加拿大阿尔伯塔大学John D. Lewis等研究人员合作发现，使用蛋白脂质载体实现安全且有效的体内DNA和RNA递送。2024年9月10日，《细胞》杂志在线发表了这项成果。
研究人员表示，基因药物在治疗多种疾病方面展现出潜力，但现有递送平台的耐受性、可扩展性和免疫原性问题限制了其临床成功率。
为克服这些挑战，研究人员开发了一种蛋白脂质载体（PLV），结合了病毒和非病毒方法的特点。PLV通过可扩展的微流控混合技术，将从融合性正黏病毒中分离的融合相关小跨膜蛋白（FAST蛋白）整合到良好耐受的脂质配方中。通过筛选FAST蛋白库，研究人员鉴定出一种具有增强膜融合活性的嵌合FAST蛋白，优化的脂质配方显著提高了基因表达。
系统性给药的FAST-PLV在小鼠和非人灵长类模型中显示出广泛的生物分布，并有效递送mRNA和DNA。FAST-PLV的免疫原性低，且在多次给药后仍能保持活性。使用FAST-PLV递送抑制素DNA基因疗法后，循环抑制素水平升高，肌肉质量和握力显著增加。这些研究结果表明，FAST-PLV在可重复使用的基因疗法和基因药物领域具有广阔的应用前景。
附：英文原文
Title: Safe and effective in vivo delivery of DNA and RNA using proteolipid vehicles
Author: 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, Brendan Todd, Angela Delmage, Somnath Gupta, Nichole McMullen, Duncan MacKenzie, Perrin H. Beatty, Henry Garcia, Manoj Parmar, Jennifer Gyoba, Chandra McAllister, Matthew Scholz, Roy Duncan, Arun Raturi, John D. Lewis
Issue&Volume: 2024-09-10
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.
DOI: 10.1016/j.cell.2024.07.023
Source: https://www.cell.com/cell/abstract/S0092-8674(24)00783-9