Comparative in vivo characterization of newly discovered myotropic adeno-associated vectors

IF 5.3 2区医学 Q2 CELL BIOLOGY

Skeletal Muscle Pub Date : 2024-05-03 DOI:10.1186/s13395-024-00341-7

Jacqueline Ji, Elise Lefebvre, Jocelyn Laporte

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引用次数: 0

Abstract

Adeno-associated virus (AAV)-based gene therapy is a promising strategy to treat muscle diseases. However, this strategy is currently confronted with challenges, including a lack of transduction efficiency across the entire muscular system and toxicity resulting from off-target tissue effects. Recently, novel myotropic AAVs named MyoAAVs and AAVMYOs have been discovered using a directed evolution approach, all separately demonstrating enhanced muscle transduction efficiency and liver de-targeting effects. However, these newly discovered AAV variants have not yet been compared. In this study, we performed a comparative analysis of these various AAV9-derived vectors under the same experimental conditions following different injection time points in two distinct mouse strains. We highlight differences in transduction efficiency between AAV9, AAVMYO, MyoAAV2A and MyoAAV4A that depend on age at injection, doses and mouse genetic background. In addition, specific AAV serotypes appeared more potent to transduce skeletal muscles including diaphragm and/or to de-target heart or liver. Our study provides guidance for researchers aiming to establish proof-of-concept approaches for preventive or curative perspectives in mouse models, to ultimately lead to future clinical trials for muscle disorders.

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新发现的肌腺相关载体的体内特性比较

基于腺相关病毒（AAV）的基因疗法是一种治疗肌肉疾病的前景广阔的策略。然而，这一策略目前面临着一些挑战，包括缺乏整个肌肉系统的转导效率以及脱靶组织效应导致的毒性。最近，人们利用定向进化方法发现了名为 MyoAAVs 和 AAVMYOs 的新型致肌 AAVs，它们都分别表现出更高的肌肉转导效率和肝脏脱靶效应。然而，这些新发现的 AAV 变种尚未进行过比较。在本研究中，我们在相同的实验条件下，按照不同的注射时间点，在两种不同的小鼠品系中对这些不同的 AAV9 衍生载体进行了比较分析。我们强调了 AAV9、AAVMYO、MyoAAV2A 和 MyoAAV4A 之间转导效率的差异，这种差异取决于注射年龄、剂量和小鼠遗传背景。此外，特定的 AAV 血清型在转导骨骼肌（包括膈肌）和/或转导心脏或肝脏时似乎更有效。我们的研究为研究人员提供了指导，他们的目标是在小鼠模型中建立预防或治疗角度的概念验证方法，最终促成未来针对肌肉疾病的临床试验。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Skeletal Muscle CELL BIOLOGY-

CiteScore

9.10

自引率

0.00%

发文量

审稿时长

12 weeks

期刊介绍： The only open access journal in its field, Skeletal Muscle publishes novel, cutting-edge research and technological advancements that investigate the molecular mechanisms underlying the biology of skeletal muscle. Reflecting the breadth of research in this area, the journal welcomes manuscripts about the development, metabolism, the regulation of mass and function, aging, degeneration, dystrophy and regeneration of skeletal muscle, with an emphasis on understanding adult skeletal muscle, its maintenance, and its interactions with non-muscle cell types and regulatory modulators. Main areas of interest include: -differentiation of skeletal muscle- atrophy and hypertrophy of skeletal muscle- aging of skeletal muscle- regeneration and degeneration of skeletal muscle- biology of satellite and satellite-like cells- dystrophic degeneration of skeletal muscle- energy and glucose homeostasis in skeletal muscle- non-dystrophic genetic diseases of skeletal muscle, such as Spinal Muscular Atrophy and myopathies- maintenance of neuromuscular junctions- roles of ryanodine receptors and calcium signaling in skeletal muscle- roles of nuclear receptors in skeletal muscle- roles of GPCRs and GPCR signaling in skeletal muscle- other relevant aspects of skeletal muscle biology. In addition, articles on translational clinical studies that address molecular and cellular mechanisms of skeletal muscle will be published. Case reports are also encouraged for submission. Skeletal Muscle reflects the breadth of research on skeletal muscle and bridges gaps between diverse areas of science for example cardiac cell biology and neurobiology, which share common features with respect to cell differentiation, excitatory membranes, cell-cell communication, and maintenance. Suitable articles are model and mechanism-driven, and apply statistical principles where appropriate; purely descriptive studies are of lesser interest.