MR-guided focused ultrasound to eradicate CNS viral reservoirs and promote neurogenesis in the HIV-infected brain

项目摘要： 此DP1应用程序响应PAR-20 - 221 "NIDA前卫奖计划， 艾滋病毒/艾滋病和药物使用障碍研究"。PI，琳达张，建议解决一个 艾滋病毒治疗或治愈方面的一个主要挑战，即目前的治疗方法 根除病毒储存库的方案，特别是那些受血脑保护的病毒 在中枢神经系统（CNS）中的血脑屏障（BBB）。艾滋病毒感染者， 使用障碍（SUD）通常具有更高的病毒载量，并遭受更严重的艾滋病毒- 相关的神经认知障碍（HAND）。她建议使用新兴技术， MR引导的聚焦超声（MRgFUS）可安全、短暂地打开BBB， 最大限度地提供长效缓释抗逆转录病毒治疗（激光ART）， 提供CRISPR-Cas9的靶向递送，以消除整合的HIV前病毒DNA， CNS病毒储库。LASER ART的组合方法，随后是AAV-CRISPR-Cas9 已经在啮齿动物模型的亚组中显示出早期的成功，但是进一步优化这些 中枢神经系统的药物是必要的。首先，艾滋病毒人源化啮齿动物模型将用于证明 显著改善了这些药物向CNS的递送，以及消除这些药物的功效。 病毒没有反弹。此外，由于相同的FUS能量和脉冲模式用于 血脑屏障开放还可以诱导神经发生和激活小胶质细胞，这些次级效应将 也要评价。最后，由于神经调节的早期临床前发现令人信服， 其他人也将探索低强度MRgFUS作为成瘾的潜在治疗方法， 药物自我给药啮齿动物模型。PI已经组建了一个优秀的团队， 合作者谁是专家，在每一个技术和方法所需的，以确保 建议的研究成果。此外，由于MRgFUS在较高强度下， 目前在临床环境中用于成功治疗原发性震颤患者 或帕金森病，并且在不同的参数（例如，脉冲高强度，低强度， 等等）。和其他神经系统疾病的临床试验中的硬件配置， 研究具有很高的临床转化潜力。鉴于现有的资源和专业知识 在马里兰州大学，试点临床试验可能在3 - 5年开始。总之， 使用MRgFUS最大限度地提供HIV消除剂的拟议研究可能 最终根除HIV病毒库，特别是CNS中的病毒库，并阻止 发展或预防HAND的发展，特别是对于SUD患者。

Project Summary: This DP1 application responds to PAR-20-221 “NIDA Avant-Garde Award Program for HIV/AIDS and Substance Use Disorder Research”. The PI, Linda Chang, proposes to tackle a major challenge in the treatment or cure for HIV, namely, the inability of current treatment regimens to eradicate the viral reservoirs, especially those that are protected by the blood brain barrier (BBB) in the central nervous system (CNS). HIV-infected persons who have substance use disorders (SUDs) often have even higher viral loads and suffer from greater severity of HIV- associated neurocognitive disorders (HAND). She proposes to use the emerging technology of MR-guided focused ultrasound (MRgFUS) to safely and transiently open the BBB in order to maximize the delivery of long-acting slow release antiretroviral therapy (LASER ART), and to provide targeted delivery of CRISPR-Cas9 to eliminate the integrated HIV proviral DNA in the CNS viral reservoirs. The combined approach of LASER ART, followed by AAV-CRISPR-Cas9 has shown early successes in subgroups of rodent models, but further optimal delivery of these agents to the CNS is needed. First, HIV-humanized rodent models will be used to demonstrate markedly improved delivery of these agents into the CNS, and the efficacy of eliminating the virus without rebounds. Furthermore, since the same FUS energy and pulse patterns used for BBB opening can also induce neurogenesis and activate microglia, these secondary effects will be evaluated as well. Lastly, due to compelling early preclinical findings with neuromodulation by others, low-intensity MRgFUS as a potential treatment for addiction will also be explored in drug self-administration rodent models. The PI has assembled an outstanding team of collaborators who are experts in each of the techniques and approaches required to ensure the success of the proposed research. Furthermore, since MRgFUS, at higher intensities, is currently being used in the clinical settings to successfully treat patients with essential tremors or Parkinson’s disease, and at different parameters (e.g., pulsed high intensity, low intensity, etc.) and hardware configurations in clinical trials of other neurological disorders, the proposed research has a high potential for clinical translation. Given the available resources and expertise at the University of Maryland, pilot clinical trials may start in years 3-5. In summary, the proposed research to use MRgFUS to maximize the delivery of HIV elimination agents may ultimately eradicate the HIV viral reservoirs, especially those in the CNS, and halt the progression or prevent the development of HAND, particularly for those with SUDs.