Cone function is dependent on rod rescue in a mouse model of Retinitis Pigmentosa gene therapy

Abstract

Purpose : Gene therapy for inherited retinal diseases often fails to halt degeneration, likely due to intervening too late in the course of the disease or by not correcting enough cells. However, it is unclear whether any visual improvement following therapy will be retained by surviving cells for a long period of time. Our goal was to characterize how rod and cone visual transmission is impacted by early (30% rod loss), middle (50% rod loss), and late (70% rod loss) treatment timepoints in a mouse model of Retinitis Pigmentosa up to 6 months following therapy. Retinal function was measured by multielectrode retinal ganglion cell recordings, and useful vision assessed by a vision dependent task: a mouse’s ability to track and capture a cricket.

Methods : We measured responses of retinal ganglion cells (RGCs) to artificial and natural visual stimuli under mesopic and photopic conditions using a mouse model of Cngb1-RP. In this model, rod death is a relatively slow process: rods progressively die until all are lost at 6-7 months. Importantly, this model can undergo genetic correction with tamoxifen, allowing us to measure responses from a model of a perfect gene therapy irrespective of inefficiencies in delivery, virus, or dosage. We measured RGC responses in animals at 1 month intervals following early, mid, or late treatment and compared responses to RGC recordings from WT and untreated mice out to 7 months. The cricket hunting behavior task was performed on treated, untreated, and WT mice by placing a mouse in a transparent recording box and introducing a cricket. Time to capture was compared across groups. Histology was also performed to correlate visual function to retinal structure.

Results : Untreated rods are non-functional in this model, however, gene replacement restored rod transmission at all treatment timepoints and persisted. In mid-treatment timepoints, rod responses increased quickly following therapy, reaching maximal information fidelity 2 months after treatment. Cone function also improved in response to gene replacement, but took >3 months. These responses were true for both cricket capture behavior and electrophysiology.

Conclusions : There is a known dependence of cone survival on rod survival: rod disorders such as Retinitis Pigmentosa also lead to eventual cone loss. However, this is the first instance of cone rescue also being dependent on first restoring rod structure and function.

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