Validating the efficacy of GMP-NPCs following subretinal injection into an animal model of retinal degeneration

Abstract

Purpose : Neural progenitor cells (NPCs) are effective in preserving both photoreceptors and visual function after subretinal injection in rodent models of retinal degeneration. These NPCs survived and distributed in the subretinal space without needing to attach to the Bruch’s membrane. The effect is partially due to the NPCs’ ability to phagocytize outer segments of photoreceptors, release pro-survival factors, and activate Nrf2 antioxidant pathway. NPCs are MHC-I low and MHC-II negative, and co-stimulatory molecules CD80, CD86 and CD40 are absent, which means that they have low immunogenicity and can survive long-term after grafting. These features of NPCs make them a good cell choice for preservation therapy for patients with multiple complex genetic or multifactorial retinal degenerative diseases. Here, we validated the efficacy of NPCs produced under GMP conditions (GMP-NPCs) following subretinal injection into a rodent model of retinal degeneration.

Methods : Four doses of GMP-NPCs were administered as a unilateral injection into the subretinal space of the Royal College of Surgeons Rats (RCS) at postnatal day (P) 21-24. Vehicle-injected and untreated rats were used as controls. Visual function was assessed by optokinetic response (OKR), and electroretinography (ERG) at P60 and P90. Retinal lamination and graft distribution were imaged by the optical coherence tomography (OCT). Animals were immunosuppressed by cyclosporine A in the drinking water. Retinas were collected for the histological examination.

Results : GMP-NPCs showed a clear dose response. The dose of the 60,000 cells turned out to be optimal for the preservation of visual function and photoreceptors. Visual function, as tested by OKR and ERG, was significantly preserved in animals receiving the dose of 60,000 cells. Higher cell concentration did not offer extra benefit, and a lower dose had a similar effect as to the controls. Correlating with vision preservation, photoreceptors was also preserved with a dose dependent manner. Also, the optimcal dose offered the best photoreceptor preservation. Grafted NPCs were distributed between the photoreceptors and RPE, and remained as neural progenitors. There was no any signs of tumor formation or unwanted pathology.

Conclusions : Neural progenitor cells have a great potential for treating patients with complex genetic or multifactorial retinal degenerative diseases.

This is an abstract that was submitted for the 2018 ARVO Annual Meeting, held in Honolulu, Hawaii, April 29 - May 3, 2018.