Rescue of Defective Electroretinographic Responses in Dp71-Null Mice With AAV-Mediated Reexpression of Dp71

Overview

Journal Invest Ophthalmol Vis Sci

Specialty Ophthalmology

Date 2020 Feb 13

PMID 32049345

Citations 6

Authors

Mirella Telles Salgueiro Barboni

Cyrille Vaillend

Anneka Joachimsthaler

Andre Mauricio Passos Liber

Hanen Khabou

Michel J Roux

Ophelie Vacca

Lucile Vignaud

Deniz Dalkara

Xavier Guillonneau

Dora Fix Ventura

Alvaro Rendon

Jan Kremers

Affiliations

Soon will be listed here.

Abstract

Purpose: To study the potential effect of a gene therapy, designed to rescue the expression of dystrophin Dp71 in the retinas of Dp71-null mice, on retinal physiology.

Methods: We recorded electroretinograms (ERGs) in Dp71-null and wild-type littermate mice. In dark-adapted eyes, responses to flashes of several strengths were measured. In addition, flash responses on a 25-candela/square meters background were measured. On- and Off-mediated responses to sawtooth stimuli and responses to photopic sine-wave modulation (3-30 Hz) were also recorded. After establishing the ERG phenotype, the ShH10-GFP adeno-associated virus (AAV), which has been previously shown to target specifically Müller glial cells (MGCs), was delivered intravitreously with or without (sham therapy) the Dp71 coding sequence under control of a CBA promoter. ERG recordings were repeated three months after treatment. Real-time quantitative PCR and Western blotting analyses were performed in order to quantify Dp71 expression in the retinas.

Results: Dp71-null mice displayed reduced b-waves in dark- and light-adapted flash ERGs and smaller response amplitudes to photopic rapid-on sawtooth modulation and to sine-wave stimuli. Three months after intravitreal injections of the ShH10-GFP-2A-Dp71 AAV vector, ERG responses were completely recovered in treated eyes of Dp71-null mice. The functional rescue was associated with an overexpression of Dp71 in treated retinas.

Conclusions: The present results show successful functional recovery accompanying the reexpression of Dp71. In addition, this experimental model sheds light on MGCs influencing ERG components, since previous reports showed that aquaporin 4 and Kir4.1 channels were mislocated in MGCs of Dp71-null mice, while their distribution could be normalized following intravitreal delivery of the same ShH10-GFP-2A-Dp71 vector.

Citing Articles

AAV-Mediated Restoration of Dystrophin-Dp71 in the Brain of Dp71-Null Mice: Molecular, Cellular and Behavioral Outcomes.

Vacca O, Zarrouki F, Izabelle C, Belmaati Cherkaoui M, Rendon A, Dalkara D Cells. 2024; 13(8.

PMID: 38667332 PMC: 11049308. DOI: 10.3390/cells13080718.

Platelet-activating factor receptor (PAFR) regulates neuronal maturation and synaptic transmission during postnatal retinal development.

Dalmaso B, Liber A, Ventura D, Jancar S, Del Debbio C Front Cell Neurosci. 2024; 18:1343745.

PMID: 38572071 PMC: 10988781. DOI: 10.3389/fncel.2024.1343745.

Assessment of the uniform field electroretinogram for mouse retinal ganglion cell functional analysis.

Lagali P, Shanmugalingam U, Baker A, Mezey N, Smith P, Coupland S Doc Ophthalmol. 2023; 147(1):29-43.

PMID: 37106219 DOI: 10.1007/s10633-023-09933-y.

Effects of fixed cutoff filtering on dark- and light-adapted ERG components and the application of variable cutoff filter.

Gao M, Barboni M, Ventura D, Nagy B Doc Ophthalmol. 2021; 144(3):191-202.

PMID: 34559355 PMC: 9192464. DOI: 10.1007/s10633-021-09853-9.

Correlations Between Dark-Adapted Rod Threshold Elevations and ERG Response Deficits in Duchenne Muscular Dystrophy.

Barboni M, Dias S, Silva L, Damico F, Vidal K, Costa M Invest Ophthalmol Vis Sci. 2021; 62(4):29.

PMID: 33891680 PMC: 8083068. DOI: 10.1167/iovs.62.4.29.

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