AAV Gene Therapy for MPS1-associated Corneal Blindness.
Abstract
Although cord blood transplantation has significantly extended the lifespan of mucopolysaccharidosis
type 1 (MPS1) patients, over 95% manifest cornea clouding with about 50% progressing
to blindness. As corneal transplants are met with high rejection rates in MPS1 children,
there remains no treatment to prevent blindness or restore vision in MPS1 children.
Since MPS1 is caused by mutations in idua, which encodes alpha-L-iduronidase, a gene
addition strategy to prevent, and potentially reverse, MPS1-associated corneal blindness
was investigated. Initially, a codon optimized idua cDNA expression cassette (opt-IDUA)
was validated for IDUA production and function following adeno-associated virus (AAV)
vector transduction of MPS1 patient fibroblasts. Then, an AAV serotype evaluation
in human cornea explants identified an AAV8 and 9 chimeric capsid (8G9) as most efficient
for transduction. AAV8G9-opt-IDUA administered to human corneas via intrastromal injection
demonstrated widespread transduction, which included cells that naturally produce
IDUA, and resulted in a >10-fold supraphysiological increase in IDUA activity. No
significant apoptosis related to AAV vectors or IDUA was observed under any conditions
in both human corneas and MPS1 patient fibroblasts. The collective preclinical data
demonstrate safe and efficient IDUA delivery to human corneas, which may prevent and
potentially reverse MPS1-associated cornea blindness.
Type
Journal articleSubject
CorneaCells, Cultured
Fibroblasts
Humans
Dependovirus
Blindness
Corneal Diseases
Mucopolysaccharidosis I
Iduronidase
Green Fluorescent Proteins
Microscopy, Confocal
Blotting, Western
Organ Culture Techniques
Transfection
Apoptosis
Genetic Vectors
HEK293 Cells
Genetic Therapy
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https://hdl.handle.net/10161/24622Published Version (Please cite this version)
10.1038/srep22131Publication Info
Vance, Melisa; Llanga, Telmo; Bennett, Will; Woodard, Kenton; Murlidharan, Giridhar;
Chungfat, Neil; ... Hirsch, Matthew L (2016). AAV Gene Therapy for MPS1-associated Corneal Blindness. Scientific reports, 6(1). pp. 22131. 10.1038/srep22131. Retrieved from https://hdl.handle.net/10161/24622.This is constructed from limited available data and may be imprecise. To cite this
article, please review & use the official citation provided by the journal.
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Show full item recordScholars@Duke
Joanne Kurtzberg
Jerome S. Harris Distinguished Professor of Pediatrics
Dr. Kurtzberg is an internationally renowned expert in pediatric hematology/oncology,
pediatric blood and marrow transplantation, umbilical cord blood banking and transplantation,
and novel applications of cord blood and birthing tissues in the emerging fields of
cellular therapies and regenerative medicine. Dr. Kurtzberg serves as the Director
of the Marcus Center for Cellular Cures (MC3), Director of the Pediatric Transplant
and Cellular Therapy Program, Director of the Carolina
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