PLGA/Antisense IL-10: Gene Therapy for Cocaine Abusers with HAD

PLGA/反义 IL-10：针对 HAD 可卡因滥用者的基因治疗

基本信息

批准号：
7495360
负责人：
Shilpa J. Buch
金额：
$ 2.73万
依托单位：
UNIVERSITY OF KANSAS MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-02-01 至 2009-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7495360
关键词：
AIDS Dementia Complex AIDS therapy Accounting Acquired Immunodeficiency Syndrome Address Agonist American Animals Antisense DNA Basal Ganglia Blood Circulation Brain CD4 Positive T Lymphocytes Case Study Cause of Death Cell Count Cell Culture Techniques Cells Cellular Immunity Characteristics Chemistry Chronic Clinical Cocaine Cocaine Abuse Collaborations Communicable Diseases DNA Disease Disease Progression Drug user Encapsulated Epidemiologic Studies Equilibrium Gene Delivery Glycolates Goals HIV HIV Infections HIV encephalitis HIV-1 Half-Life Health Human IL10 gene Immune Immune response In Vitro Individual Indolent Infection Injection of therapeutic agent Integration Host Factors Interferons Interleukin-10 Interleukin-2 Interleukin-4 Interleukins Laboratories Link Liposomes Lung Macaca Macaca mulatta Mannose Mediating Mediator of activation protein Microglia Minnesota Modeling Molecular Mus NOD/SCID mouse Needle Sharing Opioid Receptor Pathogenesis Pathology Patients Pharmaceutical Preparations Polyethylene Glycols Production Proteins Risk Serum Spleen Surface Testing Therapeutic Therapeutic Agents Therapeutic Intervention Tissues Toxic effect United States National Institutes of Health Urticaria Viral Virus Virus Replication Work Xenograft procedure base cocaine exposure cocaine use cost cytokine design experience gene therapy immunogenic immunogenicity improved in vivo innovation interest intravenous drug use lymph nodes macrophage monocyte mouse model multidisciplinary nanoparticle novel particle plasmid DNA public health relevance response simian human immunodeficiency virus translational approach transmission process treatment strategy vector virus host interaction

项目摘要

DESCRIPTION (provided by applicant): Epidemiological studies on substance-abusing drug users and HIV-I infection, link abuse of cocaine, even more than other drugs, to increased risk for, and progression to clinical disease associated with the virus. The use of cocaine therefore exacerbates host factors that promote HIV replication. Developing therapeutic interventions that curtail the exaggerated production of such host factors could, therefore prove beneficial as adjunct therapies for AIDS. Earlier studies from our and other laboratories have shown that during AIDS pathogenesis there is a shift from a T helper type 1 (Th1) response to a dominant Th2 response (exemplified by host proteins, interleukin (IL)-4 & IL-10). Therefore, in our gene therapy studies we used the approach of delivering antisense (AS) IL-4 DNA trapped in liposomes to virus-infected cells/macaques to curtail virus replication. We achieved successful abrogation of virus replication in cells in culture and, globally, in various macaque tissues. However, liposomes are cost prohibitive, and toxic when administered repeatedly. Alternatively, poly (DL-lactic-co-glycolic acid) (PLGA) particles are biodegradable, have low toxicity and immunogenicity and have been used successfully in humans. We have recently observed that Th2 cytokine, IL-10 is also critical for cocaine-mediated increase in HIV-infected macrophages. Based on these findings, the underlying central hypothesis of this proposal is that blocking IL-10 expression by AS IL-10 DNA approach, will abrogate cocaine-mediated enhancement of HIV-1 replication. In collaboration with Drs. Panyam and Berkland, who can synthesize PLGA particles of varying size & surface chemistry with high precision, we propose to test PLGA/AS IL-10 DNA particles as therapeutic agents for abrogation of cocaine-mediated viral enhancement in cell culture and in vivo using the HIVE hu- NOD/SCID mice that contain xenografts of HIV-1 infected MDMs injected into the basal ganglia. In this application the hypothesis will be tested in 2 interrelated aims: Specific Aim 1: Formulate PLGA/AS IL-10 vectors that will efficiently abrogate IL-10 production and HIV-1 replication in vitro. Specific Aim 2: Determination of virus inhibitory effects of PEG/ Mannose-conjugated PLGA/AS IL-10 vector(s) (identified from Aim 1) delivered intracranially in hu NOD/SCID mice that are administered cocaine daily. PUBLIC HEALTH RELEVANCE This proposal aims to use biodegradable nanoparticles encapsulating AS IL-10 DNA as a potential therapeutic agent for inhibition of virus replication in cocaine-abusing individuals with AIDS dementia.

描述（由申请人提供）：对物质滥用吸毒者和 HIV-1 感染的流行病学研究表明，与其他药物相比，滥用可卡因与该病毒相关临床疾病的风险增加和进展之间的联系更为紧密。因此，使用可卡因会加剧促进艾滋病毒复制的宿主因素。因此，开发抑制此类宿主因子过度产生的治疗干预措施作为艾滋病的辅助疗法可能是有益的。我们和其他实验室的早期研究表明，在 AIDS 发病过程中，辅助性 T 1 型 (Th1) 反应转变为占主导地位的 Th2 反应（以宿主蛋白、白细胞介素 (IL)-4 和 IL-10 为例）。因此，在我们的基因治疗研究中，我们采用了将脂质体中捕获的反义 (AS) IL-4 DNA 递送至病毒感染的细胞/猕猴的方法，以减少病毒复制。我们成功地消除了培养细胞以及全球各种猕猴组织中的病毒复制。然而，脂质体成本高昂，并且重复施用时有毒。另外，聚（DL-乳酸-乙醇酸）（PLGA）颗粒是可生物降解的，具有低毒性和免疫原性，并已成功用于人类。我们最近观察到，Th2 细胞因子 IL-10 对于可卡因介导的 HIV 感染巨噬细胞的增加也至关重要。基于这些发现，该提案的基本中心假设是通过 AS IL-10 DNA 方法阻断 IL-10 表达，将消除可卡因介导的 HIV-1 复制增强。与博士合作。 Panyam 和 Berkland 可以高精度合成不同尺寸和表面化学的 PLGA 颗粒，我们建议使用以下方法测试 PLGA/AS IL-10 DNA 颗粒作为治疗剂，以消除细胞培养和体内可卡因介导的病毒增强作用HIVE hu-NOD/SCID 小鼠，含有注入基底神经节的 HIV-1 感染的 MDM 异种移植物。在此应用中，该假设将在 2 个相互关联的目标中进行测试：具体目标 1：配制 PLGA/AS IL-10 载体，该载体将在体外有效消除 IL-10 产生和 HIV-1 复制。具体目标 2：确定每日给予可卡因的 hu NOD/SCID 小鼠颅内递送的 PEG/甘露糖缀合的 PLGA/AS IL-10 载体（从目标 1 中鉴定）的病毒抑制效果。公共健康相关性该提案旨在使用封装 AS IL-10 DNA 的可生物降解纳米粒子作为潜在的治疗剂，用于抑制可卡因滥用的艾滋病痴呆患者的病毒复制。