XLRS Rat with Rs1^-/Y Exon-1-Del Shows Failure of Early Postnatal Outer Retina Development

Area of Science:

• Ophthalmology
• Genetics
• Neuroscience

Background:

• X-linked retinoschisis (XLRS) is a genetic retinal disorder causing vision loss.
• Current animal models do not fully recapitulate the rapid progression and early molecular changes seen in human XLRS.

Purpose of the Study:

• To develop and characterize a novel rat model of XLRS with targeted Rs1 exon-1 deletion.
• To evaluate the pathological retinal phenotype and assess the efficacy of gene therapy in this model.

Main Methods:

• Generated a Long Evans transgenic rat with Rs1 exon-1 deletion (Rs1^-/Y).
• Evaluated retinal pathology, photoreceptor degeneration, and outer limiting membrane integrity.
• Performed electroretinography (ERG) to assess retinal function.
• Administered intravitreal AAV8-RS1 gene therapy at P5-6.

Main Results:

• The Rs1^-/Y rat model exhibited early-onset, rapid photoreceptor degeneration and disrupted outer limiting membrane by P15.
• ERG a-wave and b-wave amplitudes were significantly reduced by P17.
• Microglia and Müller glial activation observed by P7.
• AAV8-RS1 gene therapy at P5-6 induced RS1 expression and partially rescued inner nuclear layer/outer plexiform layer cavity formation and outer retinal structure.
• Observed rapid schisis cavity formation (P7-P15) followed by spontaneous disappearance (P21-P30).
• This rat model shows faster rod cell loss than the equivalent mouse model.

Conclusions:

• The Rs1^-/Y rat is a valuable model for studying XLRS, displaying rapid pathology and early retinal development alterations.
• The model provides insights into the molecular and cellular mechanisms underlying XLRS.
• Early gene therapy intervention shows potential for rescuing structural and functional deficits in XLRS.