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

• 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
• 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

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 尽管有各种抗病毒药或正在开发中的减轻疾病的干预措施，不幸的是， 到目前为止，已经很容易确定了有效的COVID-19药物治疗。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的治疗方法可以 由于其合理的设计和相对较快的发展速度， 传统的战略。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， 预防SARS-CoV-2感染。SARS-CoV-2与人血管紧张素I转换酶2结合 （ACE 2）通过其病毒体上的三聚体刺突蛋白（S蛋白），其中在病毒膜和 宿主细胞膜发生。随后，RNA病毒将在细胞内复制其基因组， 产生新的病毒体，这些病毒体将被分泌以感染其他宿主细胞。S蛋白是免疫调节的关键靶点。 开发中和抗体（Abs）、疫苗和治疗剂。我们项目的近期目标 是开发新的吸入RNA适体，特异性结合保守的和功能性的必需的， SARS-CoV-2 S蛋白的元件，作为病毒中和剂，防止病毒进入和感染。我们的中央 一种假设是，吸入性中和RNA干预将对暴露前预防 和接触后立即治疗，以提供针对SARS-CoV-2和/或未来的第一道防线。 SARS-CoV染色。除了它们作为独立拮抗剂的效用之外，适体还可以配制为 混合形式或多价形式以最大化中和效力和广度。吸入 给药将进一步最大化递送到上呼吸道和下呼吸道的上皮纤毛细胞， 病毒最初附着和感染的组织部位。最后，我们希望成功完成这项工作， 翻译阶段，并证明在临床上立即使用吸入中和RNA治疗，以保护 一线卫生保健工作者和其他SARS-CoV-2高风险暴露者。这项研究的目的是， 这是一项具有重大意义和创新性的研究，可能会改变目前治疗SARS-CoV-2感染的模式。的 从这项研究中获得的知识可以迅速用于对抗SARS未来的菌株演变， 可能成为人类健康的威胁。

项目成果

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.)
• 作者: Herrera,Alberto;Zhou,Jiehua;Song,Min-Sun;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

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
• 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