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各种抗病毒药物或缓解症状的干预措施，但遗憾的是还没有迄今为止，已经确定了治疗 COVID-19 的有效药物。鉴于迫切需要和愿意在 COVID-19 大流行期间尝试新的治疗方法，基于 RNA 的疗法可以由于其合理的设计和相对较快的开发速度，被证明是一个有吸引力的选择到传统策略。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，可以提供立即中和作用防止 SARS-CoV-2 感染。 SARS-CoV-2 与人血管紧张素 I 转换酶 2 结合 (ACE2) 通过其病毒体上的三聚刺突蛋白 (S 蛋白)，在病毒膜与病毒体融合后宿主细胞膜发生。随后，RNA病毒将在细胞内复制其基因组，并最终制造新的病毒粒子，将其分泌以感染其他宿主细胞。 S蛋白是关键靶标中和抗体（Abs）、疫苗和治疗方法的开发。我们项目的近期目标是开发新型吸入RNA适体，特异性结合保守且功能必需的RNA适体 SARS-CoV-2 S 蛋白的元素作为病毒中和剂，可防止病毒进入和感染。我们的中央假设吸入中和 RNA 干预对于暴露前预防都有用以及立即暴露后治疗，以提供针对 SARS-CoV-2 和/或未来的第一道防线 SARS-CoV 染色。除了作为独立拮抗剂的用途外，适体还可以配制为混合形式或多价形式可最大限度地提高中和效力和广度。吸入给药将进一步最大限度地递送至上呼吸道和下呼吸道的上皮纤毛细胞，最初病毒附着和感染的组织部位。最后，我们预计成功完成将带来转化阶段并证明立即在临床中使用吸入中和 RNA 疗法以保护一线医护人员和其他接触 SARS-CoV-2 高风险的人员。拟议的研究既是具有重大意义和创新性，可能会改变当前治疗 SARS-CoV-2 感染的模式。这从这项研究中获得的知识可以快速运用，以对抗未来 SARS 病毒株的演变。可能会成为人类医疗保健的威胁。

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

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

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