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

摘要 HIV感染神经系统会导致慢性感染、炎症、神经精神疾病 高达50%的艾滋病毒携带者在没有有效治疗的情况下出现问题和认知能力下降 迄今为止的治疗方法。炎症出现在疾病过程的早期，并导致进展性 神经元损伤，部分原因是激活的小胶质细胞和巨噬细胞释放的因子。在……里面 培养的神经元和小鼠，表达HIV gp120转基因这些因素诱导 细胞内钙积聚、细胞骨架损伤和局灶性肿胀，其方式类似 早期阿尔茨海默病(AD)的病理，表明疾病的共同底物 进步。P75神经营养素受体的年龄依赖性积聚发生在 疾病，被认为是通过改变神经营养因子的平衡而参与发病的 远离保护性、再生途径的信号。衰老与gp120的治疗 带有非肽p75NTR小配体LM11A-31的转基因小鼠抑制胆碱能 变性、炎症和神经元损伤。在长期感染猫科动物的猫身上 免疫缺陷病毒，口服LM11A-31十周可防止变性， 改善认知行为，降低焦虑和脑脊液病毒滴度 对全身性病毒血症、PBMC FIV负荷或CD4/CD8 T细胞比率的不良影响。由于p75NTR 正常情况下在成人脑中的表达水平很低，但在损伤或 对于疾病，它为治疗提供了一个独特的靶点，将脱靶效应的可能性降至最低。这个 药物为口服生物利用型，可通过血脑屏障，没有明显的不良反应。 在人体内的治疗浓度。探讨LM11A-31作为疾病的可能性 修改神经保护治疗，拟议的研究将建立安全性和 LM11A-31治疗在一小群稳定的病毒抑制的参与者中的耐受性 艾滋病毒和轻微的神经认知障碍。安全措施将得到补充， 用于早期检测的传统和新型生物标志物的探索性表征 脑脊液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p75NTR激活的敏感指标，具有潜在的 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预防有效性试验 认知能力下降的症状。这些研究预计将表明LM11A-31在 并为一项更大规模的疗效试验奠定基础 示范保护免受神经元损伤和认知能力下降。

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.