Intrastromal Gene Therapy Prevents and Reverses Advanced Corneal Clouding in a Canine Model of Mucopolysaccharidosis I.

Miyadera, Keiko

Conatser, Laura

Llanga, Telmo A

Carlin, Kendall

O'Donnell, Patricia

Bagel, Jessica

Song, Liujiang

Kurtzberg, Joanne

Samulski, R Jude

Gilger, Brian

Hirsch, Matthew L

2022-03-23T15:31:09Z

2022-03-23T15:31:09Z

2020-06

2022-03-23T15:31:08Z

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.

S1525-0016(20)30185-4

1525-0016

1525-0024

https://hdl.handle.net/10161/24596

eng

Elsevier BV

Molecular therapy : the journal of the American Society of Gene Therapy

10.1016/j.ymthe.2020.04.004

Animals

Animals, Genetically Modified

Dogs

Dependovirus

Corneal Diseases

Mucopolysaccharidosis I

Disease Models, Animal

Iduronidase

Fluorescent Antibody Technique

Treatment Outcome

Gene Transfer Techniques

Gene Expression

Genes, Reporter

Transgenes

Genetic Vectors

Female

Male

Gene Knockdown Techniques

Genetic Therapy

Intrastromal Gene Therapy Prevents and Reverses Advanced Corneal Clouding in a Canine Model of Mucopolysaccharidosis I.

Journal article

Kurtzberg, Joanne|0000-0002-3370-0703

1455

1463

6

Duke

School of Medicine

Clinical Science Departments

Institutes and Centers

Pathology

Pediatrics

Duke Cancer Institute

Institutes and Provost's Academic Units

Initiatives

Duke Innovation & Entrepreneurship

Pediatrics, Transplant and Cellular Therapy

Published

28