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

MR 引导聚焦超声消除 CNS 病毒库并促进 HIV 感染大脑中的神经发生

• 批准号: 10611332
• 负责人: LINDA CHANG
• 金额: $ 108.15万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-06-01 至 2027-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10611332
• 关键词: Anti-Retroviral Agents; Award; Binding; Blood - brain barrier anatomy; Brain; CRISPR/Cas technology; Central Nervous System; Clinical; Clinical Trials; DNA; Development; Emerging Technologies; Ensure; Essential Tremor; Focused Ultrasound; HIV; HIV-associated neurocognitive disorder; HIV/AIDS; Human; Maryland; Microglia; National Institute of Drug Abuse; Parkinson Disease; Patients; Pattern; Persons; Pharmaceutical Preparations; Physiologic pulse; Research; Resources; Rodent; Rodent Model; Self Administration; Severities; Source; Subgroup; Substance Use Disorder; Techniques; Translating; Treatment Protocols; Universities; Viral Load result; Viral reservoir; Virus; addiction; antiretroviral therapy; clinical translation; improved; nervous system disorder; neurogenesis; neuroregulation; pre-clinical; prevent; programs; success; targeted delivery

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.

项目总结： 此DP1应用程序响应PAR-20-221“NIDA Avant-Garde奖计划 艾滋病毒/艾滋病与物质使用障碍研究“。私家侦探琳达·张提议解决一个 艾滋病毒治疗或治愈方面的主要挑战，即无法进行目前的治疗 根除病毒库的方法，特别是那些受血脑保护的病毒库 中枢神经系统中的屏障(BBB)。有物质的艾滋病毒感染者 使用障碍(SOD)通常有更高的病毒载量，并遭受更严重的艾滋病毒- 相关神经认知障碍(手)。她建议使用新兴的技术 MR引导的聚焦超声(MRgFUS)，以安全和瞬时打开血脑屏障，以便 最大限度地提供长效缓释抗逆转录病毒疗法(激光ART)，并 提供CRISPR-Cas9的靶向递送，以消除整合的HIV前病毒DNA 中枢神经系统病毒库。激光ART与AAV-CRISPR-CAS9相结合 已经在啮齿动物模型的亚组中显示出早期的成功，但这些模型的进一步优化交付 需要派往CNS的特工。首先，将使用HIV人性化的啮齿动物模型来演示 显著改善了这些药物进入中枢神经系统的效果，并消除了 病毒没有反弹。此外，由于相同的FUS能量和脉冲图案用于 血脑屏障开放还可以诱导神经发生和激活小胶质细胞，这些次要作用将 也会被评估。最后，由于神经调节的令人信服的早期临床前发现 其他人也将探索低强度MRgFUS作为成瘾的潜在治疗方法 药物自主给药啮齿动物模型。私家侦探组建了一支出色的团队 通晓各种技术和方法的合作者，确保 拟议研究的成功。此外，由于MRgFUS在更高的强度下， 目前在临床环境中用于成功治疗特发性震颤患者 或帕金森氏病，并且在不同的参数(例如，脉冲高强度，低强度， 等)和硬件配置在其他神经疾病的临床试验中，建议 研究具有很高的临床翻译潜力。考虑到可用的资源和专业知识 在马里兰大学，试点临床试验可能在3-5年内开始。总而言之， 拟议的使用MRgFUS最大限度地提供艾滋病毒消除剂的研究可能 最终根除艾滋病毒病毒库，特别是中枢神经系统的病毒库，并阻止 防止手部疾病的发展，特别是对那些有肥皂泡的人。