Non-liver mRNA Delivery.
Non-liver mRNA Delivery.
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DOI：
10.1021/acs.accounts.1c00601
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发表时间：
2022-01-04
影响因子：
18.3
通讯作者：
Dahlman, James E
中科院分区：
文献类型：
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作者：
Loughrey, David;Dahlman, James E
mRNA药物可以预防感染性疾病和治疗孟德尔疾病，如镰状细胞贫血症，肌营养不良症和囊性纤维化，以及自身免疫和癌症。目前正在探索的mRNA递送的三个主要治疗领域是抗原生产，包括COVID-19疫苗，蛋白质替代疗法和基因组工程。30年前就证明，肌内引入体外转录的mRNA导致可检测的特异性抗原的蛋白质表达，从而保护免受流感和癌症等的侵害。然而，利用mRNA作为治疗方式是具有挑战性的。mRNA是大的和阴离子的，因此，不能被动地扩散穿过带负电荷的质膜。此外，存在于血流和组织中的RNA酶快速降解mRNA，并且其施用诱导先天免疫应答。因此，已经开发了基于脂质、聚合物、树枝状聚合物和天然膜的mRNA药物递送系统以将mRNA递送至靶细胞。已经做出了重大努力和投资，将其中一些系统转化为诊所。具体而言，全身给药的脂质纳米颗粒（LNP）已将mRNA递送至肝脏，而肌内给药的LNP已将mRNA递送至免疫细胞，以预防2019年的冠状病毒疾病。然而，在非肝组织如脾、肺、心脏、眼、中枢神经系统和神经系统中的临床相关递送需要改进的药物递送系统。我们提供了一个关键进展的概述，这些进展使我们获得了食品和药物管理局对辉瑞/BioNTech基于mRNA的SARS-CoV-2疫苗的批准，以及Moderna mRNA的紧急使用授权，基于相同疾病的疫苗，我们解释了这些发展将如何有助于靶向肝脏外的mRNA治疗的临床翻译。我们首先关注可以提高mRNA效力的化学修饰和序列优化，从而大大改善药代动力学。在详细介绍了什么是理想的mRNA有效载荷后，我们回顾了用于将有效载荷递送到靶细胞中的药物递送系统。我们描述了减少肝脏清除的努力，这是非肝脏治疗发展的关键障碍。然后，我们考虑最近的纳米粒子的例子，已交付mRNA的非肝组织。最后，我们讨论了目前的临床mRNA计划，重点是COVID疫苗，并强调了可能适用于未来mRNA药物的经验教训。
mRNA drugs can preempt infectious disease and treat Mendelian disorders, such as sickle cell anemia, muscular dystrophy, and cystic fibrosis, as well as autoimmunity and cancer. The three major therapeutic areas for which mRNA delivery is currently being explored are antigen production, including the COVID-19 vaccine, protein replacement therapy, and genome engineering. It was demonstrated 30 years ago that introducing in vitro transcribed mRNA intramuscularly results in detectable protein expression for specific antigens protecting against the likes of influenza and cancer. Utilizing mRNA as a therapeutic modality, however, is challenging. mRNA is large and anionic and, as a result, cannot passively diffuse across the negatively charged plasma membrane. In addition, RNases present in the bloodstream and tissues rapidly degrade mRNA, and its administration induces the innate immune response. In consequence, lipid-, polymer-, dendrimer-, and natural membrane-based mRNA drug delivery systems have been developed to deliver mRNA to target cells. Significant efforts and investments have been made to translate some of these systems into the clinic. Specifically, systemically administered lipid nanoparticles (LNPs) have delivered mRNA to the liver, and intramuscularly administered LNPs have delivered mRNA to immune cells to protect against coronavirus disease of 2019. However, clinically relevant delivery in non-liver tissues such as the spleen, lungs, heart, eye, central nervous system, and lymphatics requires improved drug delivery systems.In this Account, we provide an overview of key advances that have led us to Food and Drug Administration approval for the Pfizer/BioNTech mRNA-based vaccine against SARS-CoV-2 and Emergency Use Authorization for the Moderna mRNA-based vaccine against the same disease, and we explain how these developments will contribute to the clinical translation of mRNA therapeutics targeted outside of the liver. We first focus on the chemical modifications and sequence optimization that can improve the potency of mRNA, resulting in greatly improved pharmacokinetics. After detailing what makes an ideal mRNA payload, we review drug delivery systems used to deliver the payload into target cells. We describe efforts to reduce clearance by the liver, a key obstacle to the development of non-liver therapies. We then consider recent examples of nanoparticles that have delivered mRNA to non-liver tissues. Finally, we discuss current clinical mRNA programs, focusing on the COVID vaccines and highlighting lessons that may be applied to future mRNA drugs.