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Antibody Gene Therapy for Methamphetamine Abuse 1R01DA036600-01A1 Diversity Supplement

针对甲基苯丙胺滥用的抗体基因疗法 1R01DA036600-01A1 多样性补充剂

基本信息

批准号：
9376150
负责人：
ERIC C PETERSON
金额：
$ 2.17万
依托单位：
UNIV OF ARKANSAS FOR MED SCIS
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-01-01 至 2018-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9376150
关键词：
AIDS/HIV problem Active Immunization Acute Adverse effects Affinity Antibodies Antibody Affinity Antibody Formation Antibody titer measurement Behavior Therapy Behavioral Behavioral Model Binding Blood Blood Circulation Blood Pressure Brain Cardiovascular system Categories Chronic Clinical Trials Cocaine Code Conjugate Vaccines Cystic Fibrosis DNA Dependovirus Disadvantaged Disease Dose Drug Kinetics Drug usage Engineering FDA approved Future Gene Transfer Genes Goals Half-Life Haptens Heart Rate Hemophilia A Human Immune Immune response Immune system Immunoglobulin Fragments Immunologic Memory Immunotherapeutic agent Immunotherapy Knowledge Link Mediating Medical Medicine Methamphetamine Methamphetamine dependence Molecular Monoclonal Antibodies Monoclonal Antibody Therapy Motor Activity Neuraxis Nicotine Patients Pharmaceutical Preparations Pharmacology Physiological Plasma Plasmids Population Production Rattus Recovery Relapse Research Rewards Rodent Rodent Model Safety Sampling Scientist Secondary Immunization Serum Site Specificity Stream Supportive care System Techniques Technology Temperature Testing Therapeutic Therapeutic antibodies Time Treatment Failure Vaccination Virion antibody engineering base compliance behavior design drug abuser drug seeking behavior experimental study gene therapy immunogenic improved in vivo innovation methamphetamine abuse methamphetamine effect methamphetamine use monoclonal antibody production mouse model non-compliance preclinical study preclinical trial prevent protective effect psychologic public health relevance recidivism relapse patients skills

项目摘要

DESCRIPTION (provided by applicant): Medications designed to diminish the psychologically rewarding effects of methamphetamine (METH) use could offer substantial protective effects for patients trying to cease METH use, especially if these medications could reduce the medical setbacks caused by recidivism. Anti-METH monoclonal antibody medicines that tightly bind METH in the bloodstream and sequester METH away from its site(s) of action in the brain are showing promise as a viable medical therapy. Importantly anti-METH antibodies are non-addicting, long acting and suitable for use in combination with existing behavioral therapies for METH addiction. The aims of this project are to integrate innovative medical breakthroughs in antibody engineering and gene therapy technology, to generate a long-acting antibody-based medicine that will both protect patients from relapse to METH use and minimize treatment failures associated with long-term patient compliance. We will achieve these goals by utilizing adeno-associated virus (AAV) particles to deliver genes encoding high-affinity anti- METH antibody fragments discovered by our research team. We envision that AAV-mediated gene transfer could be used to deliver these purposely designed single chain variable fragment (scFv) antibodies, which have precise specificity and high affinity for METH. The specific aims include 1) use of molecular engineering techniques to strategically design therapeutic anti-METH scFv medications suitable for packaging the encoding DNA into AAV particles for gene therapy, 2) conduct pharmacokinetic studies of these AAV-scFvs and METH to objectively determine the ability of these AAV-delivered anti-METH antibody fragments to safely and favorably alter METH disposition in rodent models, 3) examine the ability of gene therapy to safely mitigate METH-induced locomotor and cardiovascular effects in rats, 4) determine the efficacy of METH abuse gene therapy in preventing relapse to METH abuse in rat behavioral models. By the end of these studies, we will know if gene therapy can safely deliver sustained doses of antibody medications sufficient to significantly reduce METH pharmacological effects. If successful, these well-integrated approaches could provide a significant medical breakthrough in the treatment options for METH addicted patients.

描述（由申请人提供）：旨在减少甲基苯丙胺（METH）使用的心理奖励作用的药物可以为试图停止使用METH的患者提供实质性的保护作用，特别是如果这些药物可以减少累犯造成的医疗挫折。抗METH单克隆抗体药物在血液中紧密结合METH并将METH从其在大脑中的作用部位隔离开，显示出作为可行的医学治疗的前景。重要的是，抗METH抗体是非成瘾性的，长效的，并且适合与现有的METH成瘾行为疗法组合使用。该项目的目的是整合抗体工程和基因治疗技术的创新医学突破，以产生一种长效的基于抗体的药物，既可以保护患者免于复发，又可以减少与长期患者依从性相关的治疗失败。我们将通过利用腺相关病毒（AAV）颗粒来递送编码我们研究团队发现的高亲和力抗METH抗体片段的基因来实现这些目标。我们设想，AAV介导的基因转移可用于递送这些特意设计的单链可变片段（scFv）抗体，其对METH具有精确的特异性和高亲和力。具体目的包括1）使用分子工程技术来策略性地设计适合于将编码DNA包装到AAV颗粒中用于基因治疗的治疗性抗METH scFv药物，2）进行这些AAV-scFv和METH的药代动力学研究以客观地确定这些AAV递送的抗METH抗体片段在啮齿动物模型中安全且有利地改变METH处置的能力，3）检查基因治疗安全地减轻大鼠中METH诱导的运动和心血管效应的能力，4）确定METH滥用基因治疗在大鼠行为模型中预防METH滥用复发的功效。在这些研究结束时，我们将知道基因治疗是否可以安全地提供足以显著降低METH药理作用的持续剂量的抗体药物。如果成功的话，这些整合良好的方法可以为METH成瘾患者的治疗选择提供重大的医学突破。