The hCNS-HIV/ARV assay system, a platform utilizing human iPSC-neurons/-microglia/-astrocytes to test HIV/AIDS therapeutics for neurotoxicity related to HIV-associated cognitive disroder (HAND)

hCNS-HIV/ARV 检测系统是一个利用人类 iPSC-神经元/-小胶质细胞/-星形胶质细胞来测试 HIV/AIDS 疗法与 HIV 相关认知障碍 (HAND) 相关神经毒性的平台

• 批准号: 10259617
• 负责人: PATRICK M MCDONOUGH
• 金额: $ 97.52万
• 依托单位: VALA SCIENCES, INC.
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-10 至 2023-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10259617
• 关键词: AIDS dementia; AIDS/HIV problem; Acquired Immunodeficiency Syndrome; Adult; Affect; Aging; Alzheimer' s Disease; Animals; Anti-Retroviral Agents; Astrocytes; Autophagocytosis; Biological Assay; Bipolar Disorder; Birth; Brain; Calcium; Cells; Child; Coculture Techniques; Cognition; Cognition Disorders; Cognitive; Collaborations; Congenital Abnormality; Data; Dementia; Development; Developmental Delay Disorders; Diagnosis; Embryo; Epigenetic Process; Exhibits; Goals; HIV; HIV Infections; HIV antiretroviral; Harvest; Human; Human immunodeficiency virus test; Image Analysis; Immune; Impaired cognition; In Vitro; Incidence; Individual; Infant; Infection; Institutes; Jordan; Lead; Life; Life Expectancy; Link; Longevity; Medical; Medical Research; Methods; Microglia; Microscopy; Monitor; Nerve Degeneration; Neuraxis; Neurites; Neurocognitive Deficit; Neurodevelopmental Disorder; Neuroglia; Neurologic Effect; Neurologic Symptoms; Neuronal Differentiation; Neurons; Oxidative Stress; Pathway interactions; Patients; Penetrance; Pennsylvania; Performance; Pharmacologic Substance; Phase; Preclinical Testing; Pregnant Women; Process; Protocols documentation; Rattus; Research; Research Contracts; Research Personnel; Rest; Rodent; Safety; Schizophrenia; Science; Standardization; Synapses; System; Tenofovir; Testing; Therapeutic; Thinking; Toxic effect; Universities; antiretroviral therapy; assay development; autism spectrum disorder; biological adaptation to stress; blood-brain barrier crossing; cell type; cerebral atrophy; digital; drug discovery; efavirenz; emtricitabine; epigenetic marker; high throughput screening; in vitro Model; induced pluripotent stem cell; microscopic imaging; nerve stem cell; neurocognitive disorder; neurodevelopment; neurogenesis; neuroinflammation; neuron loss; neurotoxicity; novel; novel therapeutics; pre-clinical; pre-clinical research; preservation; prevent; prophylactic; side effect; stem cells; targeted agent; voltage

Globally, about 40 million people live with HIV/AIDS, and HIV antiretroviral agents (ARVs) are a multi-billion dollar pharmaceutical sector with continued development of agents. Thanks to combination antiretroviral therapy (cART, in which 2 to 4 ARVs are given, simultaneously) HIV+ people have a near-normal life-span. HIV+ pregnant women also receive cART, and their children are given cART prophylactically at birth (in general, cART is given to all HIV+ infants and children). For all HIV+ patients, if cART is stopped, HIV replication restarts; thus, HIV+ people must remain on cART for the rest of their lives. For HIV+ adults, ARVs are present during aging, in which loss of central nervous system (CNS) neurons contributes to loss of cognition/dementia. For HIV+ infants and children, ARVs are present during neurodevelopment. HIV+ individuals frequently develop HIV-Associated Cognitive Disorders (HAND), which includes HIV-associated dementia (HAD,common in AIDS), and less severe forms (asymptomatic neurocognitive impairment and mild neurocognitive disorder (MND). While cART has reduced the incidence of HAD, ANI and MND remain at high levels, even when HIV load is very low. In fact, certain ARVs may contribute to HAND, and alarmingly, HIV+children on cART exhibit developmental delays in intellectual performance. Also, HIV infects/replicates in microglia (MG), an innate immune cell of the CNS, and MG are out of the reach of ARVs that are poor at crossing the blood:brain barrier. More brain-penetrant ARVs were developed, but, unexpectedly, these are linked to greater incidence of HAND. Preclinical research on ARV neurotoxicity has been conducted on primary rodent neurons and glial. Our goal is to develop an assay system (dubbed the hCNS-HIV/ARV platform) for testing ARVs for neurotoxicity and efficacy at inhibiting HIV, neurons, MG and astrocytes (another glial cells), derived from human induced pluripotent stem cells (hiPSC-neurons, hiPSC-MG, and hiPSC-ACs). In phase I, we developed methods for testing ARVs on hiPSC-neurons plated in 384-well dishes, utilizing high-throughput digital microscopy/analysis. We found neurotoxicity (reductions in neurites, synapses, and calcium transients) for elvitegravir (EVG, strongest effect, matching data with rat neurons), dolutegravir (DTG, linked to birth defects), and tenofovir disoproxil fumerate (TDF) and certain combinations of ARVs representing cART had stronger effects than the ARVs, alone. TDF also reduced the viability and elicited epigenetic changes in human neural precursor cells (hNPCs), suggesting that TDF may affect neurogenesis, a process critical for neurodevelopment and cognition. In phase II we will develop standard assay protocols/analysis methods for testing ARVs and HIV infection, itself, on hiPSC-neurons/-MG/-ACs, and on hiPSC-NPCs. The hCNS- HIV/ARV platform will enable development of ARVs that inhibit HIV with minimal neurotoxicity and will be marketed to pharmaceutical companies developing novel therapeutics for HIV/AIDs.

在全球范围内，约有4000万人感染艾滋病毒/艾滋病，而艾滋病毒抗逆转录病毒药物（ARVs）价值数十亿美元