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）：根据联合国艾滋病毒/艾滋病联合规划署（艾滋病规划署）的估计，到2006年底，全世界约有4000万人感染艾滋病毒/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，并在病毒感染和癌症的治疗中显示出前景。siRNA和壳聚糖纳米颗粒技术的组合导致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.等人，Nature Medicine，2005）。基于抑制HIV复制的初步体外数据，假设siRNA纳米复合物包含针对AIDS的潜在治疗方法。我们提案的长期目标是开发多功能siRNA纳米颗粒来保护HIV传播。然而，我们将只测试这种多功能增强型疫苗的抗病毒活性，因为安全有效的艾滋病疫苗仍然很难开发，而且在这十年内也不会上市。小干扰RNA（siRNA）已成为基因沉默的有力工具，并且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）感染的小鼠模型中使用纳米颗粒递送系统已经证明了siRNA抑制呼吸道感染的潜力。在RSV感染之前或之后用含有靶向RSV的NS 1基因的siRNA的纳米颗粒进行鼻内治疗，与对照相比，显示出肺中病毒滴度的显著降低以及炎症和气道反应性的降低。这些结果导致了工作假设，即多功能壳聚糖纳米颗粒（MCNs）可以有效地递送siRNA而没有任何显著的副作用，并提供针对病毒感染（特别是HIV）的显著保护。该前体颗粒的具体目的是抑制SHVSF 163 P3在人或猴外周血单核白细胞（PBMC）中的复制。多功能SiRNA纳米颗粒抗病毒活性的体外确认将确保未来在非人灵长类动物中的研究取得成功。该项目的提出意义重大，成功地递送抗HIV siRNA纳米颗粒以阻止HIV-1在体外复制将有助于我们在未来的非人灵长类动物研究或临床前试验。因此，新型壳聚糖纳米粒药物递送系统不仅可用于艾滋病研究，而且可用于癌症和其他疾病的研究

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