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）：关于滥用药物的吸毒者和HIV-I感染的流行病学研究，将可卡因的滥用与其他药物相比，将可卡因的滥用与与病毒相关的临床疾病的发展增加，以增加对临床疾病的风险。因此，可卡因的使用加剧了促进HIV复制的宿主因素。因此，开发削减这种宿主因素的夸大产生的治疗性干预措施可能会证明是有益的作为艾滋病的辅助疗法。我们和其他实验室的早期研究表明，在艾滋病发病机理中，从T辅助1（Th1）反应转变为显性Th2反应（由宿主蛋白介绍，介体介绍，介体介体（IL）-4＆IL-10）。因此，在我们的基因疗法研究中，我们使用了将脂质体中的反义（AS）IL-4 DNA传递到病毒感染的细胞/猕猴来减少病毒复制的方法。我们成功地废除了培养细胞和各种猕猴组织中细胞中病毒复制的成功。然而，脂质体的成本过高，反复给药时有毒。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，并且已成功用于人类。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方法阻止IL-10表达，将消除可卡因介导的HIV-1复制的增强。与Drs合作。 Panyam和Berkland可以用高精度合成不同尺寸和表面化学的PLGA颗粒，我们建议测试PLGA/AS IL-10 DNA颗粒作为治疗剂，以消除可卡因介导的病毒介导的病毒介导的细胞培养中的病毒培养，并使用HU-NOD/SCID-NOD/SCID-NOD/SCID-NOD INFRIEDS INFRIEDS INFRIEDS INFRIEDS Infried Migreds Infreds Infreds Infried Sivers Infreds Infreds Infrieds Infried Migreds Infreds Infried Sivers Infried Sivers Infried Sivers Infried Syogrations HIVS。神经节。在本应用中，将在两个相互关联的目的中检验假设：特定目的1：制定PLGA/为IL-10载体，这些向量将有效地消除IL-10的产生和HIV-1复制。具体目标2：确定PEG/甘露糖偶联的PLGA/AS IL-10载体的病毒抑制作用（从AIM 1中鉴定）在每天给予可卡因的Hu点头/SCID小鼠中颅内递送。公共卫生相关性该提案旨在使用封装为IL-10 DNA的可生物降解纳米颗粒作为潜在的治疗剂，以抑制可卡因虐待毒性痴呆的人的病毒复制。