Antisense Oligonucleotides for Targeting Nonsense-mediated mRNA Decay in Frontotemporal Dementia

反义寡核苷酸用于靶向额颞叶痴呆中无义介导的 mRNA 衰减

• 批准号: 10153636
• 负责人: Andrew D. Nguyen
• 金额: $ 37.88万
• 依托单位: SAINT LOUIS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-01 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10153636
• 关键词: Address; Affect; Antibodies; Antisense Oligonucleotides; Behavioral; Binding; Biological Markers; Brain; C-terminal; Cathepsins; Cell model; Cells; Clinical Trials; Collaborations; Complex; Cysteine; Data; Diagnosis; Disease; Duchenne muscular dystrophy; Exons; Fibroblasts; Frameshift Mutation; Frontotemporal Dementia; Goals; Human; Huntington Disease; Individual; Induced pluripotent stem cell derived neurons; Injections; Intranasal Administration; Knock-in Mouse; Light; Mediating; Messenger RNA; Methods; Modeling; Molecular; Mus; Mutation; Nerve Degeneration; Neurodegenerative Disorders; Nonsense Codon; Nonsense Mutation; Obsessive compulsive behavior; PGRN gene; Pathology; Pathway interactions; Patients; Peptide Hydrolases; Pharmacologic Substance; Phenotype; Proteins; Reporter; Social Dominance; Spinal Muscular Atrophy; Terminator Codon; Testing; Therapeutic; base; behavior test; causal variant; comparative efficacy; design; granulin; improved; in vivo evaluation; insight; mRNA Decay; mouse model; mutant; nervous system disorder; neurofilament; neuropathology; novel therapeutic intervention; pre-clinical; predictive modeling; premature; prevent; protein TDP-43; tool

Project Summary Progranulin is a lysosomal and secreted protein that contains multiple cysteine-rich granulin domains; its precise molecular function remains unknown. Progranulin (GRN) mutations are causal for frontotemporal dementia (FTD), which is a devastating disease with a mean survival of 3.8 years from diagnosis and no cure currently available. Since progranulin-deficient FTD is a disease of haploinsufficiency, strategies aimed at increasing progranulin levels are feasible therapeutic approaches. We recently generated a knock-in mouse model of FTD harboring the common patient nonsense mutation GRNR493X, and we established that the nonsense-mediated mRNA decay (NMD) pathway contributes to the markedly reduced mutant progranulin mRNA levels in this mouse model, as wel`l as in patient-derived fibroblasts containing the GRNR493X mutation. Moreover, our cell-based studies indicate that the progranulin R493X mutant protein is functional when re- expressed in progranulin-deficient cells. Based on these results, we hypothesize that inhibiting NMD-mediated degradation of the mutant GrnR493X mRNA would increase functional progranulin levels and thereby improve FTD-associated behavioral changes and neuropathology. We will test this hypothesis in the following two specific aims: Aim 1) Test in vivo efficacy of ASOs that block NMD-mediated degradation in the GrnR493X knock-in mouse model of FTD, and Aim 2) Design and test ASOs that target NMD-mediated degradation of the human GRNR493X mRNA. Completion of these studies will generate important preclinical data that provide insights into the utility of ASO-based NMD inhibition as a therapeutic approach for progranulin-deficient FTD.

项目总结