June 2023
Volume 64, Issue 8
Open Access
ARVO Annual Meeting Abstract  |   June 2023
Resolution of retinal cysts following subretinal buffer injection in a mouse model of Juvenile X-linked Retinoschisis
Author Affiliations & Notes
  • Jacob Thompson
    Ophthalmology and Visual Sciences, Institute for Vision Research, University of Iowa Hospitals and Clinics, Iowa City, Iowa, United States
  • Ying Hsu
    Ophthalmology and Visual Sciences, Institute for Vision Research, University of Iowa Hospitals and Clinics, Iowa City, Iowa, United States
  • Ella Gehrke
    Ophthalmology and Visual Sciences, Institute for Vision Research, University of Iowa Hospitals and Clinics, Iowa City, Iowa, United States
  • Salma Hassan
    Ophthalmology and Visual Sciences, Institute for Vision Research, University of Iowa Hospitals and Clinics, Iowa City, Iowa, United States
  • Sara Kathryn Mayer
    Ophthalmology and Visual Sciences, Institute for Vision Research, University of Iowa Hospitals and Clinics, Iowa City, Iowa, United States
  • Angela Mahoney
    Ophthalmology and Visual Sciences, Institute for Vision Research, University of Iowa Hospitals and Clinics, Iowa City, Iowa, United States
  • Arlene V Drack
    Ophthalmology and Visual Sciences, Institute for Vision Research, University of Iowa Hospitals and Clinics, Iowa City, Iowa, United States
  • Footnotes
    Commercial Relationships   Jacob Thompson Chakraborty Family Foundation, Code F (Financial Support); Ying Hsu Chakraborty Family Foundation, Code F (Financial Support); Ella Gehrke Chakraborty Family Foundation, Code F (Financial Support); Salma Hassan Chakraborty Family Foundation, Code F (Financial Support); Sara Mayer Chakraborty Family Foundation, Code F (Financial Support); Angela Mahoney Chakraborty Family Foundation, Code F (Financial Support); Arlene Drack Spark Therapeutics, ProQr, Fighting Blindness Canada, Chakraborty Family Foundation, Code F (Financial Support)
  • Footnotes
    Support  Chakraborty Family Foundation and the Ronald Keech Professorship
Investigative Ophthalmology & Visual Science June 2023, Vol.64, 760. doi:
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      Jacob Thompson, Ying Hsu, Ella Gehrke, Salma Hassan, Sara Kathryn Mayer, Angela Mahoney, Arlene V Drack; Resolution of retinal cysts following subretinal buffer injection in a mouse model of Juvenile X-linked Retinoschisis. Invest. Ophthalmol. Vis. Sci. 2023;64(8):760.

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

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Abstract

Purpose : Subretinal gene therapy improves retinal phenotypes in retinoschisin gene knockout mice (Rs1-KO). Some studies suggested improvements in disease phenotype even after sham injections. This study aims to investigate efficacy of subretinal buffer injection in Rs1-KO mice compared to subretinal gene therapy and natural history.

Methods : Subretinal injections of 2μL were performed on Rs1-KO mice with either AAV2/4-Ef1α -RS1 vector, 2E9 vg/mL (n=4), hypertonic (HT) buffer solution 0.001% F68/PBS pH 7.4 (n=10), or isotonic (IT) buffer 0.014% (v/v) Tween/Alcon BSS (n=3). Injections occurred at postnatal day 24-31. Endpoints include electroretinogram (ERG) and optical coherence tomography (OCT). OCT images were scored for severity of schisis using an adapted standardized cyst severity score (1: absent cysts, 2: < 30μm, 3: 30-49μm, 4: 50-69μm, 5: 70-99μm, 6: > 99μm, averaged at 4 points 500μm from optic nerve), and outer nuclear layer (ONL) thickness. Untreated mice as well as fellow eyes were used for comparison (n=10).

Results : Gene therapy vector and HT buffer treated groups tended toward reduced cyst severity scores at 3 weeks post injection (PI) (untreated: 3.150±1.664, HT buffer: 1.25±0.306, vector: 1.438±0.515) and greater ERG amplitudes. The b- to a-wave ratio was improved in the HT buffer treated group (p=0.0054), vector treated group (p=0.0026), and IT buffer treated group (p=0.024) at 1 month PI compared to untreated. Improvements in ERG amplitudes were less notable in those treated with isotonic buffer than hypertonic. 5 month follow up data for the vector and HT buffer groups showed persistent improvement. The degeneration of the ONL was comparable over five months in vector, HT buffer, and untreated groups.

Conclusions : A reduction in schisis severity score was observed in mice receiving either gene therapy or buffer injections along with improvements in ERG amplitudes. We speculate that the resolution of cysts caused the observed partial correction of ERG phenotypes, although these decreases in cyst severity did not prevent photoreceptor cell death. The unexpected improvements observed in buffer-injected mice may be dependent on either the osmolarity of the buffer or the mechanical effect of injection. The resolution of cysts after subretinal delivery of buffer alone emphasizes the need for including sham controls when evaluating gene therapy efficacy for retinoschisis.

This abstract was presented at the 2023 ARVO Annual Meeting, held in New Orleans, LA, April 23-27, 2023.

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