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The Chloroplast Expression System as a platform for orally bioavailable muscle therapeutics

叶绿体表达系统作为口服生物可利用肌肉治疗的平台

基本信息

批准号：
9904474
负责人：
Elisabeth R Barton
金额：
$ 16.86万
依托单位：
UNIVERSITY OF FLORIDA
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-04-01 至 2022-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9904474
关键词：
Address Aging Antibody Therapy Basic Science Bed rest Bioavailable Biodistribution Biological Availability Biomass Blood Circulation C-terminal Cachexia Cell Culture Techniques Cell Line Cell Nucleus Cells Chimeric Proteins Chloroplasts Clinical Clinical Trials DNA DNA amplification Detection Development Evaluation Family member Fc domain GDF8 gene Genome Goals Grant Growth Immunoglobulin G Individual Injections Insulin-Like Growth Factor I Intramuscular Intravenous Laboratories Length of Stay Lettuce - dietary Mammalian Cell Mitochondria Monitor Mus Muscle Muscle function Muscular Atrophy Neuromuscular Diseases Nicotiana Nuclear Oral Pathway interactions Peptides Plants Plastids Production Property Proteins Regulation Reporter Site Skeletal Muscle System Technology Testing Therapeutic Tobacco Treatment Protocols base clinically relevant cohort gene therapy genetic manipulation improved in vivo muscle form muscle hypertrophy muscle physiology novel preservation prevent pro-insulin-like growth factor I protein expression sarcopenia skeletal muscle growth therapeutic candidate therapeutic protein

项目摘要

ABSTRACT Two of the major pathways targeted enhance the actions of insulin-like growth factor I (IGF-I), and inhibit the anti-growth pathways of Myostatin/Gdf8 and its related family members. Several clinical trials have occurred and/or are underway examining protein/antibody and gene therapy approaches. While these approaches may provide potent regulation of these pathways, and potentially preserve functional muscle mass, no study to date has developed an orally bioavailable compound that can promote muscle growth. Thus, we assert that a major challenge for delivery of pro-growth compounds is the lack of oral bioavailability, as all current options rely on intramuscular or intravenous/arterial injections. In this application, we propose to capitalize on the oral biovailability and stability of chloroplast bioencapsulation to produce myostatin propeptide and IGF-I, which enable high production of protein relative to the total soluble protein in plants. The collaborative team will combine expertise in chloroplast expression with expertise in skeletal muscle physiology to determine if a novel delivery strategy for growth promoting agents can increase functional muscle mass in mice. In Aim 1, the murine myostatin propeptide fused to the Fc domain of IgG will be expressed in Nicotiana benthamiana and evaluated for cell-based activity and in vivo efficacy of myostatin inhibition. Likewise, in Aim 2, a similar construct of Pro-IGF-I-Fc will be made, and also tested in the same manner. At the completion of this project, a thorough evaluation of this strategy will be complete, and potentially at least 1 candidate will be identified to move forward into production in lettuce, which is a platform that is clinically relevant and affords marker free production of therapeutic proteins. Ultimately, the chloroplast expression system may be established as a potential strategy to express and deliver established factors as well as newly discovered proteins that can promote muscle growth.

抽象的两条主要靶向途径可增强胰岛素样生长因子 I (IGF-I) 的作用，并抑制 Myostatin/Gdf8 及其相关家族成员的抗生长途径。已进行多项临床试验和/或正在研究蛋白质/抗体和基因治疗方法。虽然这些方法可能对这些途径提供有效的调节，并有可能保留功能性肌肉质量，迄今为止尚无研究开发了一种口服生物可利用的化合物，可以促进肌肉生长。因此，我们断言，一个主要的递送促生长化合物的挑战是缺乏口服生物利用度，因为目前所有的选择都依赖于肌内或静脉/动脉注射。在此应用中，我们建议利用口头叶绿体生物包封产生肌生长抑制素前肽和 IGF-I 的生物利用度和稳定性，相对于植物中的总可溶性蛋白质，能够实现高蛋白质产量。协作团队将将叶绿体表达方面的专业知识与骨骼肌生理学方面的专业知识相结合，以确定是否有一种新颖的生长促进剂的递送策略可以增加小鼠的功能性肌肉质量。在目标 1 中，与 IgG Fc 结构域融合的鼠肌生长抑制素前肽将在烟草中表达 Benthamiana 并评估了肌生长抑制素抑制的基于细胞的活性和体内功效。同样，在《目标》中如图2所示，将制备类似的Pro-IGF-I-Fc构建体，并以相同的方式进行测试。完成时在该项目中，将完成对该战略的彻底评估，并且可能至少有 1 名候选人确定进入生菜生产，这是一个具有临床相关性并提供无标记生产治疗性蛋白质。最终，叶绿体表达系统可能是被确立为表达和传递既定因素以及新发现因素的潜在策略可以促进肌肉生长的蛋白质。