Fabry disease is a lysosomal storage disease (LSD) affecting 1 in 40,000 to 117,000 live births. Thecurrent treatment is enzyme replacement therapy (ERT) with recombinant human α-galactosidase A (GalA). Amajor 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 recombinantprotein 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 chickenswill 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 G0chimeras, delaying the assessment of chimerism until six months later when their semen is genotyped. Ournovel approach will generate chimeric roosters and hens with both somatic and germline chimerism, whichgreatly accelerate transgenic chicken construction. In Phase I, we will engineer chicken cell lines with GalA expression cassette knock-in at the highlytranscribed OVA locus and construct the chimeric chickens. The chimeric hens will provide eggs for rapidassessment of GalA abundance and activity. This validation will show the feasibility of this approach for thefuture generation of chicken with heterozygous and homozygous OVA-GalA knock-in.
Public Health Relevance Statement: Project Narrative
In the present work, we propose to develop a chicken egg bioreactor producing human α-galactosidase
A, an essential enzyme to treat Fabry disease, with our novel rapid transgenic chicken construction approach.
The success of the project will significantly reduce the production cost of this therapeutic enzyme and increase
its supply security and availability and therefore is of great commercial value. The proposed transgenic chickens
also have the potential to produce a wide range of other highly valuable protein therapeutics to lower the burden
of the US healthcare system.
Project Terms: <α-galactosidase>|
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