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：
10221025
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/10221025
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 Pluripotent Stem Cells 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 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.

基于DNA的治疗最近已取得了巨大进步，作为新兴潜力增加的证据基因置换和反义寡核苷酸等疗法可以改变剪接或下调额外的剪接等位基因。这些疗法有望治疗许多IDD。但是，必须解决重大挑战实现成功的临床试验。这种疗法的安全至关重要，因为许多基因剂量敏感。因此，至关重要的是确定对目标参与敏感的结果度量和可以检测到过度治疗和意想不到的功能获得表型转换为功能丧失表型，反之亦然。在这里，我们专注于mecp2-（Rett vs. Mecp2重复），RAI1-（Smith-Magenis 与Potocki-Lupski综合征）和Shank3-（Phelan-McDermid与Shank3复制）相关疾病作为由这些剂量依赖性基因改变引起的IDD的测试用例。我们建议确定这些基因的剂量改变的分子和神经记录介质/效应子，包括外周和集中，开发复合生物标志物，对每个人的基因剂量有反应特定疾病阶段。为了实现这一目标，我们利用了贝勒学院的既定患者同伙医学，哪个在研究这些疾病及其遗传学方面有悠久的历史。在AIM 1中，我们将建立源自两个成纤维细胞的人类诱导神经元（INS）的患者特异性分子特征使用代谢组学和转录组学，以及可诱导的多能干细胞以及血液。在AIM 2中，我们将建立瞬时疾病阶段的患者特定自主神经和感觉神经记录的特征使用新型的脉冲抑制范式，化学计量法和诱发电位的严重程度。这些签名从同一受试者（相隔8-12个月）将获得两次，以评估稳定性。然后我们将整合来自每个受试者的这些密集的多模式数据集以生成一个复合生物标志物，以准确在该特定时间代表对基因剂量水平的个性化反应。与传统相反人口研究 - 本着精确医学的精神 - 该分析框架依赖于完整和每个参与的不同数据集，因为个人层面的安全至关重要，以避免造成意外表型。由于能够从所有的核心。我们制定的策略将提供一个模板，以推动基于DNA的治疗的使用治疗许多单基因疾病，可以帮助许多疾病，这些疾病是基因剂量的依赖。患者特异性的细胞系，分子和电路数据将用于科学永久性社区将补充自然历史研究，并将为未来的临床试验提供信息。最后，研究神经记录和集成数据分析方法的新方法多个级别有可能提供变革性的工具和分析算法，用于评估，安全给药和多个基因剂量依赖性IDD的加速临床试验。