权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

CRISPR gene therapies targeting tau in Alzheimer's disease and tauopathies

针对阿尔茨海默病和 tau 病中 tau 蛋白的 CRISPR 基因疗法

基本信息

批准号：
10752745
负责人：
Todd Jonathan Cohen
金额：
$ 42.41万
依托单位：
UNIV OF NORTH CAROLINA CHAPEL HILL
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-09-01 至 2025-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10752745
关键词：
Alzheimer&apos s Disease Alzheimer&apos s disease brain Alzheimer&apos s disease model Alzheimer&apos s disease patient Alzheimer&apos s disease related dementia Alzheimer&apos s disease therapeutic Antisense Oligonucleotides Biochemical Brain CRISPR/Cas technology Cell Line Clustered Regularly Interspaced Short Palindromic Repeats Cognitive Complex DNA DNA Damage Data Defect Dementia Development Disease Disease Progression Effectiveness Epitopes Flowers Functional disorder Genome Genomic DNA Goals Guide RNA Human Human Cell Line Immunotherapy Impaired cognition In Vitro Injections Lentivirus Libraries MAPT gene Measures Mediating Memory Loss Methods Modality Modeling Mus Nerve Degeneration Nervous System Neurons Onset of illness Pathology Patients Penetrance Penetration Peripheral Pick Disease of the Brain Progressive Supranuclear Palsy Property Protein Isoforms RNA Serotyping Site Specificity Synapses System Tauopathies Technology Testing Therapeutic Time Transcript Validation Variant behavioral study chemical stability corticobasal syndrome efficacy testing gene therapy histological studies improved in vivo innovation interest intravenous injection knock-down mouse model multi-electrode arrays novel preclinical efficacy targeted treatment tau Proteins tau aggregation therapeutic evaluation tool tumorigenesis

项目摘要

PROJECT SUMMARY / ABSTRACT The MAPT gene encoding the tau protein is an ideal target for Alzheimer’s disease (AD) therapeutics since it forms hallmark pathology in all AD patients. In mice, tau aggregation drives disease progression, while depleting tau leads to cognitive improvements, suggesting targeting tau may benefit human patients as well. A major question has been how to achieve this goal. CRISPR technology (Clustered Regularly Interspaced Short Palindromic Repeats) has blossomed in recent years, and we can now leverage this approach to specifically deplete tau in neurons. By targeting different tau isoforms with site-specific guide RNAs of interest, one can conceivably target the specific tau variants that are present in 3R-tauopathies (e.g., Pick’s disease), 4R tauopathies (e.g., corticobasal syndrome), or mixed 3R/4R tauopathies (e.g., AD patients). Thus, we turned to a newly developed CRISPR/Cas13 technology, which allows targeting and depletion of RNA transcripts rather than DNA itself, the latter of which can have unwanted effects on the genome including DNA damage and even tumorigenesis. CRISPR/Cas13 technology could provide new opportunities for therapeutic tau reduction and potentially overcome many of the limitations that have plagued tau depletion strategies. In fact, our preliminary findings show that we can computationally predict which guides will successfully target and deplete tau, and we demonstrated this in a human cell line and primary human neurons, suggesting we have found an optimal pipeline for guide prediction, development, and validation. Therefore, we have an exciting opportunity to develop an effective, non-invasive tool for tau gene therapy in the nervous system (CNS). In Aim-1, we will develop and refine the CRISPR/Cas13 system to target tau and will comprehensively identify the most optimal guide RNAs that target either 3R-tau, 4R-tau, or total tau. We will deliver those guides to neurons and determine their effectiveness and ability to restore normal neuronal function. In Aim-2, we will perform preclinical efficacy testing and determine whether our most optimal CRISPR/Cas13 complexes have therapeutic potential in AD model mice. By delivering tau-targeting guides peripherally using brain-penetrant AAV methods, we will evaluate their therapeutic impact by performing a battery of biochemical, histological, and behavioral studies at either early (preventative) or late (therapeutic) stages of disease progression. This study is innovative and significant since it will both develop the CRISPR technology needed to target tau, and also advance gene therapy approaches to deplete tau in humans including AD and other dementia patients. The clear implications are that targeting and reducing tau levels, even modestly, could provide a new treatment modality for dementia patients.

项目摘要/摘要