Supercharged protein-surfactant bioconjugates for next-generation cell therapies

用于下一代细胞疗法的增压蛋白质-表面活性剂生物缀合物

基本信息

批准号：
MR/X01116X/1
负责人：
Adam Perriman
金额：
$ 73.4万
依托单位：
University of Bristol
依托单位国家：
英国
项目类别：
Fellowship
财政年份：
2023
资助国家：
英国
起止时间：
2023 至无数据
项目状态：
未结题

来源：
https://gtr.ukri.org/projects?ref=MR%2FX01116X%2F1
关键词：
Supercharged protein surfactant bioconjugates next

项目摘要

Artificial membrane binding proteins (AMBPs) have the potential to impact on the efficacy of adoptive cell therapies, as the introduction of exogenous proteins to provide additional functionality to therapeutic cells could be highly advantageous for site-directed tissue repair. The methodology is centred on the rational design of modular bifunctional supercharged protein-polymer surfactant complexes that spontaneously insert into the plasma membrane of stem cells to impart oxygen delivery and chemotropic homing properties. This could address many of the challenges in cell therapies, including the lack of viable cell engraftment, which results in limited functional integration. Several cell therapy studies have shown that intravenous or intra-arterial infusion of stem cells leads to accumulation in tissue sinks, such as the lungs and spleen. These off-target effects reduce the efficiency of systemic delivery and increase the likelihood of producing lethal microemboli. Accordingly, this research programme describes the rational design of a new class of bifunctional AMBPs with responsive oxygen delivery and chemotrophic homing properties that will help overcome these limitations and have far-reaching implications in cell therapies for disease and regenerative medicine.The new approach circumvents the need for covalent cell-surface chemistry, and offers a high degree of flexibility, as the approach can be applied to a wide range of proteins for use on potentially any cell type. The AMBP methodology pioneered by the PI involves the rational design of an AMBP in two key steps: (i) supercharging the AMBP anchor to amplify the positive surface charge density (ii) electrostatic grafting of polymer surfactant chains to the cationic sites on the membrane anchor. The resulting polymer surfactant corona allows the cell membrane affinity to be systematically tuned to facilitate spontaneous insertion of the AMBP into the cell membrane, whilst retaining the native function of the cell-bound protein. The PI has successfully applied this methodology to the oxygen-binding protein myoglobin, as well as supercharged green fluorescent protein fused to the fibronectin binding domain of a bacterial adhesin motif CshA. Here, the AMBPs rapidly inserted into the membranes of adult bone-marrow derived hMSCs and provided either responsive oxygen delivery or chemotactic stem cell homing to cardiac tissue. The research programme has a strong (but not exclusive) focus on developing AMBPs for cardiac stem cell therapies, as cardiovascular disease (CVD) is the leading cause of death globally (2021 World Health Organisation estimate is 17.9 million deaths p.a.). Here, the conceptual advance is centred on developing humanised bifunctional AMBP chimeras that can responsively deliver oxygen to the cells via a supercharged myoglobin anchor module (to improve cell viability in hypoxic in vivo environments), fused to a module that provides cardiac extracellular matrix targeting. Accordingly, the ability to display multiple copies of these AMBPs, which can deliver oxygen and have been evolutionarily optimised to recognise and bind specific molecular targets in the cardiac endothelium, has the potential to advance cardiac cell therapy.The AMBP platform is likely to have clinical impact beyond cell therapies for CVD, as it could be readily applied to other cell types and vesicles (e.g., monocytes, natural killer cells, exosomes, or lipid nanoparticles) and involve other homing protein- or peptide-based molecules (e.g., integrins, nanobodies, or other bacterial adhesins). The research programme describes a scientific methodology that combines both in-house techniques for biophysics, synthetic biology and regenerative medicine, as well as cutting-edge techniques available at large-scale facilities. As there is a strong medical focus within the programme, the applicant has engaged clinical scientists and industrial partners to aid with medical translation.

