Clade F AAVHSCs cross the blood brain barrier and transduce the central nervous system in addition to peripheral tissues following intravenous administration in nonhuman primates

Clade F AAVHSCs cross the blood brain barrier and transduce the central nervous system in addition to peripheral tissues following intravenous administration in nonhuman primates

An AAV Vector for Inducible Gene Expression Preferentially in Muscles

Emerging Therapies

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