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Bridging the translational divide from cells to patients: toward reliable neuromarkers of Batten disease

弥合从细胞到患者的翻译鸿沟：寻找巴顿病的可靠神经标志物

基本信息

批准号：
10633140
负责人：
Kuan Hong Wang
金额：
$ 27.46万
依托单位：
UNIVERSITY OF ROCHESTER
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-08-01 至 2025-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10633140
关键词：
Acceleration Attention Auditory Auditory Evoked Potentials Auditory Perception Auditory area Biological Assay Biological Markers Blindness CLN3 gene Categories Cells Ceroid Child Childhood Chromosome 16 Chronic Clinical Clinical Trials DNA Sequence Alteration Data Dementia Development Disease Disease Marker Disease Progression Disease model Electroencephalography Frequencies Future Hearing Tests Human Hypertrophy Impaired cognition Individual Intellectual and Developmental Disabilities Research Centers Interneurons Intervention Lead Lipofuscin Measurement Measures Memory Methods Modeling Motor Mus Mutation Neurodevelopmental Disorder Neurologic Neuronal Ceroid-Lipofuscinosis Neurons Outcome Measure Participant Pathology Patient-Focused Outcomes Patients Pattern Persons Phonetics Positioning Attribute Reporter Reporting Research Project Grants Retinal Diseases Seizures Sensory Severities Severity of illness Speech Perception Spielmeyer-Vogt Disease Staging Techniques Testing Time Transgenic Mice Universities Work auditory processing auditory stimulus autosome base biomarker identification calcium indicator cell type cognitive function density design early adolescence effectiveness testing endophenotype excitatory neuron experimental study human disease improved improved outcome in vivo two-photon imaging inhibitory neuron innovation juvenile neuronal ceroid lipofuscinosis lipopigments mouse model neuromechanism neuron loss neuropathology neurophysiology novel therapeutics patient/disease registry pre-clinical preclinical development response semantic processing therapeutic effectiveness therapeutic evaluation verbal young adult

项目摘要

PROJECT SUMMARY Neuronal Ceroid Lipofuscinoses (NCLs) are a group of neurodevelopmental diseases categorized as autosomal recessive lysosomal storage disorders. Clinical features include retinopathy, intracellular accumulation of lysosomal ceroid and lipofuscin, seizures, motor decline and dementia. CLN3 disease (Juvenile Neuronal Ceroid Lipofuscinosis, JNCL) is one of the most common types of NCL, and results from mutations in the CLN3 gene on chromosome 16. Individuals with the CLN3 mutation show a consistent decline in cognitive functioning and verbal intellectual abilities over the course of later childhood and early adolescence. The precise neuropathological bases of this decline are not yet well understood and objective neurologic biomarkers (neuromarkers) of disease progression are not currently available. Yet, our preliminary data indicate that a good candidate for a biomarker of CLN3 disease that tracks with disease severity can be identified using high-density electroencephalography (EEG) in the context of auditory mismatch negativity experiments. Using these methods we have been able to show consistent declines in the P1 component of the auditory evoked response as CLN3 disease severity increases. Here we propose to further develop our understanding of auditory processing in children and young adults with CLN3 disease with a focus on validating a biomarker of the disease. Simultaneously we propose to use a mouse model of CLN3 disease with the same genetic mutation to identify an endophenotype that is shared in both patients and mice. We will also test whether the accumulation of autofluorescent lipopigments preferentially occur in specific subsets of interneurons and predict their subsequent loss as well as the hypertrophy of remaining interneurons. This three-pronged, convergence of techniques and approaches in both species has the potential to yield unique opportunities to understand the underlying neurophysiology of CLN3 mutations and their impact on auditory processing, as well as encourage testing of future treatments for CLN3 disease first in mice and secondarily in patients. This innovative approach, tying the patient neurophysiological markers to identical measures in the murine model of the disease will permit improved and more efficient pre-clinical development of novel therapeutics, improved measurement of disease progression in clinical trials, and with these advances, lead to improved outcomes for patients with CLN3 mutations.

项目总结