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.

概括唐氏综合症是由 21 号染色体 (HSA21) 上的一个基因子集的三倍体引起的。个人有 DS 一致表现出某种程度的精神发育迟滞（MR）。 MR 被归因于大脑发育受损（即神经发生）以及细胞进行性死亡突触发生（即神经变性）。三个 HSA21 染色体之一的沉默拯救了 DS 表型，但这种治疗方法实际上受到基因组编辑效率和能力的限制专门针对单个 HSA21 染色体。在 NIH INCLUDE 的先前资助下，我们开发了一种新颖的改良 CRISPR 方法，大大增强了 HSA21 上基因组材料的整合，我们还设计了一种方法，通过基于 SNP 的 PAM 专门针对单个 HSA21 副本 gRNA 靶向。可行性已在文化模型系统中得到体现。我们现在提出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 93% 的 HSA21q 蛋白编码基因得到表达并可调节。总的来说，如果这些研究成功的话将显示出至少部分逆转 DS 神经表型的潜在能力。资助的提案是确定 XIST 沉默的效率是否有效的下一步必要的步骤体内的第三个 HSA21 拷贝将转化为可观察到的临床效果。