Targeted Delivery of siRNA Nanoparticles to Prevent HIV-1 Transmission

靶向递送 siRNA 纳米颗粒以预防 HIV-1 传播

• 批准号: 7554936
• 负责人: Weidong Xu
• 金额: $ 18.15万
• 依托单位: TRANSGENEX NANOBIOTECH, INC.
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-01 至 2009-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7554936
• 关键词: AIDS Vaccines; AIDS/HIV problem; Abbreviations; Acquired Immunodeficiency Syndrome; Adverse effects; Age; Antibodies; Antiviral Agents; Attenuated Live Virus Vaccine; Biopolymers; CCR5 gene; Cells; Child; Chitosan; Clinical; Complex; Data; Dendritic Cells; Development; Disease; Drug Delivery Systems; Ensure; Enzyme-Linked Immunosorbent Assay; Future; Gene Silencing; Genes; Goals; HIV; HIV-1; Human; In Vitro; Infection; Investigation; Joints; Last Name; Life; Lung; Macaca; Malignant Neoplasms; Measures; Medicine; Modeling; Monkeys; Monoclonal Antibodies; Mononuclear Leukocytes; Mus; Nature; PTPN11 gene; Peripheral Blood Mononuclear Cell; Phase; Phase II Clinical Trials; Phase III Clinical Trials; Polymerase Chain Reaction; Prevention; Prophylactic treatment; RNA; RNA Interference; Research; Research Personnel; Respiratory Syncytial Virus Infections; Respiratory Tract Infections; Respiratory syncytial virus; Small Interfering RNA; Small RNA; Specificity; Staging; System; T-Lymphocyte; Technology; Testing; Therapeutic; Time; Transfection; Translating; United Nations; Vaccines; Viral; Viral Cancer; Viral Genes; Virus; Virus Diseases; Work; airway inflammation; atrial natriuretic factor receptor A; base; day; env Genes; melanoma; mouse model; nanoparticle; nonhuman primate; novel; peripheral blood; preclinical study; prevent; programs; respiratory; simian human immunodeficiency virus; success; targeted delivery; tool; transmission process

DESCRIPTION (provided by applicant): According to estimates by the Joint United Nations Program on HIV/AIDS (UNAIDS), approximately 40 million people will be living with HIV/AIDS worldwide by the end of 2006. However, safe and effective AIDS vaccine remains difficult to develop. Small interference RNA (siRNA) has emerged as a powerful tool in gene silencing, and appears promising in treatment of viral infections and cancers. The combination of siRNA and chitosan nanoparticle technology led to the development nanocomplex antivirals capable of inhibiting respiratory syncytial virus infections (Zhang et. al. Nature Medicine, 2005). Based on the preliminary in vitro data for suppressing HIV replication, it is hypothesized that siRNA nanocomplexes comprise a potential therapeutic approach against AIDS. The long-term goal of our proposal is to develop multifunctional siRNA nanoparticles to protect HIV transmission. However, we will only test the antiviral activities of the multifunctio intensified, since a safe and effective AIDS vaccine remains difficult to develop and won't be available in this decade. Small interfering RNA (siRNA) has emerged as a powerful tool in gene silencing, and preclinical studies have shown promise in treatment of viral infection and cancer. The potential of siRNA for inhibiting respiratory infections has been demonstrated using a nanoparticle delivery system in a mouse model of respiratory syncytoial virus (RSV) infection. Intranasal treatment before or after RSV infection with nanoparticles containing siRNA targeting the NS1 gene of RSV showed substantially decreased virus titers in the lung and decreased inflammation and airway reactivity compared to controls. These results have led to the working hypothesis that multifunctional chitosan nanoparticles (MCNs) can effectively deliver siRNA without any significant adverse effects and provide significant protection against viral infections, specifically HIV. The specific aims of this proparticles in inhibiting SHVSF163P3 replication in human or monkey peripheral blood mononuclear leukocytes (PBMCs). In vitro confirmation of the antiviral activity of the multifunctional siRNA nanoparticles will ensure the success in future studies in non-human primates. The proposed project is significant, successful delivery of anti-HIV siRNA nanoparticles to prevent HIV-1 replication in vitro will help us in non-human primate studies or preclinical trials in the future. Thus, the novel chitosan nanoparticle drug delivery system will be useful not only in AIDS research but also in studies in cancer and other diseases

描述（由申请人提供）：根据联合国艾滋病规划署（UNAIDS）的估计，到2006年底，全球将有大约4000万人感染艾滋病。然而，安全有效的艾滋病疫苗仍然难以研制。小干扰RNA （siRNA）已成为基因沉默的有力工具，在治疗病毒感染和癌症方面前景光明。siRNA和壳聚糖纳米颗粒技术的结合导致了能够抑制呼吸道合胞病毒感染的纳米复合物抗病毒药物的开发（Zhang et. al. Nature Medicine, 2005）。基于体外抑制HIV复制的初步数据，假设siRNA纳米复合物包含一种潜在的治疗艾滋病的方法。我们建议的长期目标是开发多功能siRNA纳米颗粒来保护艾滋病毒的传播。然而，我们将只测试多功能强化的抗病毒活性，因为安全有效的艾滋病疫苗仍然难以开发，并且在本十年内不会可用。小干扰RNA （siRNA）已成为基因沉默的有力工具，临床前研究已显示出在治疗病毒感染和癌症方面的前景。在呼吸道合胞病毒（RSV）感染的小鼠模型中，利用纳米颗粒递送系统证明了siRNA抑制呼吸道感染的潜力。与对照组相比，在RSV感染前后用含有靶向RSV NS1基因的siRNA纳米颗粒进行鼻内治疗可显著降低肺部病毒滴度，降低炎症和气道反应性。这些结果导致了多功能壳聚糖纳米颗粒（MCNs）可以有效地递送siRNA而没有任何明显的副作用，并提供对病毒感染，特别是HIV的显著保护的工作假设。该原粒子抑制SHVSF163P3在人或猴外周血单核白细胞（PBMCs）中的复制的具体目的。在体外确认多功能siRNA纳米颗粒的抗病毒活性将确保未来在非人灵长类动物研究中的成功。该项目意义重大，成功递送抗hiv siRNA纳米颗粒以防止HIV-1在体外复制将有助于我们在未来的非人类灵长类动物研究或临床前试验。因此，新型壳聚糖纳米颗粒给药系统不仅在艾滋病研究中具有重要的应用价值，而且在癌症和其他疾病的研究中具有重要的应用价值

项目成果

A Multiple siRNA-Based Anti-HIV/SHIV Microbicide Shows Protection in Both In Vitro and In Vivo Models.

• DOI: 10.1371/journal.pone.0135288
• 发表时间: 2015
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Boyapalle S;Xu W;Raulji P;Mohapatra S;Mohapatra SS
• 通讯作者: Mohapatra SS