Develop novel inhaled neutralizing RNA therapeutics against COVID-19

开发针对 COVID-19 的新型吸入中和 RNA 疗法

基本信息

批准号：
10238638
负责人：
John Joseph Rossi
金额：
$ 39.6万
依托单位：
BECKMAN RESEARCH INSTITUTE/CITY OF HOPE
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-07-06 至 2023-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10238638
关键词：
2019-nCoV Aerosols Affinity Animal Model Antibodies Antiviral Agents Aptamer Technology Avidity Binding Binding Sites Bioinformatics COVID-19 COVID-19 pandemic COVID-19 therapeutics COVID-19 treatment Case Fatality Rates Cell Communication Cell membrane Cells Charge Chemicals China Clinic Clinical Communities Cultured Cells Development Disease Disease Progression Dose Drug Delivery Systems Elements Engineering Epithelial Epitopes Evolution Formulation Future Generations Genome Health Health Personnel Healthcare Human Immune response In Vitro Infection Inhalation Inhalation Drug Administration Intervention Knowledge Lead Lower respiratory tract structure Masks Measures Mediating Membrane Modality Modeling Molecular Mus Mutation Nature Nose Nucleic Acids Pathway interactions Penetration Peptidyl-Dipeptidase A Pharmaceutical Preparations Pharmacotherapy Prophylactic treatment Proteins RNA RNA Viruses Readiness Research Resistance Respiratory System Respiratory Tract Infections Ribonucleases Risk SARS coronavirus SARS-CoV-2 exposure SARS-CoV-2 infection SARS-CoV-2 inhibitor SARS-CoV-2 spike protein Safety Saline Severe Acute Respiratory Syndrome Severity of illness Site Specificity Speed Stains System Technology Testing Therapeutic Time Tissues Transgenic Mice Tube Vaccines Viral Viral Load result Virion Virus Diseases Virus Replication aerosolized anti-viral efficacy aptamer base combinatorial deep sequencing design drug candidate drug inhalation experience high risk in vivo innovation mouse model neutralizing antibody novel novel therapeutic intervention pandemic disease pandemic preparedness pre-exposure prophylaxis prevent prophylactic receptor binding reduce symptoms resilience therapeutic RNA therapeutic development vaccine development willingness

项目摘要

Project Abstract Despite various antiviral agents or symptom-alleviating interventions under development, unfortunately no effective drug treatment for COVID-19 have been readily identified so far. Given the desperate need for and willingness to try new therapeutic approaches during the COVID-19 pandemic, RNA-based therapeutics could prove to be an attractive option due to their rational design and relatively faster speed of development compared to conventional strategies. Utilizing our extensive experience and expertise in nucleic acid aptamer technology, we will seek to design and develop RNA aptamer-based drug candidates that can provide immediate neutralizing protection against SARS-CoV-2 infection. The SARS-CoV-2 binds to human angiotensin I converting enzyme 2 (ACE2) through its trimeric spike protein (S protein) on the virion, where after fusion of the viral membrane and host cell membrane occurs. Subsequently, the RNA virus will replicate its genome inside the cells and ultimately make new virions that will be secreted to infect other host cells. The S protein is the key target for the development of neutralizing antibodies (Abs), vaccine and therapeutics. The immediate objective of our project is to develop novel inhaled RNA aptamers that specifically bind to the conserved and functional essential elements of SARS-CoV-2 S protein, as viral neutralizing agents, to prevent viral entry and infection. Our central hypothesis is that the inhaled neutralizing RNA intervention will have utility for both pre-exposure prophylaxis and immediate post-exposure treatment to provide a 1st line of defense against SARS-CoV-2 and/or future SARS-CoV stains. In addition to their utility as stand-alone antagonists, the aptamer can also be formulated as cocktailed format or multivalent modality to maximize neutralization potency and breadth. The inhalation administration will further maximize delivery to the epithelial cilial cells of the upper and lower respiratory tract, the tissue sites of initial viral attachment and infection. To the end, we expect successful completion to lead to a translational stage and justify the use of inhaled neutralizing RNA therapeutics immediately in the clinic to protect 1st line health care workers and others at high risk of SARS-CoV-2 exposure. The proposed research is both significant and innovative, and could change current paradigms in the treatment of SARS-CoV-2 infection. The knowledge gained from this study can be rapidly deployed for combating a future strain evolution of SARS that may emerge as a human healthcare threat.

