Pilot Study Assessing the Impact of Intrathecal Administration of Variants AAV-PHP.B and AAV-PHP.eB on Brain Transduction in Adult Rhesus Macaques

Arotcarena, Marie-Laure; Doveró, Sandra; Biendon, Nathalie; Dutheil, Nathalie; Planche, Vincent; Bézard, Erwan; Dehay, Benjamin

doi:10.3389/fbioe.2021.762209

Cited by 13 publications

(6 citation statements)

References 42 publications

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“…2). Expression was especially low in subcortical structures, as reported previously [41][42][43][44][45] .…”

Section: Characterization In Newborn Macaques and Infant Green Monkey...supporting

confidence: 87%

“…In addition to CAP-Mac's utility as a tool to study the primate brain, it is also a compelling potential delivery vehicle for genetic medicine in humans. It provides an unprecedented opportunity to deepen our understanding of pharmacodynamics in Old World primate models 30,83,84 and its broad and uniform distribution throughout the CNS opens access to subcortical and midbrain regions for neuroscience researchers, currently difficult in NHPs [41][42][43][44][45] . Additionally, CAP-Mac's enhanced transduction of cultured human neurons supports its potential as a gene-delivery vehicle in humans.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Intravenous functional gene transfer throughout the brain of non-human primates using AAV

Chuapoco¹,

Flytzanis

Goeden

et al. 2023

Preprint

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Adeno-associated viruses (AAVs) promise robust gene delivery to the brain through non-invasive, intravenous delivery. However, unlike in rodents, few neurotropic AAVs efficiently cross the blood-brain barrier in non-human primates (NHPs). Here we describe AAV.CAP-Mac, an engineered variant identified by screening in adult marmosets and newborn macaques with improved efficiency in the brain of multiple NHP species: marmoset, rhesus macaque, and green monkey. CAP-Mac is neuron-biased in infant Old World primates, exhibits broad tropism in adult rhesus macaques, and is vasculature-biased in adult marmosets. We demonstrate applications of a single, intravenous dose of CAP-Mac to deliver (1) functional GCaMP for ex vivo calcium imaging across multiple brain areas, and (2) a cocktail of fluorescent reporters for Brainbow-like labeling throughout the macaque brain, circumventing the need for germline manipulations in Old World primates. Given its capabilities for systemic gene transfer in NHPs, CAP-Mac promises to help unlock non-invasive access to the brain.

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“…2). Expression was especially low in subcortical structures, as reported previously [41][42][43][44][45] .…”

Section: Characterization In Newborn Macaques and Infant Green Monkey...supporting

confidence: 87%

Section: Discussionmentioning

confidence: 99%

Intravenous functional gene transfer throughout the brain of non-human primates using AAV

Chuapoco¹,

Flytzanis

Goeden

et al. 2023

Preprint

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“…Intrathecal injection can also be targeted towards specific cell types aiming in a more limited biodistribution and fewer off‐target side effects. For such cases we suggest the employment of engineered tissue‐selective viral capsids (Arotcarena et al., 2021; Barnes et al., 2019) and/or the use of tissue‐specific promoters that provide cell‐specific expression (Kagiava, Karaiskos, et al., 2021; Kagiava et al., 2018; Kagiava et al., 2019; Kagiava, Richter, et al., 2021; Kagiava et al., 2016; Schiza et al., 2019).…”

Section: Commentarymentioning

confidence: 99%

Lumbar Intrathecal Injection in Adult and Neonatal Mice

Stavrou,

Georgiou,

Kleopa

2024

Current Protocols

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This article describes a step‐by‐step process of lumbar intrathecal injection of Evans blue dye and AAV9‐EGFP in adult (2‐month‐old) and neonatal (postnatal day 10) mice. Intrathecal injection is a clinically translatable technique that has already been extensively applied in humans. In mice, intrathecal injection is considered a challenging procedure that requires a trained and experienced researcher. For both adult and neonatal mice, lumbar intrathecal injection is directed into the L5‐L6 intervertebral space. Intrathecally injected material enters the cerebrospinal fluid (CSF) within the intrathecal space from where it can directly access the central nervous system (CNS) parenchyma. Simultaneously, intrathecally injected material exits the CSF with pressure gradient and enters the endoneurial fluid and ultimately the peripheral nerves. While in the CSF, the injectable material also enters the bloodstream and systemic circulation through the arachnoid villi. A successful lumbar intrathecal injection results in adequate biodistribution of the injectable material in the CNS, PNS, and peripheral organs. When correctly applied, this technique is considered as minimally invasive and non‐disruptive and can be used for the lumbar delivery of any solute. © 2024 Wiley Periodicals LLC.Basic Protocol 1: C57BL/6 adult and P10 mice lumbar intrathecal injectionBasic Protocol 2: Tissue collection and preparation for evaluating Evans blue dye diffusionBasic Protocol 3: Tissue collection and preparation for immunohistochemistry stainingBasic Protocol 4: Tissue collection and vector genome copy number analysis

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“…Moreover, GFP can be detected in cerebellar Purkinje cells, the medulla, and discrete nuclei after intracisternal and intralumbar injection of rAAV9-GFP in 5-day-old pigs ( Bevan et al, 2011 ). Studies showed that rAAV-PHP.eB was superior to rAAV9 in brain transduction rate after intracisternal injection in adult rats and after intrathecal injections in non-human primates ( Arotcarena et al, 2021 ; Chatterjee et al, 2022 ). However, the PHP.eB variant raises concerns about their species and strain specificity as discussed above.…”

Section: Delivery Into the Csfmentioning

confidence: 99%

Routes of administration for adeno-associated viruses carrying gene therapies for brain diseases

Zhou

Han

Wang

et al. 2022

Front. Mol. Neurosci.

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Gene therapy is a powerful tool to treat various central nervous system (CNS) diseases ranging from monogenetic diseases to neurodegenerative disorders. Adeno-associated viruses (AAVs) have been widely used as the delivery vehicles for CNS gene therapies due to their safety, CNS tropism, and long-term therapeutic effect. However, several factors, including their ability to cross the blood–brain barrier, the efficiency of transduction, their immunotoxicity, loading capacity, the choice of serotype, and peripheral off-target effects should be carefully considered when designing an optimal AAV delivery strategy for a specific disease. In addition, distinct routes of administration may affect the efficiency and safety of AAV-delivered gene therapies. In this review, we summarize different administration routes of gene therapies delivered by AAVs to the brain in mice and rats. Updated knowledge regarding AAV-delivered gene therapies may facilitate the selection from various administration routes for specific disease models in future research.

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Pilot Study Assessing the Impact of Intrathecal Administration of Variants AAV-PHP.B and AAV-PHP.eB on Brain Transduction in Adult Rhesus Macaques

Cited by 13 publications

References 42 publications

Intravenous functional gene transfer throughout the brain of non-human primates using AAV

Intravenous functional gene transfer throughout the brain of non-human primates using AAV

Lumbar Intrathecal Injection in Adult and Neonatal Mice

Routes of administration for adeno-associated viruses carrying gene therapies for brain diseases

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