July 2019
Volume 60, Issue 9
Free
ARVO Annual Meeting Abstract  |   July 2019
Preserving functional vision through combined treatment of the retina and brain using genetically modified autologous mesenchymal stem cells in a canine model of CLN2 disease
Author Affiliations & Notes
  • Rebecca Whiting
    Ophthalmology, University of Missouri, Columbia, Missouri, United States
  • Grace Robinson
    Ophthalmology, University of Missouri, Columbia, Missouri, United States
  • Christopher Tracy
    Ophthalmology, University of Missouri, Columbia, Missouri, United States
  • Jacqueline Pearce
    Veterinary Medicine & Surgery, University of Missouri, Columbia, Missouri, United States
  • Juri Ota-Kuroki
    Ophthalmology, University of Missouri, Columbia, Missouri, United States
  • Lauren Gillespie
    Ophthalmology, University of Missouri, Columbia, Missouri, United States
  • Leilani Castaner
    Ophthalmology, University of Missouri, Columbia, Missouri, United States
    Veterinary Medicine & Surgery, University of Missouri, Columbia, Missouri, United States
  • Joan R. Coates
    Veterinary Medicine & Surgery, University of Missouri, Columbia, Missouri, United States
  • Martin L Katz
    Ophthalmology, University of Missouri, Columbia, Missouri, United States
  • Footnotes
    Commercial Relationships   Rebecca Whiting, Patent app. no. 15/125,542 (P); Grace Robinson, None; Christopher Tracy, Patent app. no. 15/125,542 (P); Jacqueline Pearce, Patent app. no. 15/125,542 (P); Juri Ota-Kuroki, None; Lauren Gillespie, None; Leilani Castaner, None; Joan Coates, Patent app. no. 15/125,542 (P); Martin Katz, Patent app. no. 15/125,542 (P)
  • Footnotes
    Support  NIH grant 1R01EY023968; Batten Disease Research Association, Noah’s Hope/Hope 4 Bridget, and Drew’s Hope; Knights Templar Pediatric Eye Foundation; Washington University Institute of Clinical and Translational Science; Mizzou Advantage, University of Missouri
Investigative Ophthalmology & Visual Science July 2019, Vol.60, 4485. doi:
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      Rebecca Whiting, Grace Robinson, Christopher Tracy, Jacqueline Pearce, Juri Ota-Kuroki, Lauren Gillespie, Leilani Castaner, Joan R. Coates, Martin L Katz; Preserving functional vision through combined treatment of the retina and brain using genetically modified autologous mesenchymal stem cells in a canine model of CLN2 disease. Invest. Ophthalmol. Vis. Sci. 2019;60(9):4485.

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

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Abstract

Purpose : A primary sign of CLN2 disease is progressive vision loss due to degeneration of both the retina and visual centers in the brain caused by mutations in CLN2 resulting in deficiencies of the lysosomal enzyme TPP1. Studies are ongoing in a validated canine model of CLN2 to test the hypothesis that combined implantation of TPP1-producing mesenchymal stem cells (MSCs) into the vitreous and into the cerebrospinal fluid (CSF) will inhibit degeneration of the entire visual system and preserve functional vision.

Methods : Autologous MSCs from CLN2-affected dogs were transduced with an AAV2-CAG-TPP1 vector causing them to over-produce and secrete TPP1. TPP1-MSCs were implanted into the lateral ventricles of the brain and the vitreous of one eye prior to the onset of disease signs. The contralateral eye served as the control and was injected with GFP-expressing MSCs. A well-characterized panel of biomarkers was employed monthly to monitor disease progression in treated dogs including electroretinography (ERG), in vivo retinal imaging, and a novel method to assess functional vision in dogs. Results were compared to age-matched data from normal and untreated CLN2-affected dogs.

Results : A single intravitreal injection of TPP1-MSCs resulted in long-term preservation of retinal function and structure. Treated eyes exhibited normal ERG amplitudes for 3 months longer than control eyes, and amplitudes were greater in treated eyes for the entire disease course. Treatment also prevented disease-related development of focal retinal detachment lesions. CSF implantation of TPP1-MSCs was well tolerated with no adverse signs, and preliminary data indicate that the cells survive long term in the CNS. Studies are on-going to achieve significant delay of neurologic deficits with this approach. The functional vision test detected differences between normal control dogs and a CLN2-affected dog, which exhibited progressive loss of visual acuity correlating with progressive decline in retinal function and development of neurologic signs of disease.

Conclusions : Enzyme delivery via genetically modified MSCs implanted in the vitreous and the CSF holds promise for preserving the entire visual pathway to prevent vision loss in CLN2 disease. If successful in the canine model, this approach may be translated to treat children affected by CLN2 disease.

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

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