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Rapid egg bioreactor construction for Fabry disease therapeutics

用于法布里病治疗的快速鸡蛋生物反应器构建

基本信息

批准号：
10481061
负责人：
Qilong Ying
金额：
$ 25.95万
依托单位：
ATGC, INC.
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-08-08 至 2024-08-07
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10481061
关键词：
Affect Alpha-galactosidase Animals Biological Assay Bioreactors Blastoderm CRISPR/Cas technology Cell Culture Techniques Cell Line Cell Transplantation Cells Chicken Cells Chickens Chimera organism Chimerism Clinical Trials Code Collaborations Color Custom DNA cassette Development Drug Costs Egg White Engineering Enzymes FDA approved Fabry Disease Feathers Female Funding Future Generations Gene Targeting Gene Transfer Techniques Genetic Transcription Genotype Goals Gonadal structure Healthcare Healthcare Systems Heritability Human In Vitro Knock-in Live Birth Lysosomal Storage Diseases Mainstreaming Mammalian Cell Mammalian Oviducts Methods Mus Oryctolagus cuniculus Ovalbumin Patients Pattern Pharmaceutical Preparations Phase Price Process Production Productivity Rattus Recombinant Proteins Recombinants Secure Security Seminal fluid Serum Signal Transduction Structure of primordial sex cell System Therapeutic Tissues Transgenes Transgenic Animals Transgenic Organisms Transplantation United States National Institutes of Health Validation Wolman Disease Work chicken egg clinical development cost cost effective egg embryonic stem cell enzyme replacement therapy genome editing inhibitor male novel novel strategies pre-clinical protein expression stem cells success therapeutic enzyme therapeutic protein trait

项目摘要

Abstract Fabry disease is a lysosomal storage disease (LSD) affecting 1 in 40,000 to 117,000 live births. The current treatment is enzyme replacement therapy (ERT) with recombinant human α-galactosidase A (GalA). A major healthcare burden from this treatment is the high drug cost at $350k per patient-year. To reduce the drug cost for Fabry disease, we propose to develop a rapid approach to construct cost- effective chicken egg bioreactor for GalA production, which has the potential to produce 50 mg recombinant protein per egg for less than $10. Previously, a similar egg bioreactor was developed for another LSD, lysosomal acid lipase (LAL) deficiency. The drug sebelipase alfa for LAL deficiency has been the only FDA- approved therapeutics from transgenic chicken eggs. The traditional blastoderm transgenesis of chicken is limited by its efficiency and thousands of chickens will be screened to obtain a positive clone. Another mainstream approach with primordial germ cells (PGCs) suffers from the fact that PGCs contribute to the germline but not somatic cells, and only generate male G0 chimeras, delaying the assessment of chimerism until six months later when their semen is genotyped. Our novel approach will generate chimeric roosters and hens with both somatic and germline chimerism, which greatly accelerate transgenic chicken construction. In Phase I, we will engineer chicken cell lines with GalA expression cassette knock-in at the highly transcribed OVA locus and construct the chimeric chickens. The chimeric hens will provide eggs for rapid assessment of GalA abundance and activity. This validation will show the feasibility of this approach for the future generation of chicken with heterozygous and homozygous OVA-GalA knock-in.

摘要