Down Syndrome: a potential treatment XISTs

唐氏综合症：一种潜在的治疗方法 XIST

基本信息

批准号：
10525816
负责人：
VOLNEY L SHEEN
金额：
$ 169.33万
依托单位：
BETH ISRAEL DEACONESS MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-01 至 2025-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10525816
关键词：
Address Alzheimer&apos s Disease Behavioral Biological Models Brain CRISPR/Cas technology Cell Death Cell Proliferation Cell physiology Cells Chromatin Chromosome 21 Chromosome Territory Chromosomes Code Cognitive Communication Complex DNA Defect Development Disease Down Syndrome Early Onset Alzheimer Disease Embryo Embryonic Development Epigenetic Process Exonuclease Functional disorder Funding Future Gene Expression Gene Silencing Genes Genetic Genetic Diseases Genetic Recombination Genomic DNA Genomics Guide RNA Hippocampus (Brain)Histologic Human Impairment In Vitro Individual Infection Knock-in Live Birth Longevity Maintenance Mental Retardation Messenger RNA MicroRNAs Modification Mus Nerve Degeneration Neurocognitive Deficit Neurologic Neurons Oligodendroglia Open Reading Frames Pathway interactions Pharmacology Phenotype Plasmids Pluripotent Stem Cells Polycomb Polymers Proliferating Proteins Proto-Oncogene Proteins c-akt Seizures Short-Term Memory Single-Stranded DNA Somatic Cell Synapses Testing Therapeutic Therapeutic Intervention Transcript Transfection Transgenes Translating Trisomy United States National Institutes of Health Untranslated RNA Work X Chromosome X Inactivation autosome base cell type clinical effect ds-DNA experimental study genome editing in utero in vivo mouse model myelination nerve stem cell neurogenesis neurophysiology novel optimal treatments postnatal postnatal period prenatal progenitor recruit repaired synaptogenesis tau phosphorylation transcriptomics

项目摘要

Summary Down syndrome arises from the triplication of a subset of genes on chromosome 21 (HSA21). Individuals with DS uniformly demonstrate some degree of mental retardation (MR). The MR has been attributed to impairments in brain development (i.e. neurogenesis) as well as progressive cell death with altered synaptogenesis (i.e. neurodegeneration). Silencing of one of the three HSA21 chromosomes rescues the DS phenotype but such a therapeutic approach is limited practically by the efficiency of genomic editing and ability to specifically target a single HSA21 chromosome. With prior funding from NIH INCLUDE, we have developed a novel modified CRISPR approach which greatly enhances the integration of genomic material on HSA21 and we have also devised a means with which to specifically target a single HSA21 copy by SNP based PAM targeting with gRNA. Feasibility has been shown in culture model systems. We now propose experiments to assess the efficiency of these approaches in the TcMAC1 mouse model of DS. The TcMAC21 mouse contains 93% of HSA21q protein coding genes that are expressed and regulatable. Overall, if successful, these studies would show the potential ability to reverse, at least partially, the DS neurological phenotype. The funded proposal is the necessary next step to ascertain whether the efficiency of silencing by XIST of a third HSA21 copy in vivo would translate into an observable clinical effect.

概括唐氏综合症源于染色体21（HSA21）上的一部分基因的三分一式定序。有个人 DS均匀地表现出一定程度的智力障碍（MR）。 MR被归因于大脑发育障碍（即神经发生）以及随着改变的渐进细胞死亡突触发生（即神经变性）。沉默的三个HSA21染色体之一拯救了DS 表型但这种治疗方法实际上受到基因组编辑和能力的效率的限制专门针对单个HSA21染色体。随着NIH的先前资助，我们已经开发了一种新颖的修改CRISPR方法，可大大增强基因组材料在HSA21和我们还设计了一种手段，该方法可以专门针对基于SNP的PAM的单个HSA21副本用grna靶向。可行性已在文化模型系统中显示。我们现在建议实验评估这些方法在DS的TCMAC1小鼠模型中的效率。 TCMAC21鼠标包含表达和调节的HSA21Q蛋白编码基因的93％。总的来说，如果成功，这些研究将显示至少部分逆转DS神经系统表型的潜在能力。资助的提案是确定XIST沉默效率的必要下一步第三HSA21体内副本将转化为可观察到的临床效应。