Safe and effective in vivo delivery of DNA and RNA using proteolipid vehicles

IF 45.5 1区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Cell Pub Date : 2024-09-10 DOI:10.1016/j.cell.2024.07.023

Douglas W. Brown, Ping Wee, Prakash Bhandari, Amirali Bukhari, Liliya Grin, Hector Vega, Maryam Hejazi, Deborah Sosnowski, Jailal Ablack, Eileen K. Clancy, Desmond Pink, Jitendra Kumar, Maria Paola Solis Ares, Suellen Lamb, Rodrigo Quevedo, Bijal Rawal, Fahed Elian, Natasha Rana, Luis Morales, Natasha Govindasamy, John D. Lewis

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引用次数: 0

Abstract

Genetic medicines show promise for treating various diseases, yet clinical success has been limited by tolerability, scalability, and immunogenicity issues of current delivery platforms. To overcome these, we developed a proteolipid vehicle (PLV) by combining features from viral and non-viral approaches. PLVs incorporate fusion-associated small transmembrane (FAST) proteins isolated from fusogenic orthoreoviruses into a well-tolerated lipid formulation, using scalable microfluidic mixing. Screening a FAST protein library, we identified a chimeric FAST protein with enhanced membrane fusion activity that improved gene expression from an optimized lipid formulation. Systemically administered FAST-PLVs showed broad biodistribution and effective mRNA and DNA delivery in mouse and non-human primate models. FAST-PLVs show low immunogenicity and maintain activity upon repeat dosing. Systemic administration of follistatin DNA gene therapy with FAST-PLVs raised circulating follistatin levels and significantly increased muscle mass and grip strength. These results demonstrate the promising potential of FAST-PLVs for redosable gene therapies and genetic medicines.

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利用蛋白脂载体安全有效地在体内输送 DNA 和 RNA

基因药物有望治疗各种疾病，但目前的递送平台在耐受性、可扩展性和免疫原性方面的问题限制了临床成功。为了克服这些问题，我们结合病毒和非病毒方法的特点，开发了一种蛋白脂载体（PLV）。蛋白脂载体利用可扩展的微流体混合技术，将从融合原生病毒中分离出来的融合相关小跨膜（FAST）蛋白纳入耐受性良好的脂质配方中。通过筛选 FAST 蛋白库，我们发现了一种具有增强膜融合活性的嵌合 FAST 蛋白，它能改善优化脂质配方的基因表达。在小鼠和非人灵长类动物模型中，全身给药的 FAST-PLV 显示出广泛的生物分布和有效的 mRNA 和 DNA 递送。FAST-PLVs 的免疫原性低，重复给药后仍能保持活性。使用FAST-PLVs进行全身给药的follistatin DNA基因治疗提高了循环中follistatin的水平，并显著增加了肌肉质量和握力。这些结果表明，FAST-PLVs 在可重复使用的基因疗法和基因药物方面具有巨大潜力。

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来源期刊

Cell 生物-生化与分子生物学

CiteScore

110.00

自引率

0.80%

发文量

396

审稿时长

2 months

期刊介绍： Cells is an international, peer-reviewed, open access journal that focuses on cell biology, molecular biology, and biophysics. It is affiliated with several societies, including the Spanish Society for Biochemistry and Molecular Biology (SEBBM), Nordic Autophagy Society (NAS), Spanish Society of Hematology and Hemotherapy (SEHH), and Society for Regenerative Medicine (Russian Federation) (RPO). The journal publishes research findings of significant importance in various areas of experimental biology, such as cell biology, molecular biology, neuroscience, immunology, virology, microbiology, cancer, human genetics, systems biology, signaling, and disease mechanisms and therapeutics. The primary criterion for considering papers is whether the results contribute to significant conceptual advances or raise thought-provoking questions and hypotheses related to interesting and important biological inquiries. In addition to primary research articles presented in four formats, Cells also features review and opinion articles in its "leading edge" section, discussing recent research advancements and topics of interest to its wide readership.