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: 10386886
• 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/10386886
• 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.

项目摘要： 此DP1申请对“ NIDA前卫奖”计划的响应 艾滋病毒/艾滋病和药物使用障碍研究”。pi，琳达·张（Linda Chang），提议应对 艾滋病毒治疗或治疗的主要挑战，即目前治疗 消除病毒储层的方案，尤其是那些受血大脑保护的储层 中枢神经系统（CNS）中的屏障（BBB）。具有底物的艾滋病毒感染者 使用疾病（SUD）通常具有更高的病毒载量，并且艾滋病毒严重程度更高 相关的神经认知障碍（手）。她建议使用新兴技术 MR引导聚焦超声（MRGFU）安全，瞬时打开BBB 最大化长效缓慢释放抗逆转录病毒疗法（激光ART）的递送，并 提供有针对性的CRISPR-CAS9的送达，以消除综合的HIV提供商DNA 中枢神经系统病毒库。激光艺术的综合方法，然后是AAV-Crispr-Cas9 在啮齿动物模型的亚组中显示了早期的成功，但进一步的最佳输送 需要CNS的代理。首先，HIV人性化的啮齿动物模型将用于证明 明显提高了这些代理到中枢神经系统的递送，以及消除效率 没有弹药的病毒。此外，由于用于使用相同的FUS能量和脉冲图案 BBB开放也可以诱导神经发生并激活小胶质细胞，这些次要作用将 也可以评估。最后，由于引人注目的早期临床前发现和神经调节 其他人则低强度MRGFU作为成瘾的潜在治疗方法也将在 药物自我管理啮齿动物模型。 PI组成了一支杰出的团队 在每种技术和方法中都是专家的合作者 拟议研究的成功。此外，由于Mrgfus较高，因此 目前正在临床环境中用于成功治疗基本震颤的患者 或帕金森氏病，以及不同的参数（例如，脉冲高强度，低强度， 等）以及其他神经系统疾病的临床试验中的硬件配置，提议 研究具有很高的临床翻译潜力。鉴于可用的资源和专业知识 在马里兰大学，试点临床试验可能从3 - 5年开始。总而言之， 建议使用MRGFU来最大化艾滋病毒消除剂的拟议研究可能 最终将艾滋病毒病毒储存剂，尤其是中枢神经系统的hiv病毒储存剂，并停止 进展或阻止手的发展，特别是对于那些泡沫的人。