Journal Article10.1016/j.addr.2024.115346
Exploring the potential of cell-derived vesicles for transient delivery of gene editing payloads
Kevin Leandro,David Rufino-Ramos,Koen Breyne,Emilio Di Ianni,Sara Lopes,Rui Jorge Nobre,Benjamin P. Kleinstiver,Pedro R.L. Perdigão,Xandra O. Breakefield,Luís Pereira de Almeida +9 more
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TL;DR: Exploring the potential of cell-derived vesicles for transient delivery of gene editing payloads TLDR: Cell-derived vesicles offer a promising approach for transient delivery of gene editing payloads, addressing the limited efficacy of in vivo delivery and paving the way for new genetic therapies.
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Abstract: Gene editing technologies have the potential to correct genetic disorders by modifying, inserting, or deleting specific DNA sequences or genes, paving the way for a new class of genetic therapies. While gene editing tools continue to be improved to increase their precision and efficiency, the limited efficacy of in vivo delivery remains a major hurdle for clinical use. An ideal delivery vehicle should be able to target a sufficient number of diseased cells in a transient time window to maximize on-target editing and mitigate off-target events and immunogenicity. Here, we review major advances in novel delivery platforms based on cell-derived vesicles − extracellular vesicles and virus-like particles − for transient delivery of gene editing payloads. We discuss major findings regarding packaging, in vivo biodistribution, therapeutic efficacy, and safety concerns of cell-derived vesicles delivery of gene-editing cargos and their potential for clinical translation.
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Citations
Extracellular vesicles-associated AAVs for the treatment of Machado-Joseph disease
Carina Henriques,Patrícia Albuquerque,David Rufino-Ramos,Miguel M. Lopes,Kevin Leandro,Catarina O. Miranda,Rita Almeida,João de Sousa-Lourenço,Sara M Lopes,Laetitia S Gaspar,Diana D Lobo,Ana Carolina Silva,Teresa M. Ribeiro-Rodrigues,Henrique Girão,Célia M Gomes,Rafael Baganha,Sónia Duarte,Casey A Maguire,Magda M. Santana,Luís Pereira de Almeida,Rui Jorge Nobre,Catarina Miranda,Diana Lobo +22 more
Abstract: Machado-Joseph disease (MJD) is the most common dominant autosomal inherited ataxia worldwide, caused by the over-repetition of the trinucleotide CAG in the ATXN3 gene. This leads to the accumulation of ataxin-3 protein and neurodegeneration. Currently, treatment remains symptomatic, though gene therapy has emerged as a promising approach. However, efficient and minimally invasive delivery to the brain remains a challenge. Extracellular vesicle-associated adeno-associated vectors (EV-AAVs) are a novel delivery system, combining AAVs' ability to deliver genes with extracellular vesicles' capacity to bypass the immune system and cross the blood-brain barrier (BBB). Previous studies, however, have only combined AAV serotypes known to efficiently cross the BBB with EVs as a non-invasive delivery system to the brain. Thus, the ability of EV-AAVs to cross the BBB remained inconclusive. In this study we evaluated whether AAV1/2 serotype, combined with rabies virus glycoprotein (RVg)-coated EVs, could effectively target the brain. Two isolation methods, differential ultracentrifugation and size exclusion chromatography (SEC) were compared, with SEC yielding higher EV recovery. Moreover, RVg-EV-AAV1/2 successfully crossed the BBB and transduced mouse brains, leading to motor and neuropathological improvements in an MJD mouse model. This study demonstrates that RVg-EV-AAVs are promising non-invasive delivery systems for MJD gene therapy.
Investigating the kinetics of single-chain expansion upon release in theta conditions
TL;DR: Langevin dynamics simulations investigate single-chain expansion kinetics in theta solvents, revealing a two-stage process with distinct timescales and scaling behaviors, validated by kinetic theory and simulations, and interpreted through radial expansion and diffusive mechanisms.
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