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Correction of Neurological Disease via Allele Specific Excision of Pathogenic Repeats

通过等位基因特异性切除致病重复序列来纠正神经系统疾病

基本信息

批准号：
10668665
负责人：
JENNIFER A DOUDNA
金额：
$ 468.35万
依托单位：
UNIVERSITY OF CALIFORNIA BERKELEY
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：
2023-05-15 至 2028-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10668665
关键词：
Alleles Amyotrophic Lateral Sclerosis Animal Model Animals Behavior Biodistribution Biological Assay Biotechnology C9ALS C9ORF72 CRISPR/Cas technology Cells Clinical Clustered Regularly Interspaced Short Palindromic Repeats Collaborations Convection Dedications Dependovirus Development Disease Disease model Dose Engineering Excision Feedback Fibroblasts Formulation Genes Genetic Guide RNA Haplotypes Heterozygote Histologic Human Huntington Disease In Vitro Induced pluripotent stem cell derived neurons Injections Investigational Therapies Lead Mendelian disorder Modeling Molecular Mus Mutation Nerve Degeneration Neurodegenerative Disorders Neurons Nucleotides Outcome Pathogenicity Patients Pharmacology Pharmacology and Toxicology Phenotype Preparation Process Production Property Rattus Reagent Research Research Personnel Research Project Grants Resources Ribonucleoproteins Rodent Model Route Serotyping Side Sum System Technology Testing Therapeutic Therapeutic Index Toxic effect Toxicology Transfection Triplet Multiple Birth Viral Virus Work animal tissue brain parenchyma brain tissue brain volume cell transformation design efficacy evaluation efficacy study experience genome editing improved in vivo innovation knock-down lead candidate manufacture mortality mouse model mutant nervous system disorder nonhuman primate novel peptide amphiphiles postmitotic pre-clinical prevent programs response screening synergism therapeutic genome editing tool

项目摘要

PROJECT SUMMARY / ABSTRACT A central promise of genome editing is its potential to treat monogenic disease. Despite early-stage clinical progress for CRISPR-Cas based approaches, monogenic neurodegenerative conditions and nucleotide triplet expansion disorders have not been a focus of any biotechnology company in this space. Our proposal brings together a team of academic investigators to develop a synergistic suite of first-in-class CRISPR-Cas based therapeutics for Huntington's disease (HD) and C9ORF72 amyotrophic lateral sclerosis (ALS). We will engineer and deploy an editing approach that excises, with IND-grade potency and mutant allele-selectivity, the disease- causing expansion repeat from human HTT and C9ORF72 loci, respectively. Our strategy is based on identifying alleles of commonly heterozygous SNPs that reside on the same haplotype as the disease-causing repeat expansion, and then engineering CRISPR-Cas9 for high selectivity of cleavage, on one or both sides of the mutant allele repeat, to drive its excision, with two tiers of delivery innovation. Our trailblazer project (Research Project 1, RP1) will develop an HD therapeutic by packaging mutant HTT-specific CRISPR-Cas9 into a newly developed serotype of adeno-associated virus (AAV) with robust and broad biodistribution in the brain parenchyma of nonhuman primates (NHP). We will implement an innovative strategy in which the CRISPR-Cas9 cassette temporally limits its own expression. We will identify and advance the preclinical lead composition through IND-enabling studies leveraging 3 dedicated Resource Cores to (i) assess molecular outcomes at the genetic level, (ii) administer reagents to animals and observe their behavior, and (iii) assess molecular and histological outcomes from cells and animal tissues. An Administrative Core led by experienced developers of genome editing-based therapeutics, will provide project-management support and lead on preparation of regulatory submissions, aiming to file an HD IND by program end. In RP2, we will apply the AAV-based excision approach to build a cognate experimental therapeutic for C9ORF72-driven ALS. Synergies with RP1 include CMC innovation to manufacture novel AAV, re-use of the self-regulating CRISPR-Cas cassette and virus harboring it, and regulatory feedback on IND-enabling pharmacology, toxicology, and biodistribution studies. We will advance RP2 through pre-IND. For RP3, we will establish a first-in-class, transformative paradigm for in vivo genome editing therapy by reformulating the preclinical lead CRISPR-Cas9 combination used in RP1 into a highly innovative “Cas9 RNP monoparticle” in which amphiphilic peptides deliver the gene editor to neurons upon injection. We will develop approaches for monoparticle manufacture to enable ex vivo and in vivo efficacy studies in HD models. Extensive synergies with RP1 project and comprehensive support by the RCs will enable us to advance this approach to pre-IND by program end. The sum total of this effort will establish a fundamentally new paradigm for in vivo genome editing applicable to all nucleotide repeat expansion disorders, and advance preclinical lead formulations for one disease, HD, to IND, and another such disease, C9ORF ALS, to pre-IND.

项目摘要/摘要