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Clinical trial readiness biomarkers for gene dosage-dependent disorders

基因剂量依赖性疾病的临床试验准备生物标志物

基本信息

批准号：
10427281
负责人：
MIRJANA MALETIC-SAVATIC
金额：
$ 20.06万
依托单位：
BAYLOR COLLEGE OF MEDICINE
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：
2020-07-22 至 2025-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10427281
关键词：
Address Algorithms Alleles Antisense Oligonucleotide Therapy Antisense Oligonucleotides Attention Auditory Evoked Potentials Bioinformatics Biological Biological Markers Biosensor Blinking Blood Brain Cell Line Cells Clinical Clinical Trials Cognition Communities Complement Complementary DNA Complex Copy Number Polymorphism DNA Data Data Analyses Data Set Development Developmental Gene Disease Dose Enrollment Evoked Potentials Fibroblasts Foundations Future Gene Dosage Gene Expression Gene Mutation Genes Genetic Goals Human Impairment Individual Intellectual and Developmental Disabilities Research Centers Intellectual functioning disability Learning Machine Learning Mass Spectrum Analysis Measurement Measures Mediator of activation protein Medicine Memory Mendelian disorder Methodology Molecular Molecular Profiling Mus Mutation Natural History Neurologic Neurons Outcome Measure Participant Pathology Patients Perception Peripheral Phenotype Physiological Population Study Potocki-Lupski syndrome Proteins Pupil RNA Splicing Readiness Recording of previous events Research Research Project Grants Safety Sensory Services Severities Single Nucleotide Polymorphism Spinal Muscular Atrophy Stimulus Sum Symptoms Syndrome Testing Time Treatment Efficacy Treatment-related toxicity Visual Work base biomarker signature clinical phenotype clinical trial readiness cognitive function cohort college design dosage gain of function gene replacement improved individual patient induced pluripotent stem cell innovation insight interest loss of function metabolome metabolomics molecular marker mouse model multimodal data neural circuit new technology next generation novel overexpression overtreatment precision medicine prepulse inhibition response social skills somatosensory tool transcriptome transcriptome sequencing transcriptomics

项目摘要

DNA-based therapy has made tremendous advances recently, as evident by the increase in emerging potential therapies such as gene replacement and antisense oligonucleotides to alter splicing or downregulate an extra allele. These therapies hold the promise to treat many IDDs; however, major challenges must be addressed to achieve successful clinical trials. Safety of such therapies is of the utmost importance since many of the genes are dosage sensitive. It is therefore critical to identify outcome measures sensitive to target engagement and able to detect overtreatment and unintended conversion of gain-of-function phenotypes into a loss-of-function phenotypes, and vice versa. Here, we focus on MECP2- (Rett vs. MECP2 Duplication), RAI1- (Smith-Magenis vs. Potocki-Lupski syndrome) and SHANK3- (Phelan-McDermid vs. SHANK3 Duplication) associated disorders as test cases of IDDs that are caused by alterations of these dosage-dependent genes. We propose to identify molecular and neurocircuitry mediators/effectors of dosage alterations of these genes, both peripherally and centrally, to develop composite biomarkers that are responsive to gene dosage in each individual at their particular disease stage. Toward this goal, we capitalize on the established patient cohorts at Baylor College of Medicine, which has an extensive history in studying these disorders and their genetics. In Aim 1, we will establish patient-specific molecular signatures of human induced neurons (iNs), derived from both fibroblasts and inducible pluripotent stem cells, and blood, using metabolomics and transcriptomics. In Aim 2, we will establish patient-specific autonomic and sensory neurocircuitry signatures of the momentary disease stage and severity using novel pre-pulse inhibition paradigm, pupillometry, and evoked potentials. These signatures will be obtained twice from the same subject, 8-12 months apart, to assess stability. We will then integrate these dense multimodal datasets from each subject to generate a composite biomarker that accurately represents personalized response to the gene dosage level at that particular time. In contrast to conventional population studies – and in the spirit of precision medicine – this analysis framework relies on complete and diverse datasets from each participant because safety at the individual level is paramount to avoid causing unintended phenotypes. This project is possible because of the ability to access the innovative services from all the cores. The strategies we develop will provide a template to advance the use of DNA-based therapy for treatment of many monogenic disorders and could help inform many disorders that are gene dosage- dependent. The patient-specific cell lines, molecular, and circuit data will be available for the scientific community in perpetuity, will complement natural history studies, and will inform future clinical trials. Lastly, the new methodologies for examining neurocircuitry and the integrative data analysis approaches at multiple levels will potentially provide transformative tools and analytical algorithms for assessment, safe dosing, and accelerated clinical trials for multiple gene dosage-dependent IDDs.

以dna为基础的治疗最近取得了巨大的进步，这一点从新兴潜力的增加就可以看出