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
基本信息
- 批准号:10762833
- 负责人:
- 金额:$ 69.89万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 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:
- 关键词:AIDS clinical trial groupAdultAdverse effectsAdverse eventAftercareAgingAlzheimer&aposs disease pathologyAnimal ModelAnti-Retroviral AgentsAttentionBehaviorBiological AssayBiological AvailabilityBiological MarkersBloodBrainCD8-Positive T-LymphocytesCXCL10 geneCalciumCell CountChronicCognitiveCytoskeletonDNADataDiseaseDisease ProgressionEarly identificationEnzyme-Linked Immunosorbent AssayEquilibriumFeline Immunodeficiency VirusFelis catusFoundationsFunctional Magnetic Resonance ImagingGelatinase BGoalsHIVHIV Envelope Protein gp120HIV InfectionsHIV-associated neurocognitive disorderHeterogeneityHumanImmuneImpaired cognitionIn VitroIndividualInfectionInflammationInflammatoryInterventionLigandsLightMacrophageMagnetic Resonance ImagingMaintenanceMeasurementMeasuresMemoryMental HealthMicrogliaMotorMusNGFR ProteinNerve DegenerationNeurocognitiveNeurocognitive DeficitNeurodegenerative DisordersNeuronal DysfunctionNeuronsNeurophysiology - biologic functionNeuroprotective AgentsNeuropsychological TestsNeuropsychologyOralParticipantPathogenesisPerformancePeripheral Blood Mononuclear CellPersonsPharmaceutical PreparationsPhasePlasmaPopulationProcessRNARegenerative pathwayRegulationResourcesRestSafetySamplingSignal TransductionStructureSwellingTREM2 geneTabletsTest ResultTherapeuticTransgenesTransgenic MiceVerbal LearningViralViremiaage relatedantiretroviral therapyanxiety reductionblood-brain barrier crossingcholinergicchronic infectioncognitive functioncohortcytokinedesignearly detection biomarkerseffective therapyefficacy evaluationefficacy trialexecutive functionfollow-uphigh riskimprovedindexinginflammatory markermild neurocognitive impairmentnerve injurynervous system infectionneuralneurofilamentneurograninneuroprotectionneuropsychiatryneurotrophic factornovelnovel markerphase 1 studypre-clinicalpreventprevention efficacy trialprimary endpointprocessing speedrecruitrelease factorresponse to injurytargeted treatmenttranscriptional coactivator p75treatment durationtreatment responsetrial designverbal
项目摘要
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
项目成果
期刊论文数量(0)
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RICK B MEEKER其他文献
RICK B MEEKER的其他文献
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{{ truncateString('RICK B MEEKER', 18)}}的其他基金
Neural network dysfunction in early HIV neuropathogenesis
HIV早期神经发病机制中的神经网络功能障碍
- 批准号:
10204135 - 财政年份:2018
- 资助金额:
$ 69.89万 - 项目类别:
Neural network dysfunction in early HIV neuropathogenesis
HIV早期神经发病机制中的神经网络功能障碍
- 批准号:
9975935 - 财政年份:2018
- 资助金额:
$ 69.89万 - 项目类别:
Neural network dysfunction in early HIV neuropathogenesis
HIV早期神经发病机制中的神经网络功能障碍
- 批准号:
9751991 - 财政年份:2018
- 资助金额:
$ 69.89万 - 项目类别:
Neural network dysfunction in early HIV neuropathogenesis
HIV早期神经发病机制中的神经网络功能障碍
- 批准号:
10448257 - 财政年份:2018
- 资助金额:
$ 69.89万 - 项目类别:
A degradomics strategy for the analysis of inflammation-associated neuronal vulnerability
分析炎症相关神经元脆弱性的降解组学策略
- 批准号:
9374952 - 财政年份:2017
- 资助金额:
$ 69.89万 - 项目类别:
LM11A-31 neuroprotective efficacy in an animal model of HIV
LM11A-31 在 HIV 动物模型中的神经保护功效
- 批准号:
8896088 - 财政年份:2014
- 资助金额:
$ 69.89万 - 项目类别:
LM11A-31 neuroprotective efficacy in an animal model of HIV
LM11A-31 在 HIV 动物模型中的神经保护功效
- 批准号:
8789501 - 财政年份:2014
- 资助金额:
$ 69.89万 - 项目类别:
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