July 2019
Volume 60, Issue 9
Free
ARVO Annual Meeting Abstract  |   July 2019
Intracorneal AAV Gene Therapy Prevents and Reverses Corneal Clouding in a Mucopolysaccharidosis I Canine Model – Translational Lessons and Promises
Author Affiliations & Notes
  • Keiko Miyadera
    Department of Clinical Sciences & Advanced Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States
  • Courtney Spector
    Department of Clinical Sciences & Advanced Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States
  • Laura Conatser
    Gene Therapy Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States
    Department of Ophthalmology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States
  • Telmo Llanga
    Gene Therapy Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States
    Department of Ophthalmology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States
  • Brian C Gilger
    Department of Clinical Sciences, North Carolina State University, Raleigh, North Carolina, United States
  • Matthew Hirsch
    Gene Therapy Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States
    Department of Ophthalmology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States
  • Footnotes
    Commercial Relationships   Keiko Miyadera, Tamid Bio (F); Courtney Spector, None; Laura Conatser, None; Telmo Llanga, None; Brian Gilger, None; Matthew Hirsch, Tamid Bio (F), Tamid Bio (C), Tamid Bio (P)
  • Footnotes
    Support  MPS1 Research Foundation, National MPS Society, Tamid Bio
Investigative Ophthalmology & Visual Science July 2019, Vol.60, 5201. doi:https://doi.org/
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      Keiko Miyadera, Courtney Spector, Laura Conatser, Telmo Llanga, Brian C Gilger, Matthew Hirsch; Intracorneal AAV Gene Therapy Prevents and Reverses Corneal Clouding in a Mucopolysaccharidosis I Canine Model – Translational Lessons and Promises. Invest. Ophthalmol. Vis. Sci. 2019;60(9):5201. doi: https://doi.org/.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Purpose : Mucopolysaccharidosis I (MPS I) is a lysosomal storage disease caused by mutations in IDUA with an ocular phenotype of corneal clouding, ultimately necessitating corneal transplantation. Hematopoietic stem cell transplantation has proven successful in improving the non-ocular phenotypes. However, it fails to prevent the corneal phenotype. We therefore developed a local augmentation of IDUA via intracorneal AAV gene therapy for proof-of-concept in the naturally-occurring canine model of MPS I.

Methods : Intracorneal AAV injection was performed in 10 MPS I dogs at age 9-13 months (n=4) exhibiting advanced corneal disease with diffuse clouding and vascularization, and at age 4 months (n=6) at the early corneal disease stage with minimal vascularization. One eye was injected with AAV-IDUA and the contralateral control eye with AAV-GFP. Safety and efficacy were assessed by ophthalmic examinations including ultrasound biomicroscopy and anterior segment OCT. The animals were followed for up to 12 months post-injection. Tissues were then collected for immunohistochemistry and biodistribution assays.

Results : Intrastromal AAV injections were well tolerated short term in all the corneas. In the IDUA-treated corneas, clearing of storage was evident as early as 1-week post-injection; extensive vascularization observed in advanced disease was also cleared, while corneas injected at early disease remained vascular free during the follow-up. In contrast, the contralateral control corneas continued to show disease progression with no sign of reversal of prevention of storage disease. While significant treatment effect was observed in all the IDUA-treated corneas, delayed and transient corneal edema was observed in a subset of eyes of both IDUA-treated and control groups. This was successfully managed and reversed with a short course of steroid treatment. Post-mortem histological analyses demonstrated correction of multiple disease indicators that correlated to the presence of IDUA.

Conclusions : A single injection of AAV-IDUA is effective for clearing the corneal storage in MPS I. The primary adverse effect was corneal edema observed in a subset of IDUA-treated and control eyes albeit transient and controllable. The long-term implications of this adverse effect as well as prospects for translational application in patients will be discussed.

This abstract was presented at the 2019 ARVO Annual Meeting, held in Vancouver, Canada, April 28 - May 2, 2019.

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