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: 10237675
• 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 2026-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10237675
• 关键词: AIDS/HIV problem; Anti-Retroviral Agents; Award; Blood - brain barrier anatomy; Brain; CRISPR/Cas technology; Clinical; Clinical Trials; DNA; Development; Emerging Technologies; Ensure; Essential Tremor; Focused Ultrasound; HIV; HIV-associated neurocognitive disorder; Human; Life; Maryland; Microglia; National Institute of Drug Abuse; Neuraxis; 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.

项目概要： 此 DP1 应用程序响应 PAR-20-221“NIDA 前卫奖计划” “艾滋病毒/艾滋病和药物滥用障碍研究”。首席研究员 Linda Chang 提议解决一个问题。 治疗或治愈艾滋病毒的主要挑战，即目前的治疗无力 根除病毒库的方案，尤其是那些受血脑保护的病毒库 艾滋病毒感染者体内有物质的中枢神经系统（CNS）屏障（BBB）。 使用障碍（SUD）通常具有更高的病毒载量，并且遭受更严重的 HIV- 她建议使用新兴技术。 MR 引导聚焦超声 (MRgFUS) 可安全、短暂地打开血脑屏障，以便 最大限度地提供长效缓释抗逆转录病毒疗法（激光艺术），并 提供 CRISPR-Cas9 的靶向递送，以消除整合的 HIV 原病毒 DNA CNS 病毒库。激光 ART 和 AAV-CRISPR-Cas9 的组合方法。 已在啮齿动物模型亚组中显示出早期成功，但这些模型的进一步优化交付 首先，将使用 HIV 人源化啮齿动物模型来进行演示。 显着改善了这些药物向中枢神经系统的输送，并消除了 此外，由于使用相同的 FUS 能量和脉冲模式。 BBB开放还可以诱导神经发生并激活小胶质细胞，这些次级效应将 最后，由于令人信服的神经调节早期临床前发现。 其他人也将探索低强度 MRgFUS 作为成瘾的潜在治疗方法 药物自我给药啮齿动物模型。 PI组建了一支优秀的团队。 合作者是每种技术和方法的专家，以确保 此外，由于 MRgFUS 在较高强度下是成功的。 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，并在不同的参数下（例如，脉冲高强度、低强度、 等）和其他神经系统疾病临床试验中的硬件配置，建议 鉴于现有资源和专业知识，研究具有很高的临床转化潜力。 在马里兰大学，试点临床试验可能会在第 3-5 年开始。 拟议的使用 MRgFUS 最大限度地输送 HIV 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中的病毒库，并阻止艾滋病毒的传播 进展或预防 HAND 的发展，特别是对于那些患有 SUD 的患者。