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

描述(由申请人提供)：旨在减少甲基苯丙胺(冰毒)使用带来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因再次犯罪而造成的医疗挫折。抗冰毒单抗药物将冰毒紧密结合在血液中，并将冰毒从大脑中的作用部位(S)隔离开来，显示出作为一种可行的医学疗法的前景。重要的是，抗冰毒抗体不会上瘾，作用时间长，适合与现有的冰毒行为疗法结合使用。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，产生一种长效的基于抗体的药物，既保护患者免受冰毒复发的影响，又将与患者长期依从性相关的治疗失败降至最低。我们将通过使用腺相关病毒(AAV)颗粒来传递我们的研究团队发现的编码高亲和力抗冰毒抗体片段的基因来实现这些目标。我们设想，AAV介导的基因转移可以用来传递这些特意设计的单链可变区(ScFv)抗体，这些抗体对冰毒具有精确的特异性和高亲和力。具体目标包括1)利用分子工程技术策略性地设计适合于将编码DNA包装成AAV颗粒用于基因治疗的治疗性抗冰毒单链抗体药物；2)对这些AAV-scFv和冰毒进行药代动力学研究，以客观地确定这些AAV-scFv和冰毒抗体片段安全和有利地改变啮齿动物模型中冰毒的处置的能力；3)检测基因治疗安全缓解冰毒诱导的大鼠的运动和心血管效应的能力；4)确定冰毒滥用基因治疗在防止大鼠行为模型中再次滥用冰毒的有效性。到这些研究结束时，我们将知道基因治疗是否可以安全地提供足以显著减少冰毒药理作用的持续剂量的抗体药物。如果成功，这些整合良好的方法可能会在治疗冰毒成瘾患者的选择上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.