项目摘要尽管正在开发的各种抗病毒剂或症状 - 静音干预措施，但不幸的是到目前为止，已经很容易确定Covid-19的有效药物治疗。考虑到迫切需要愿意在19009年大流行期间尝试新的治疗方法，基于RNA的治疗方法可以由于其合理的设计和相比的发展速度，因此被证明是一个有吸引力的选择传统策略。利用我们在核酸适体技术方面的丰富经验和专业知识，我们将寻求设计和开发基于RNA适体的候选药物，这些药物可以立即中和防止SARS-COV-2感染。 SARS-COV-2与人血管紧张素I I转化酶2结合2 （ACE2）通过其三聚峰蛋白（S蛋白）在病毒座上，在融合病毒膜和宿主细胞膜发生。随后，RNA病毒将在细胞内复制其基因组，最终将其重复制作新的病毒体，以感染其他宿主细胞。 S蛋白是开发中和抗体（ABS），疫苗和治疗剂。我们项目的直接目标是开发新型吸入的RNA适体，这些适体特异性结合到保守和功能性必不可少的 SARS-COV-2 S蛋白的元素是病毒中和剂，以防止病毒进入和感染。我们的中心假设是吸入的中和RNA干预措施将具有两种预防前预防的实用性并立即进行暴露后治疗，以对SARS-COV-2和/或将来提供第一道防线 SARS-COV污渍。除了作为独立拮抗剂的实用性外，适体还可以配制为鸡尾酒格式或多价模态，以最大程度地提高中和效率。吸入给药将进一步最大化上和下呼吸道上皮细胞的递送，初始病毒附着和感染的组织部位。最后，我们希望成功完成转化阶段并证明立即在诊所中使用吸入中和的RNA疗法以保护第一线卫生保健工作者和其他有SARS-COV-2暴露风险的其他人。拟议的研究都是重要而创新的，并且可以改变当前的SARS-COV-2感染治疗范例。这可以迅速部署从这项研究中获得的知识来打击未来的SARS的应变演变可能会成为人类的医疗威胁。

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）

Evolution of Cell-Type-Specific RNA Aptamers via Live Cell-Based SELEX.

通过基于活细胞的 SELEX 进化细胞类型特异性 RNA 适体。

DOI：
10.1007/978-1-0716-3191-1_22
发表时间：
2023
期刊：
Methods in molecular biology (Clifton, N.J.)
影响因子：
0
作者：
Herrera,Alberto;Zhou,Jiehua;Song,Min-Sun;Rossi,JohnJ
通讯作者：
Rossi,JohnJ

Chitosan Oleate Coated PLGA Nanoparticles as siRNA Drug Delivery System.

DOI：
10.3390/pharmaceutics13101716
发表时间：
2021-10-17
期刊：
Pharmaceutics
影响因子：
5.4
作者：
Miele D;Xia X;Catenacci L;Sorrenti M;Rossi S;Sandri G;Ferrari F;Rossi JJ;Bonferoni MC
通讯作者：
Bonferoni MC

Stereopure oligo therapy for ALS.

用于 ALS 的 Stereopure 寡核苷酸疗法。

DOI：
10.1016/j.ymthe.2022.04.026
发表时间：
2022
期刊：
Molecular therapy : the journal of the American Society of Gene Therapy
影响因子：
0
作者：
Rossi,JohnJ
通讯作者：
Rossi,JohnJ

Detecting blood clots with aptamers: A potentially lifesaving new tool in medicine.

DOI：
10.1016/j.omtn.2023.02.018
发表时间：
2023-03-14
期刊：
MOLECULAR THERAPY NUCLEIC ACIDS
影响因子：
0
作者：
Rossi, John J.
通讯作者：
Rossi, John J.

MTL-CEBPA Combined with Immunotherapy or RFA Enhances Immunological Anti-Tumor Response in Preclinical Models.

DOI：
10.3390/ijms22179168
发表时间：
2021-08-25
期刊：
International journal of molecular sciences
影响因子：
5.6
作者：
Huang KW;Tan CP;Reebye V;Chee CE;Zacharoulis D;Habib R;Blakey DC;Rossi JJ;Habib N;Sodergren MH
通讯作者：
Sodergren MH