June 2021
Volume 62, Issue 8
Open Access
ARVO Annual Meeting Abstract  |   June 2021
Rho 1-2 meganuclease, an allele-specific gene-editing therapy, rejuvenates rod photoreceptor structure and function in a pig model of autosomal dominant Retinitis Pigmentosa (adRP).
Author Affiliations & Notes
  • archana jalligampala
    Ophthalmology and Visual Sciences, University of Louisville School of Medicine, Louisville, Kentucky, United States
  • Jennifer Noel
    Ophthalmology and Visual Sciences, University of Louisville School of Medicine, Louisville, Kentucky, United States
  • James W Fransen
    Ophthalmology and Visual Sciences, University of Louisville School of Medicine, Louisville, Kentucky, United States
  • Wei Wang
    Ophthalmology and Visual Sciences, University of Louisville School of Medicine, Louisville, Kentucky, United States
  • Maha Jabbar
    Ophthalmology and Visual Sciences, University of Louisville School of Medicine, Louisville, Kentucky, United States
  • Nazarul Hasan
    Ophthalmology and Visual Sciences, University of Louisville School of Medicine, Louisville, Kentucky, United States
    Biochemistry and Molecular Genetics, University of Louisville, Louisville, Kentucky, United States
  • Gobinda Pangeni
    Ophthalmology and Visual Sciences, University of Louisville School of Medicine, Louisville, Kentucky, United States
  • Bhubanananda Sahu
    Ophthalmology and Visual Sciences, University of Louisville School of Medicine, Louisville, Kentucky, United States
  • Whitney Lewis
    Precision Biosciences Inc, Durham, North Carolina, United States
  • Jeff Smith
    Precision Biosciences Inc, Durham, North Carolina, United States
  • Victor Bartsevich
    Precision Biosciences Inc, Durham, North Carolina, United States
  • Kristi Viles
    Precision Biosciences Inc, Durham, North Carolina, United States
  • Derek Jantz
    Precision Biosciences Inc, Durham, North Carolina, United States
  • Maureen A McCall
    Ophthalmology and Visual Sciences, University of Louisville School of Medicine, Louisville, Kentucky, United States
    Anatomical Sciences and Neurobiology, University of Louisville School of Medicine, Louisville, Kentucky, United States
  • Footnotes
    Commercial Relationships   archana jalligampala, Precision Biosciences (F); Jennifer Noel, Precision Biosciences (F); James Fransen, Precision Biosciences (F); Wei Wang, Precision Biosciences (F); Maha Jabbar, Precision Biosciences (F); Nazarul Hasan, Precision Biosciences (F); Gobinda Pangeni, Precision Biosciences (F); Bhubanananda Sahu, Precision Biosciences (F); Whitney Lewis, Precision Biosciences (E); Jeff Smith, Precision Biosciences (E); Victor Bartsevich, Precision Biosciences (E); Kristi Viles, Precision Biosciences (E); Derek Jantz, Precision Biosciences (E); Maureen McCall, Precision Biosciences (F), Precision Biosciences (C)
  • Footnotes
    Support  EY026158
Investigative Ophthalmology & Visual Science June 2021, Vol.62, 1478. doi:
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      archana jalligampala, Jennifer Noel, James W Fransen, Wei Wang, Maha Jabbar, Nazarul Hasan, Gobinda Pangeni, Bhubanananda Sahu, Whitney Lewis, Jeff Smith, Victor Bartsevich, Kristi Viles, Derek Jantz, Maureen A McCall; Rho 1-2 meganuclease, an allele-specific gene-editing therapy, rejuvenates rod photoreceptor structure and function in a pig model of autosomal dominant Retinitis Pigmentosa (adRP).. Invest. Ophthalmol. Vis. Sci. 2021;62(8):1478.

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Abstract

Purpose : The P23H mutation in the rhodopsin (RHO) gene represents the most common form of adRP in North America. Elimination of the causative mutant allele, while leaving the wild-type (WT) allele intact should eliminate vision loss in adRP patients. To this end, we studied the efficacy of the engineered Meganuclease, Rho1-2, in the transgenic P23H human rhodopsin (TgP23H) pig model of adRP.

Methods : Rho1-2, packaged in a self-complementary AAV5 vector and driven by the GRK1 photoreceptor-specific promoter was delivered subretinally (40 ul) to one eye of TgP23H piglets postnatally (P3-7,n=23). The fellow eye served as a control and either was uninjected or injected with vehicle. The efficacy of 2x109, 6x109, 2x1010, and 6x1010 vg were compared at regular post injection intervals. Fundus imaging and optical coherence tomography (OCT) assessed retinal structure. Full-field electroretinography (ffERG) assessed rod and cone function (ISCEV protocol). All pigs were assessed through P140 and a subset was assessed through P300. Immunohistochemistry/confocal assessed retinal morphology.

Results : From birth, untreated TgP23H pigs have no rod isolated ffERG response (Fernandez de Castro et al., IOVS, 2014). Regardless of dose, treatment with Rho1-2 was well tolerated, with no signs of an immune response. Treatment with two Rho1-2 doses (2 or 6x1010) produced a significant rod isolated ffERG b-wave response as early as P60 ((~14 uV; p =0.04 and 0.0003) n = 6 and 12 pigs, respectively). Mean b-wave amplitudes increased at P120 (~25-30 uV; p = 0.002, <0.0001 respectively) and were maintained through P300. There is a strong correlation between rod isolated function and rod morphology. Rho1-2 treated Tg P23H rods are more numerous, have elongated outer segments, and correctly localized rhodopsin in contrast to untreated areas in the same retina or in untreated Tg retinas. The ONL measured in OCT and retinal sections was significantly thicker in the treated vs. untreated areas/retinas (p<0.001).

Conclusions : Our results show that Rho1-2 meganuclease effectively rejuvenates rod structure and function in this TgP23H pig model of adRP and this gene therapy is well tolerated. This strongly indicates that Rho1-2 has the potential to effectively treat rod degeneration in P23H adRP patients

This is a 2021 ARVO Annual Meeting abstract.

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