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SCGE Disease Models Studies Supplement: Correction of RHO P23H adRP

SCGE 疾病模型研究补充：RHO P23H adRP 的校正

基本信息

批准号：
10619167
负责人：
RANDALL S PRATHER
金额：
$ 49.45万
依托单位：
UNIVERSITY OF MISSOURI-COLUMBIA
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-06-01 至 2024-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10619167
关键词：
Accounting Address Administrative Supplement Alleles Animals Blindness Canis familiaris Cells Clinic Clinical Clinical Trials Complement Cone Data Development Disease Disease Progression Disease model Dose Electroretinography Engineering Eye Family suidae Frequencies Future GRK1 gene Genes Genetic Transcription Genome Genomics Goals Gonadal structure Human Immunohistochemistry Injections Intervention Investigational Therapies Modality Modeling Morphology Mus Mutate Mutation Night Blindness Ophthalmic examination and evaluation Optical Coherence Tomography Organoids Patients Physiological Prevention Proteins Rare Diseases Reagent Research Personnel Retina Retinal Cone Retinitis Pigmentosa Rhodopsin Rod Safety Savings Site Specificity Structure Study models Technology Therapeutic Therapeutic Intervention Time TimeLine Tissues Transgenes Validation Variant Vertebrate Photoreceptors Viral Vision Work adeno-associated viral vector alternative treatment base clinically relevant effectiveness measure efficacy evaluation experimental study genome editing human model humanized mouse in vivo individualized medicine interest mutant next generation sequencing nonhuman primate nuclease participant enrollment pig genome porcine model preclinical evaluation preservation promoter response retinal rods somatic cell gene editing subretinal injection therapeutically effective tool treatment response vector

项目摘要

Project Summary The broad, long-term objective of this work is to establish a rubric to evaluate safety and efficacy of somatic cell genome editing technologies. These goals will be addressed in the context of an experimental therapy for retinitis pigmentosa caused by the RHO P23H variant. The specific aims of this proposal address refinement of the therapeutic window for this therapy, the minimum number of cells that must be edited to save vision, and the general safety of the therapeutic strategy. These aims will be met through the use of AAV5 to deliver an engineered meganuclease that specifically targets the dominant P23H allele while saving the wildtype allele that differs by only one base. This reagent will be evaluated in a validated, rapidly progressing swine model that harbors a human RHO P23H transgene. A previously optimized dose that produces a durable response will be delivered via subretinal injection and the animals will be followed for 32 weeks to repeatedly measure effectiveness over time via clinical eye exam, Full-Field Electroretinogram (ffERG), and Optical Coherence Tomography (OCT). At the end of the experiment, eyes will be examined via immunohistochemistry (IHC) to determine the regional, minimum number of rods that must be edited to save cone function and therefore to save vision. These experiments will be performed at two different stages in disease progression that are hypothesized to represent the last treatable state and the first non-treatable state so that guidance can be provided for criteria of enrollment of patients in a future clinical trial. In parallel, animals will be similarly treated and then sacrificed at two weeks post injection to determine the range of adjacent tissues to which the AAV5 vector will migrate. These animals will also be used to determine the level of editing that occurs in non-intended tissues, including the germline. All animals will be used to obtain data on general physiological response to the therapy.

项目总结