Antibody Gene Therapy for Methamphetamine Abuse

描述（由申请人提供）：设计用于减少甲基苯丙胺（冰毒）使用的心理奖励效应的药物可以为试图停止使用冰毒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由再犯引起的医疗挫折。抗甲基苯丙胺单克隆抗体药物可以将甲基苯丙胺紧密结合在血液中，并将甲基苯丙胺从其在大脑中的作用部位隔离开来，这种药物有望成为一种可行的药物治疗方法。重要的是，抗甲基苯丙胺抗体不成瘾，长效，适合与现有的甲基苯丙胺成瘾行为疗法联合使用。该项目的目标是整合抗体工程和基因治疗技术方面的创新医学突破，以产生一种长效抗体为基础的药物，既可以保护患者免于再次使用冰毒，又可以最大限度地减少患者长期依从性相关的治疗失败。我们将利用腺相关病毒（AAV）颗粒传递编码高亲和力抗甲基苯丙胺抗体片段的基因，以实现这些目标。我们设想aav介导的基因转移可以用来传递这些专门设计的单链可变片段（scFv）抗体，这些抗体对甲基安非他明具有精确的特异性和高亲和力。具体目标包括：1)利用分子工程技术，有策略地设计治疗性抗甲基苯丙胺scFv药物，适合将编码DNA包装到AAV颗粒中进行基因治疗；2)对这些AAV-scFv和甲基苯丙胺进行药代动力学研究，客观地确定这些AAV递送的抗甲基苯丙胺抗体片段在啮齿动物模型中安全、有利地改变甲基苯丙胺倾向的能力。3)研究基因治疗安全减轻冰毒诱导的大鼠运动和心血管影响的能力；4)在大鼠行为模型中确定冰毒滥用基因治疗在预防冰毒滥用复发方面的效果。在这些研究结束时，我们将知道基因疗法是否可以安全地提供持续剂量的抗体药物，足以显著减少甲基苯丙胺的药理作用。如果成功的话，这些整合良好的方法可以为冰毒成瘾患者的治疗选择提供重大的医学突破。

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.