key: cord-0719408-pzmiwfmd
authors: Kaplan, Henry J.
title: Innovations in retinitis pigmentosa – Metabolic rescue of cones, gene therapy, retinal transplantation
date: 2021-12-09
journal: Taiwan J Ophthalmol
DOI: 10.4103/tjo.tjo_50_21
sha: 21317d88530825eadb415f023cb24e225a6a8b1f
doc_id: 719408
cord_uid: pzmiwfmd

nan

T he December issue of the Taiwan Journal of Ophthalmology expands on the theme introduced in September -management and treatment of inherited retinal dystrophies. Retinitis pigmentosa (RP) is a group of inherited retinal diseases with variable clinical presentations from mild nyctalopia to total blindness. The gene mutations responsible for RP occur overwhelmingly in rod photoreceptors. Although the visual disability from rod dysfunction is significant, it is the subsequent loss of central vision in later life due to cone degeneration that is catastrophic. Until recently, the reason for cone dysfunction in RP was unknown. However, it is now recognized that cones degenerate losing outer segment (OS) synthesis and inner segment disassembly because of glucose starvation. [1, 2] Rod OS phagocytosis by the apical microvilli of retinal pigment epithelium (RPE) is necessary for the transport of glucose from the choriocapillaris to the subretinal space. Although cones lose OS with the onset of rod degeneration in RP, regardless of the gene mutation in rods, cone nuclei remain viable for years (i.e., enter cone dormancy) so that therapies aimed at reversing glucose starvation can prevent and/or recover cone function and central vision. [3] The Metabolic Rescue of Cone Photoreceptors in RP by Kaplan et al. explores these events in more detail.

Rhodopsin (RHO)-mediated autosomaldominant RP is the most common type of hereditary retinal degeneration in North America with a Pro23His (P232H) mutation in RHO the most frequent cause. [4] Multiple approaches are being pursued to correct this genetic defect either involving replacement or editing the mutant gene in rod photoreceptors. In gene therapy for RP by Piri et al., antisense oligonucleotide-based therapy, short hairpin RNA-based therapy, gene editing (CRISPR-Cas, meganuclease), and optogenetics are discussed. Recently, there have been advances in gene therapy for the treatment of Leber congenital amaurosis type 2 (NCT00999609), which is the result of a null mutation or biallelic loss of function in the RPE65 gene. Treatment involves replacement of the null mutation in the RPE through subretinal injection of an adeno-associated virus vector carrying a human RPE65 gene. This resulted in the first and only Food and Drug Administration-approved gene therapy for retinal degeneration to date in the United States (voretigene neparvovec-rzyl: Luxturna). [5] An alternative to metabolic or gene therapy to maintain vision in RP is retinal transplantation. Restoring damaged retinal circuitry by transplanting photoreceptors is an appealing idea. Recent developments in stem cell technology, retinal imaging techniques, tissue engineering, and transplantation techniques have brought us closer to this goal. The recent availability of human embryonic stem cells, induced pluripotent stem cells, and retinal organoids 

Nil.

Two-step reactivation of dormant cones in retinitis pigmentosa

Metabolic deregulation of the blood-outer retinal barrier in retinitis pigmentosa

Restoration of cone photoreceptor function in retinitis pigmentosa

Retinal function and rhodopsin levels in autosomal dominant retinitis pigmentosa with rhodopsin mutations

Efficacy, safety, and durability of voretigene neparvovec-rzyl in RPE65 mutation-associated inherited retinal dystrophy: Results of phase 1 and 3 trials

The authors declare that there are no conflicts of interest of this paper.