June 2022
Volume 63, Issue 7
Open Access
ARVO Annual Meeting Abstract  |   June 2022
Laterally Spreading AAV.SPR-hRS1 Vector for Treatment of XLRS
Author Affiliations & Notes
  • Linda Couto
    Atsena Therapeutics, Durham, North Carolina, United States
  • Dana Elmore
    Atsena Therapeutics, Durham, North Carolina, United States
  • James Peterson
    Division of Cellular and Molecular Therapy, Department of Pediatrics, University of Florida, Gainesville, Florida, United States
  • Hangning Zhang
    Division of Cellular and Molecular Therapy, Department of Pediatrics, University of Florida, Gainesville, Florida, United States
  • Laurence Ocelli
    Charles River Laboratories Inc Mattawan, Mattawan, Michigan, United States
  • Ryan Boyd
    Charles River Laboratories Inc Mattawan, Mattawan, Michigan, United States
  • Lauren Knupp
    Charles River Laboratories Inc Mattawan, Mattawan, Michigan, United States
  • Sanford Boye
    Division of Cellular and Molecular Therapy, Department of Pediatrics, University of Florida, Gainesville, Florida, United States
  • Shannon Boye
    Division of Cellular and Molecular Therapy, Department of Pediatrics, University of Florida, Gainesville, Florida, United States
  • Footnotes
    Commercial Relationships   Linda Couto Mirum Pharmaceuticals, Atsena Therapeutics, Code C (Consultant/Contractor), Atsena Therapeutics, Code E (Employment), Atsena Therapeutics, Code I (Personal Financial Interest); Dana Elmore Atsena Therapeutics, Code E (Employment), Atsena Therapeutics, Code I (Personal Financial Interest); James Peterson None; Hangning Zhang None; Laurence Ocelli None; Ryan Boyd None; Lauren Knupp None; Sanford Boye Atsena Therapeutics, Code C (Consultant/Contractor), Atsena Therapeutics, Code F (Financial Support), Atsena Therapeutics, Code I (Personal Financial Interest), Atsena Therapeutics, Code P (Patent); Shannon Boye Atsena Therapeutics, Code C (Consultant/Contractor), Atsena Therapeutics, Code F (Financial Support), Atsena Therapeutics, Code I (Personal Financial Interest), Atsena Therapeutics, Code P (Patent)
  • Footnotes
    Support  None
Investigative Ophthalmology & Visual Science June 2022, Vol.63, 2825 – A0341. doi:
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    • Get Citation

      Linda Couto, Dana Elmore, James Peterson, Hangning Zhang, Laurence Ocelli, Ryan Boyd, Lauren Knupp, Sanford Boye, Shannon Boye; Laterally Spreading AAV.SPR-hRS1 Vector for Treatment of XLRS. Invest. Ophthalmol. Vis. Sci. 2022;63(7):2825 – A0341.

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

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Abstract

Purpose : The presence of schisis cavities in the central retina has hampered safe and effective delivery of AAV-RS1 to XLRS patients. The novel AAV.SPR capsid laterally spreads well beyond the margins of the subretinal injection (SRI) bleb, providing a means to perform peripheral SRI (without detaching the fovea and avoiding schisis cavities) and effectively deliver RS1 to both the peripheral and central retina. The purpose of this study was to (1) evaluate the efficacy of AAV.SPR-hRS1 in Rs1 knock-out (RS1KO) mice and (2) compare the extent of central retina transduction mediated by AAV.SPR and AAV5 vectors encoding myc-tagged RS1 following peripheral SRI.

Methods : GFP, hRS1 or myc-RS1 were packaged into AAV.SPR and AAV5. RS1KO mice were treated via SRI with 3 different doses of vector, and retinal structure and function were assessed over 6 mo by OCT and ERG, respectively. Cynomolgus macaques were treated via SRI with AAV vectors expressing myc/hRS1 alone or both AAV-GFP and AAV-myc/hRS1. Vectors were delivered in either one or two extrafoveal blebs, and wide field color fundus, cSLO and OCT images were collected for up to 6 wk post-injection. Immunohistochemistry and biodistribution analysis were performed post mortem.

Results : Improvements in both retinal structure (resolution of schisis cavities), and function (scotopic and photopic b-waves) were observed in a dose-dependent manner, and hRS1 expression was observed in PR inner segments of RS1KO mice treated with AAV.SPR-hRS1. GFP and myc/RS1 expression was observed well beyond the bleb margins in NHPs treated with AAV.SPR (but not AAV5) vectors, including the majority of foveal cones, and myc/RS1 expression mimicked that of endogenous NHP RS1. Biodistribution of AAV.SPR compared favorably to AAV5.

Conclusions : A novel AAV vector has been developed for the treatment of XLRS. AAV.SPR delivered therapeutic levels of hRS1 to subretinally injected RS1KO mice, resulting in improvements in both retinal structure and function. In addition, AAV.SPR safely and efficiently mediated hRS1 expression in the central retina of primate eyes following peripheral subretinal injection. Contrary to previous vectors delivered intravitreally, SRI of AAV.SPR represents a safer (avoids surgical manipulation of schisised retina and fovea) and potentially more effective (promotes efficient transduction of photoreceptors) option for the treatment of XLRS.

This abstract was presented at the 2022 ARVO Annual Meeting, held in Denver, CO, May 1-4, 2022, and virtually.

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