人造膜结合蛋白（AMBP）具有影响收养细胞疗法疗效的潜力，因为引入外源蛋白来为治疗细胞提供额外的功能可能对现场定向的组织修复具有很高的优势。该方法集中在模块化双功能增压蛋白聚合物表面活性剂复合物的合理设计上，该复合物自发地插入干细胞的质膜中，以赋予氧气递送和趋化性归纳性能。这可以解决细胞疗法中的许多挑战，包括缺乏可行的细胞植入，从而导致功能积分有限。几项细胞疗法研究表明，干细胞的静脉内或动脉内输注会导致组织下沉（例如肺和脾脏）积累。这些非目标效应降低了全身传递的效率，并增加了产生致命微栓塞的可能性。因此，该研究计划描述了一类新的双功能AMBP的合理设计，其反应性氧气和化学的归巢特性将有助于克服这些局限性，并在疾病的细胞疗法中具有深远的影响，对疾病的细胞疗法和再生医学的细胞疗法。新的方法可以限制对共价细胞化学的范围，并且可以使用柔韧性的范围，并且可以使用一种范围的范围。潜在的任何细胞类型。 PI率先使用的AMBP方法涉及AMBP的合理设计，分为两个关键步骤：（i）增压AMBP锚以将聚合物表面活性剂链静电嫁接放大到膜锚上的阳离子位置。所得的聚合物表面活性剂电晕允许系统调节细胞膜亲和力，以促进AMBP自发插入细胞膜，同时保留细胞结合蛋白的天然功能。 PI已成功将此方法应用于氧结合蛋白肌红蛋白，以及融合到细菌粘附蛋白基序CSHA的纤连蛋白结合结构域的增压绿色荧光蛋白。在这里，AMBP迅速插入成人骨row的膜中，衍生出HMSC，并提供了反应性的氧气递送或趋化的干细胞归巢于心脏组织。该研究计划强烈（但不是排他性的）专注于为心脏干细胞疗法开发AMBP，因为心血管疾病（CVD）是全球死亡的主要原因（2021年世界卫生组织估计为1790万死亡P.A.）。在这里，概念上的进步集中在开发人性化的双功能AMBP嵌合体上，该双功能可以通过增压肌红蛋白锚模块（以提高体内缺氧的细胞活力）融合到一个模块中，该模块可响应地将氧气递送到细胞上，并提供了可提供心脏外部心外基质矩阵靶向的模块。 Accordingly, the ability to display multiple copies of these AMBPs, which can deliver oxygen and have been evolutionarily optimised to recognise and bind specific molecular targets in the cardiac endothelium, has the potential to advance cardiac cell therapy.The AMBP platform is likely to have clinical impact beyond cell therapies for CVD, as it could be readily applied to other cell types and vesicles (e.g., monocytes, natural killer cells, exosomes, or脂质纳米颗粒）并涉及其他归巢蛋白或肽的分子（例如整联蛋白，纳米词或其他细菌粘附素）。该研究计划描述了一种科学方法，该方法结合了内部技术，用于生物物理学，合成生物学和再生医学，以及大型设施可用的尖端技术。由于该计划中有强烈的医疗重点，因此申请人聘请了临床科学家和工业伙伴来协助医疗翻译。

项目成果

期刊论文数量（6）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Technological advances in the use of viral and non-viral vectors for delivering genetic and non-genetic cargos for cancer therapy.

DOI：
10.1007/s13346-023-01362-3
发表时间：
2023-11
期刊：
DRUG DELIVERY AND TRANSLATIONAL RESEARCH
影响因子：
5.4
作者：
Dogbey, Dennis Makafui;Torres, Valeria Esperanza Sandoval;Fajemisin, Emmanuel;Mpondo, Liyabona;Ngwenya, Takunda;Akinrinmade, Olusiji Alex;Perriman, Adam W.;Barth, Stefan
通讯作者：
Barth, Stefan

Modular Bioorthogonal Lipid Nanoparticle Modification Platforms for Cardiac Homing.

DOI：
10.1021/jacs.3c07811
发表时间：
2023-10-18
期刊：
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
影响因子：
15
作者：
Cruz-Samperio, Raquel;Hicks, Corrigan L.;Scott, Aaron;Gispert Contamina, Ignacio;Elani, Yuval;Richardson, Rebecca J.;Perriman, Adam W.
通讯作者：
Perriman, Adam W.

Development of a Novel Hierarchically Biofabricated Blood Vessel Mimic Decorated with Three Vascular Cell Populations for the Reconstruction of Small-Diameter Arteries