June 2020
Volume 61, Issue 7
Free
ARVO Annual Meeting Abstract  |   June 2020
Preclinical efficacy of AAV5-Nr2e3 in the mouse model of Nr2e3 mutation associated inherited retinal degeneration
Author Affiliations & Notes
  • Arun Kumar Upadhyay
    R&D, Ocugen, Inc., Malvern, Pennsylvania, United States
  • Shyamtanu Datta
    Department of Ophthalmology, Schepens Eye Research Institute, Massachusetts Eye and Ear, Massachusetts, United States
  • Emily Brabbit
    Department of Ophthalmology, Schepens Eye Research Institute, Massachusetts Eye and Ear, Massachusetts, United States
  • Zoe Love
    Department of Ophthalmology, Schepens Eye Research Institute, Massachusetts Eye and Ear, Massachusetts, United States
  • Neena B Haider
    Department of Ophthalmology, Schepens Eye Research Institute, Massachusetts Eye and Ear, Massachusetts, United States
  • Rasappa Arumugham
    R&D, Ocugen, Inc., Malvern, Pennsylvania, United States
  • Footnotes
    Commercial Relationships   Arun Upadhyay, Ocugen, Inc. (E), Ocugen, Inc. (P); Shyamtanu Datta, None; Emily Brabbit, None; Zoe Love, None; Neena Haider, Ocugen, Inc. (F), Ocugen, Inc. (C), Ocugen, Inc. (P); Rasappa Arumugham, Ocugen, Inc. (E), Ocugen, Inc. (P)
  • Footnotes
    Support  None
Investigative Ophthalmology & Visual Science June 2020, Vol.61, 4466. doi:
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      Arun Kumar Upadhyay, Shyamtanu Datta, Emily Brabbit, Zoe Love, Neena B Haider, Rasappa Arumugham; Preclinical efficacy of AAV5-Nr2e3 in the mouse model of Nr2e3 mutation associated inherited retinal degeneration. Invest. Ophthalmol. Vis. Sci. 2020;61(7):4466.

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

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Abstract

Purpose : The purpose of this study is to develop a road map for IND studies leading to phase 1/2a clinical trial of Nr2e3 associated retinal disease. Inherited retinal degenerations are caused by mutations in over 100 genes. Mutations in the nuclear receptor gene, NR2E3, have been identified in patients with enhanced S-cone syndrome (ESCS), Goldman-Favre syndrome (GFS), clumped pigmentary retinopathy, and retinitis pigmentosa. We developed a modifier gene therapy platform technology where the nuclear hormone receptor gene NR2E3 can be used as a therapeutic to improve retinal degeneration in multiple inherited retinal degenerative diseases. Here, we evaluated the efficacy of AAV5-Nr2e3 in an animal model.

Methods : Nr2e3 plasmid construct was designed for optimal expression and packaged in AAV5 vector. AAV5-Nr2e3 (1x109gc/0.5μl/eye) was delivered subretinal or intravitreally into the eye of retinal degeneration 7 (rd7) mice, which lack a functional Nr2e3 gene, at P30 and P90 (N≥5). One-month post injection, fundus and optical coherence tomography (OCT) were performed using the Micron III Retinal Imaging Microscope (Phoenix Research Laboratories) and Bioptigen OCT respectively. Animals were subsequently euthanized, and eyes were enucleated for histology to evaluate retinal structure; and immunochemistry to evaluate expression of photoreceptor specific opsins.

Results : rd7 mice exhibit pan retinal spotting, whorls and rosettes in the photoreceptor layer due to an extra number of blue opsin expressing cone cells at eye opening, followed by progressive degeneration of rod and cone photoreceptor cells. AAV5-Nr2e3 delivery to rd7 mice through intravitreal and subretinal routes was effective in reversing the retinal spotting and restored the normal levels of opsin proteins. OCT and histological examination of AAV5-Nr2e3 treated retina animals showed restoration of normal retinal cell layer structure and preservation of photoreceptors compared to control animals.

Conclusions : Nr2e3 plays a major role in the development and maintenance of a healthy retina and inhibits the progression of photoreceptors degeneration in rd7 mice, an animal model for human NR2E3-associated retinal disease. Based on these results, Ocugen has developed a road map to initiate phase1/2a clinical evaluation in human patients.

This is a 2020 ARVO Annual Meeting abstract.

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