Enhanced CNS transduction from AAV.PHP.eB infusion into the cisterna magna of older adult rats compared to AAV9

Chatterjee, Diptaman; Marmion, David J.; McBride, Jodi L.; Manfredsson, Fredric P.; Butler, David; Messer, Anne; Kordower, Jeffrey H.

doi:10.1038/s41434-021-00244-y

Cited by 27 publications

(26 citation statements)

References 29 publications

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“…The CRISPR-mediated knockdown allowed us to investigate the VMAT2- dependent dopamine signaling in the striatum, while structurally preserving neuronal integrity. [ 18 F]GE-180 results suggest that glial activation is not the source of dopaminergic synaptic dysfunction, and exclude the occurrence of inflammatory responses arising from the surgical procedure and the chosen AAV-serotype, which could influence our readout, in line with recent reports [49]. Our data reveal that the targeted gene knockdown in the SNc leads to an expected reduction of dopamine release in the striatum, paralleled by [ 11 C]raclopride binding changes.…”

Section: Discussionsupporting

confidence: 84%

Combining CRISPR/Cas9 and brain imaging: from genes to molecules to networks

Marciano

Ionescu

Saw

et al. 2021

Preprint

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Understanding how functional connections between brain regions are arranged and influenced by genes, in the healthy and diseased states, is a major goal in neuroscience. Functional connectivity alterations are linked to molecular changes in several neurodegenerative disorders and could serve as early markers of pathology. Yet, the underlying molecular signatures driving the functional alterations remain largely unknown. Here, we combine CRISPR/Cas9 gene-editing with in vivo positron emission tomography (PET) and functional magnetic resonance imaging (fMRI) to investigate the direct link between genes, proteins, and the brain connectome. The extensive knowledge of the Slc18a2 gene encoding the vesicular monoamine transporter (VMAT2), involved in the storage and release of dopamine, makes it an excellent basis for studying the gene networks relationships. We edited Slc18a2 into the substantia nigra pars compacta of adult rats and used in vivo molecular imaging, behavioral, histological, and biochemical assessments to characterize the CRISPR/Cas9-mediated VMAT2 knockdown. Simultaneous PET/fMRI was performed to inspect the functional brain adaptations, beyond the predicted dopaminergic changes. Further, [11C]flumazenil PET was carried out to investigate the dopamine-GABA interplay. We found a regional increase in postsynaptic dopamine receptor availability, preceded by a reorganization of brain networks that adapt to reduced dopamine transmission states by becoming functionally connected and organized. The hyperconnectivity within and between brain networks spreads from the contralateral thalamus and prefrontal cortical regions to the striata and hippocampi. Additionally, impaired striatal dopamine release reduces GABA-A receptor availability, complementing the increased synchrony and functional connectivity between networks observed at rest. Our study reveals that recruiting different brain networks may be an early response to the dopaminergic dysfunction preceding neuronal cell loss, postsynaptic changes, and motor impairment in neurodegenerative disorders such as Parkinson's disease. We anticipate our combinatorial approach to be a starting point to investigate the impact of specific genes on brain molecular and functional dynamics, aiding in the identification of early neurobiological markers and promising therapeutic interventions.

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Section: Discussionsupporting

confidence: 84%

Combining CRISPR/Cas9 and brain imaging: from genes to molecules to networks

Marciano

Ionescu

Saw

et al. 2021

Preprint

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“…B recently reported an enhanced AAV-PHP. B variant (AAV-PHP.eB) that shows further improvements in neurons and glia transduction efficiency throughout the CNS after intravenous delivery in adult mice ( Chan et al, 2017 ; Mathiesen et al, 2020 ), or after intravascular ( Dayton et al, 2018 ) and cisterna magna ( Chatterjee et al, 2021 ) administration in adult rats. As a face-to-face comparison of AAV-PHP.…”

Section: Introductionmentioning

confidence: 99%

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

Doveró

Biendon

et al. 2021

Front. Bioeng. Biotechnol.

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Adeno-associated virus (AAV) vectors are increasingly used as an effective and safe approach to deliver genetic material to the central nervous system (CNS). The AAV9-derived variants, AAV-PHP. B and AAV-PHP.eB, reportedly broadly transduce cells throughout the CNS compared to the original serotype 9, AAV9. As non-human primate data are scarce, we here evaluated the CNS transduction efficiencies after lumbar intrathecal bolus delivery of identical doses of either AAV-PHP. B:CAG-EGFP or AAV-PHP. eB:CAG-EGFP in rhesus macaque monkeys. AAV-PHP.eB achieved a more efficient and widespread CNS transduction compared to AAV-PHP.B. We report a strong neuronal and oligodendroglial tropism for both variants in the putamen and in the hippocampus. This proof-of-concept experiment highlights the potential value of intrathecal infusions of AAV-PHP.eB to distribute genetic material in the CNS with cell-type specificity and introduces a new opportunity to model brain diseases in rhesus macaque monkeys and further develop gene therapies targeting the CNS in humans.

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“…In NHPs, IT delivery has been shown to be the most efficient route capable of global delivery to the brain (Yang et al, 2014;Hinderer et al, 2018a;Hordeaux et al, 2018a;Liguore et al, 2019). IT-CM delivery has also been shown to allow highly efficient delivery in mice, even demonstrating disease modification in a mouse model of GM1-Gangliosidosis (Hinderer et al, 2020;Chatterjee et al, 2021). As expected with IT therapy, there is considerably less peripheral uptake to all organs, including the liver (Yang et al, 2014;Hinderer et al, 2018a;Hordeaux et al, 2018a;Liguore et al, 2019).…”

Section: Intra-thecal Delivery Routesmentioning

confidence: 99%

“…This mechanism allows for higher brain penetration than vectors, which do not possess this trait (Zincarelli et al, 2008). Although AAV9 and other naturally occurring vectors cross the BBB, they do so with low efficiency and many vectors have been engineered to improve BBB crossing properties (Chan et al, 2017;Hanlon et al, 2019). This will be discussed in more depth later in the manuscript.…”

Section: Evaluation Of Intravenous Delivery and Meta-analysis Of Pre-clinical Studiesmentioning

confidence: 99%

“…Figure 2 is a meta-analysis of 12 published mouse studies (Pulicherla et al, 2011;Yang et al, 2014;Choudhury et al, 2016;Chan et al, 2017;Hordeaux et al, 2018a,b;Marshall et al, 2018;Hanlon et al, 2019;Huang et al, 2019;Lim et al, 2019;Bailey et al, 2020;Kumar et al, 2020) and 4 studies in NHPs (Yang et al, 2014;Hinderer et al, 2018a;Hordeaux et al, 2018a;Liguore et al, 2019). These studies used a variety of route and serotype combinations for gene delivery to the brain.…”

Section: Evaluation Of Intravenous Delivery and Meta-analysis Of Pre-clinical Studiesmentioning

confidence: 99%

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

Fischell

Fishman

2021

Front. Neurosci.

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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.

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Enhanced CNS transduction from AAV.PHP.eB infusion into the cisterna magna of older adult rats compared to AAV9

Cited by 27 publications

References 29 publications

Combining CRISPR/Cas9 and brain imaging: from genes to molecules to networks

Combining CRISPR/Cas9 and brain imaging: from genes to molecules to networks

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

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

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