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Intrastromal Gene Therapy Prevents and Reverses Advanced Corneal Clouding in a Canine Model of Mucopolysaccharidosis I
- Source :
- Mol Ther
- Publication Year :
- 2020
- Publisher :
- Elsevier BV, 2020.
-
Abstract
- Mucopolysaccharidosis type I (MPS I) is an autosomal recessive lysosomal storage disease characterized by severe phenotypes, including corneal clouding. MPS I is caused by mutations in alpha-l-iduronidase (IDUA), a ubiquitous enzyme that catalyzes the hydrolysis of glycosaminoglycans. Currently, no treatment exists to address MPS I corneal clouding other than corneal transplantation, which is complicated by a high risk for rejection. Investigation of an adeno-associated virus (AAV) IDUA gene addition strategy targeting the corneal stroma addresses this deficiency. In MPS I canines with early or advanced corneal disease, a single intrastromal AAV8G9-IDUA injection was well tolerated at all administered doses. The eyes with advanced disease demonstrated resolution of corneal clouding as early as 1 week post-injection, followed by sustained corneal transparency until the experimental endpoint of 25 weeks. AAV8G9-IDUA injection in the MPS I canine eye with early corneal disease prevented the development of advanced corneal changes while restoring clarity. Biodistribution studies demonstrated vector genomes in ocular compartments other than the cornea and in some systemic organs; however, a capsid antibody response was detected in only the highest dosed subject. Collectively, the results suggest that intrastromal AAV8G9-IDUA therapy prevents and reverses visual impairment associated with MPS I corneal clouding.
- Subjects :
- Male
Pathology
medicine.medical_specialty
genetic structures
Mucopolysaccharidosis I
medicine.medical_treatment
Genetic enhancement
Genetic Vectors
Fluorescent Antibody Technique
Gene Expression
Corneal Diseases
Animals, Genetically Modified
Glycosaminoglycan
Iduronidase
03 medical and health sciences
Mucopolysaccharidosis type I
Dogs
0302 clinical medicine
Stroma
Genes, Reporter
Cornea
Drug Discovery
Genetics
Lysosomal storage disease
medicine
Animals
Transgenes
Molecular Biology
Corneal transplantation
030304 developmental biology
Pharmacology
0303 health sciences
business.industry
Gene Transfer Techniques
Genetic Therapy
Dependovirus
medicine.disease
eye diseases
Disease Models, Animal
Treatment Outcome
medicine.anatomical_structure
Gene Knockdown Techniques
030220 oncology & carcinogenesis
Molecular Medicine
Original Article
Female
sense organs
business
Subjects
Details
- ISSN :
- 15250016
- Volume :
- 28
- Database :
- OpenAIRE
- Journal :
- Molecular Therapy
- Accession number :
- edsair.doi.dedup.....93abd572904d48271b0ce3491634c7a0