Selection of an Efficient AAV Vector for Robust CNS Transgene Expression

Hanlon, Killian S.; Meltzer, Jonah C; Buzhdygan, Tetyana; Cheng, Ming; Sena‐Esteves, Miguel; Bennett, Rachel E.; Sullivan, Timothy P.; Razmpour, Roshanak; Gong, Yi; Ng, Carrie; Nammour, Josette; Maiz, Daniela; Dujardin, Simon; Ramirez, Servio H.; Hudry, Eloïse; Maguire, Casey A.

doi:10.1016/j.omtm.2019.10.007

Cited by 117 publications

(110 citation statements)

References 26 publications

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“…Despite having one of the best CNS transduction profiles among naturally occurring AAVs, recombinant AAV9 vectors have limitations in cell type transduction translatability between species (i.e between mice and non-human primates), as well as high pre-existing immunogenicity in the general population that may limit eligibility for treatment (35). Due to technological limitations of the existing vectors, a big effort in the field is now focused on creating novel capsids with improved properties for use in CNS (31,(39)(40)(41)(42)(43)(44)(45)(46).…”

Section: Discussionmentioning

confidence: 99%

MCOLN1gene-replacement therapy corrects neurologic dysfunction in the mouse model of mucolipidosis IV

DeRosa

Salani

Smith

et al. 2020

Preprint

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Mucolipidosis IV (MLIV, OMIM 252650) is an orphan disease leading to debilitating psychomotor deficits and vision loss. It is caused by loss-of-function mutations in the MCOLN1 gene that encodes thethe lysosomal transient receptor potential channel mucolipin 1 (TRPML1). With no existing therapy, the unmet need in this disease is very high. Here we show that AAV-mediated gene transfer of the human MCOLN1 gene rescues motor function and alleviates brain pathology in the Mcoln1−/− MLIV mouse model. Using the AAV-PHP.b vector for initial proof-of-principle experiments in symptomatic mice, we showed long-term reversal of declined motor function and significant delay of paralysis. Next, we designed self-complimentary AAV9 vector for clinical use and showed that its intracerebroventricular administration in post-natal day 1 mice significantly improved motor function and myelination and reduced lysosomal storage load in the MLIV mouse brain. We also showed that CNS targeted gene transfer is necessary to achieve therapeutic efficacy in this disease. Based on our data and general advancements in the gene therapy field, we propose scAAV9-mediated CSF-targeted MCOLN1 gene transfer as a therapeutic strategy in MLIV.

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Section: Discussionmentioning

confidence: 99%

MCOLN1gene-replacement therapy corrects neurologic dysfunction in the mouse model of mucolipidosis IV

DeRosa

Salani

Smith

et al. 2020

Preprint

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“…Variants AAV-DJ (Grimm et al, 2008), AAV2.5T (Excoffon et al, 2009), NP84 (Paulk et al, 2018) and OLIG001 (Powell et al, 2016) are derived from shuffled DNA libraries. Variants AAV-F (Hanlon et al, 2019), AAV-PHP.B (Deverman et al, 2016), 7m8 (Dalkara et al, 2013) and rAAV2-retro (Tervo et al, 2016) are derived from peptide insertion libraries. Variants SCH2, SCH9 (Ojala et al, 2018), LI-A and LI-C (Marsic et al, 2014) are derived from more complex rationally designed libraries.…”

Section: Methodsmentioning

confidence: 99%

Parent-map: analysis of parental contributions to evolved or engineered protein or DNA sequences

Marsic¹

2021

JOSS

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Parent-map analyzes protein or DNA sequences which are derived from one or multiple parent sequences, and shows parental contributions as well as differences from relevant parents. Originally developed to analyze capsid protein sequences obtained by directed evolution, parentmap can be used in any case where variant sequences are to be compared to parent sequences from which they are derived. Parent-map detects sequence shuffling as well as substitutions, insertions and deletions, and displays results in user-friendly formats. Parent-map is an opensource, platform-independent Python 3 script, available as a Bioconda package as well as a Windows program.

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“…The treatment of many gene-deficient brain diseases must compensate for the correct genes to every cell in the whole brain [44]. Some natural and engineered adeno-associated viruses can transduce most CNS neurons by axon terminal absorption or blood-brain barrier transportation, such as AAV-TT [44], AAV2-Retro [5], AAV9-SLR [12], MNM004 [46], AAV-PHP.eB [47], and AAV-F [48], among others. However, AAVs with these two important features have not been reported.…”

Section: Introductionmentioning

confidence: 99%

AAV9-Retro mediates efficient transduction with axon terminal absorption and blood–brain barrier transportation

Kuang

Zhong

et al. 2020

Mol Brain

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Recombinant adeno-associated viruses (rAAVs), particularly those that permit efficient gene transfer to neurons from axonal terminals or across the blood–brain barrier, are useful vehicles for structural and functional studies of the neural circuit and for the treatment of many gene-deficient brain diseases that need to compensate for the correct genes in every cell in the whole brain. However, AAVs with these two advantages have not been reported. Here, we describe a new capsid engineering method, which exploits the combination of different capsids and aims to yield a capsid that can provide more alternative routes of administration that are more suitable for the wide-scale transduction of the central nervous system (CNS). A new AAV variant, AAV9-Retro, was developed by inserting the 10-mer peptide fragment from AAV2-Retro into the capsid of AAV9, and the biodistribution properties were evaluated in mice. By intracranial and intravenous injection in the mice, we found that AAV9-Retro can retrogradely infect projection neurons with an efficiency comparable to that of AAV2-Retro and retains the characteristic of AAV9, which can be transported across the nervous system. Our strategy provides a new tool for the manipulation of neural circuits and future preclinical and clinical treatment of some neurological and neurodegenerative disorders.

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Selection of an Efficient AAV Vector for Robust CNS Transgene Expression

Cited by 117 publications

References 26 publications

MCOLN1gene-replacement therapy corrects neurologic dysfunction in the mouse model of mucolipidosis IV

MCOLN1gene-replacement therapy corrects neurologic dysfunction in the mouse model of mucolipidosis IV

Parent-map: analysis of parental contributions to evolved or engineered protein or DNA sequences

AAV9-Retro mediates efficient transduction with axon terminal absorption and blood–brain barrier transportation

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