Generation of a Large Animal Model of Sialidosis to Enable Future Translation of Novel Therapeutics

生成唾液酸贮积症的大型动物模型，以实现新疗法的未来转化

• 批准号: 10578286
• 负责人: Heather L Gray-Edwards
• 金额: $ 50.56万
• 依托单位: UNIV OF MASSACHUSETTS MED SCH WORCESTER
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-01-01 至 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10578286
• 关键词: Adolescent; Advanced Development; Animal Model; Animals; Ataxia; Attenuated; Autopsy; Biochemical; Biological Assay; Biological Markers; Blindness; Breeding; CRISPR/Cas technology; Cells; Cessation of life; Chemistry; Childhood; Clinic; Clinical; Clinical Trials; Clustered Regularly Interspaced Short Palindromic Repeats; Collaborations; Complete Blood Count; Data; Data Set; Databases; Dependovirus; Development; Developmental Delay Disorders; Disease; Dose; Electroencephalography; Electroporation; Embryo; Ensure; Enzymes; Evaluation; Exhibits; Felis catus; Fibroblasts; Functional Magnetic Resonance Imaging; Future; Gangliosidosis GM1; Generations; Genes; Genetic; Genetic Diseases; Germ Lines; Glycopeptides; Goals; Guide RNA; Heterozygote; Histopathology; Human; Image; Implant; Learning; Life; Lipomucopolysaccharidoses; Lysosomal Storage Diseases; Magnetic Resonance Imaging; Medical; Modeling; Mus; Mutation; Mutation Analysis; Myoclonus; National Human Genome Research Institute; Natural History; Neuraminidase; Neurodegenerative Disorders; Neurologic; Neurologic Examination; Oligosaccharides; Organ; Outcome Measure; Pathogenesis; Pathologic; Patients; Peripheral; Persons; Phenotype; Physical Examination; Physicians; Point Mutation; Research; Ribonucleoproteins; Route; Sampling; Sandhoff Disease; Seizures; Serum; Sheep; Sialic Acids; Standardization; Tay-Sachs Disease; Technology; Testing; Therapeutic; Translating; Translational Research; Translations; United States National Institutes of Health; Validation; Veterinarians; Viral Genes; access restrictions; clinical trial implementation; clinically relevant; cognitive testing; disease phenotype; enzyme activity; experience; experimental study; falls; fetal; first-in-human; gene therapy; genome editing; human data; human model; infancy; loss of function; mouse model; nervous system disorder; novel therapeutics; pre-clinical; preservation; prime editing; programs; rapid testing; research clinical testing; sheep model; sialylation; somatic cell nuclear transfer; success; therapeutic development; therapeutic evaluation; treatment strategy; trial design

Project Summary Sialidosis is a rare, fatal, neurological disorder caused by a mutation in the NEU1 gene resulting in vision loss, seizures, involuntary myoclonus, and ataxia. Our team has a strong track record in brining gene therapies to the clinic and has plans to develop a gene therapy to treat sialidosis. Our previous experience has shown that testing in large animal models of human genetic diseases better approximates what will happen and patients and use of these models increases the likelihood of efficacy. We have developed a founder sheep with a mutation like type 1 sialidosis patients and will breed him to generate a colony of animals. Since the last submission we have created several severe mutations using CRISPR/spCas9 editing, therefore in this aim we will use Prime genome editing of embryos, to recreate two human mutations (Type 1 and Type 2) with the end goal of a mutation that recapitulates the human condition (Aim 1). We will evaluate each model for its ability to reliably mimic sialidosis then select the best model (Aim 2). This phenotyping includes in-life clinical metrics like MRI, EEG, EMG, neurological and cognitive testing as well as in depth post-mortem assays to determine if it reproduces biochemical and histopathological aspects of disease. External evaluation of in-life clinical testing will be performed by our clinical collaborator Dr. Tifft. Additionally, Dr. Tifft will make human samples available for comparison with the new sheep model. The biochemical aspects of disease will be externally validated by by Dr. d’Azzo (the leader in field of sialidosis) and pathological features characterized by Dr. Koehler a veterinary neuropathologist. After completion of these studies, this fully validated model will be used to learn more about sialidosis as a disorder, and also used in the development of an adeno associated viral gene therapy or other future treatment strategies for sialidosis.

项目总结