Study to establish safety, tolerability and feasibility of LM11A-31 as a neuroprotective agent in aging people living with HIV and neurocognitive impairment on antiretroviral therapy

研究确定 LM11A-31 作为神经保护剂对老年艾滋病毒感染者和抗逆转录病毒治疗神经认知障碍患者的安全性、耐受性和可行性

• 批准号: 10762833
• 负责人: RICK B MEEKER
• 金额: $ 69.89万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-15 至 2028-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10762833
• 关键词: AIDS clinical trial group; Adult; Adverse effects; Adverse event; Aftercare; Aging; Alzheimer' s disease pathology; Animal Model; Anti-Retroviral Agents; Attention; Behavior; Biological Assay; Biological Availability; Biological Markers; Blood; Brain; CD8-Positive T-Lymphocytes; CXCL10 gene; Calcium; Cell Count; Chronic; Cognitive; Cytoskeleton; DNA; Data; Disease; Disease Progression; Early identification; Enzyme-Linked Immunosorbent Assay; Equilibrium; Feline Immunodeficiency Virus; Felis catus; Foundations; Functional Magnetic Resonance Imaging; Gelatinase B; Goals; HIV; HIV Envelope Protein gp120; HIV Infections; HIV-associated neurocognitive disorder; Heterogeneity; Human; Immune; Impaired cognition; In Vitro; Individual; Infection; Inflammation; Inflammatory; Intervention; Ligands; Light; Macrophage; Magnetic Resonance Imaging; Maintenance; Measurement; Measures; Memory; Mental Health; Microglia; Motor; Mus; NGFR Protein; Nerve Degeneration; Neurocognitive; Neurocognitive Deficit; Neurodegenerative Disorders; Neuronal Dysfunction; Neurons; Neurophysiology - biologic function; Neuroprotective Agents; Neuropsychological Tests; Neuropsychology; Oral; Participant; Pathogenesis; Performance; Peripheral Blood Mononuclear Cell; Persons; Pharmaceutical Preparations; Phase; Plasma; Population; Process; RNA; Regenerative pathway; Regulation; Resources; Rest; Safety; Sampling; Signal Transduction; Structure; Swelling; TREM2 gene; Tablets; Test Result; Therapeutic; Transgenes; Transgenic Mice; Verbal Learning; Viral; Viremia; age related; antiretroviral therapy; anxiety reduction; blood-brain barrier crossing; cholinergic; chronic infection; cognitive function; cohort; cytokine; design; early detection biomarkers; effective therapy; efficacy evaluation; efficacy trial; executive function; follow-up; high risk; improved; indexing; inflammatory marker; mild neurocognitive impairment; nerve injury; nervous system infection; neural; neurofilament; neurogranin; neuroprotection; neuropsychiatry; neurotrophic factor; novel; novel marker; phase 1 study; pre-clinical; prevent; prevention efficacy trial; primary endpoint; processing speed; recruit; release factor; response to injury; targeted treatment; transcriptional coactivator p75; treatment duration; treatment response; trial design; verbal

Abstract HIV infection of the nervous system results in chronic infection, inflammation, neuropsychiatric problems and cognitive decline in up to 50% of people living with HIV with no effective treatments to-date. Inflammation appears early in the disease process and causes progressive neuronal damage due, in part, to factors released by activated microglia and macrophages. In cultured neurons and mice, expressing the HIV gp120 transgene these factors induce intracellular calcium accumulation, cytoskeletal damage and focal swelling, in a fashion similar to early Alzheimer’s disease (AD) pathology, suggesting a common substrate for disease progression. Age-dependent accumulation of the p75 neurotrophin receptor occurs early in disease and is thought to contribute to pathogenesis by shifting the balance of neurotrophin signaling away from protective, regenerative pathways. Treatment of aging and gp120 transgenic mice with a small non-peptide p75NTR ligand, LM11A-31, suppressed cholinergic degeneration, inflammation and neuronal damage. In cats chronically infected with feline immunodeficiency virus, ten weeks of oral treatment with LM11A-31 prevented degeneration, improved cognitive behaviors, reduced anxiety and CSF viral titers in the absence of any adverse effects on systemic viremia, PBMC FIV burden, or CD4:CD8 T cell ratios. Since p75NTR is normally expressed at very low levels in adult brain but is upregulated in response to injury or disease, it provides a unique target for therapy with minimal potential for off-target effects. The drug is orally bioavailable, crosses the blood brain barrier and has no significant adverse effects in humans at therapeutic concentrations. To explore the potential of LM11A-31 as a disease modifying neuroprotective treatment, the proposed studies will establish the safety and tolerability of LM11A-31 treatment in a small cohort of stable virally-suppressed participants with HIV and mild neurocognitive impairment. Safety measures will be supplemented with exploratory characterization of traditional and novel biomarkers for early detection of inflammation and neurodegeneration in CSF and blood. A novel fMRI Hcorr analysis will be used to provide a sensitive measure of early immune and p75NTR activation with the potential to identify individuals in early stages of neurodegeneration. Serial neuropsychological test results will provide preliminary data and facilitate transition to a subsequent efficacy trial for prevention of cognitive decline. These studies are expected to show that LM11A-31 is safe to use in people living with HIV and to lay the groundwork for a larger efficacy trial designed to demonstration protection from neuronal damage and cognitive decline.

摘要 HIV感染的神经系统导致慢性感染、炎症、神经精神疾病 高达50%的艾滋病毒感染者存在问题和认知能力下降， 治疗至今。炎症出现在疾病过程的早期， 神经元损伤部分是由于活化的小胶质细胞和巨噬细胞释放的因子。在 培养的神经元和小鼠，表达HIV gp 120转基因，这些因子诱导 细胞内钙积聚、细胞骨架损伤和局灶性肿胀，其方式类似于 早期阿尔茨海默病（AD）病理学，表明疾病的共同基质 进展p75神经营养因子受体的依赖性积聚发生在 疾病，并被认为有助于通过改变神经营养因子的平衡发病机制 远离保护性再生途径的信号。治疗衰老和gp 120 具有小的非肽p75 NTR配体LM 11 A-31的转基因小鼠抑制了胆碱能 变性、炎症和神经元损伤。在猫慢性感染猫 免疫缺陷病毒，用LM 11 A-31口服治疗10周防止变性， 改善认知行为，减少焦虑和CSF病毒滴度， 对系统性病毒血症、PBMC FIV负荷或CD 4：CD 8 T细胞比率的不良影响。由于p75 NTR 通常在成人脑中以非常低的水平表达，但在对损伤或 疾病，它提供了一个独特的治疗目标，具有最小的脱靶效应的可能性。的 药物是口服生物可利用的，穿过血脑屏障，没有明显的副作用 在治疗浓度下的人体内。探索LM 11 A-31作为一种疾病的潜力 修改神经保护治疗，拟议的研究将建立安全性和 LM 11 A-31治疗在一小群稳定的病毒抑制参与者中的耐受性 HIV和轻度神经认知障碍安全措施将补充 用于早期检测的传统和新型生物标志物的探索性表征 CSF和血液中的炎症和神经变性。一种新的fMRI Hcorr分析将是 用于提供早期免疫和p75 NTR激活的灵敏测量， 识别处于神经退化早期阶段的个体。系列神经心理测试结果 将提供初步数据，并促进过渡到随后的有效性试验， 认知能力下降这些研究预计将表明，LM 11 A-31是安全的， 艾滋病毒感染者，并为一项更大规模的疗效试验奠定基础， 证明了对神经元损伤和认知能力下降的保护。