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Review
. 2021 Apr 26;22(9):4534.
doi: 10.3390/ijms22094534.

An Update on Gene Therapy for Inherited Retinal Dystrophy: Experience in Leber Congenital Amaurosis Clinical Trials

Wei Chiu  1   2 , Ting-Yi Lin  2   3 , Yun-Chia Chang  4 , Henkie Isahwan-Ahmad Mulyadi Lai  2   5 , Shen-Che Lin  1 , Chun Ma  2   6 , Aliaksandr A Yarmishyn  2 , Shiuan-Chen Lin  1   2 , Kao-Jung Chang  1   2   7 , Yu-Bai Chou  1   4 , Chih-Chien Hsu  1   4 , Tai-Chi Lin  2   4 , Shih-Jen Chen  2   4 , Yueh Chien  2   8 , Yi-Ping Yang  2   8   9 , De-Kuang Hwang  2   4
Affiliations
Review

An Update on Gene Therapy for Inherited Retinal Dystrophy: Experience in Leber Congenital Amaurosis Clinical Trials

Wei Chiu et al. Int J Mol Sci. .

Abstract

Inherited retinal dystrophies (IRDs) are a group of rare eye diseases caused by gene mutations that result in the degradation of cone and rod photoreceptors or the retinal pigment epithelium. Retinal degradation progress is often irreversible, with clinical manifestations including color or night blindness, peripheral visual defects and subsequent vision loss. Thus, gene therapies that restore functional retinal proteins by either replenishing unmutated genes or truncating mutated genes are needed. Coincidentally, the eye's accessibility and immune-privileged status along with major advances in gene identification and gene delivery systems heralded gene therapies for IRDs. Among these clinical trials, voretigene neparvovec-rzyl (Luxturna), an adeno-associated virus vector-based gene therapy drug, was approved by the FDA for treating patients with confirmed biallelic RPE65 mutation-associated Leber Congenital Amaurosis (LCA) in 2017. This review includes current IRD gene therapy clinical trials and further summarizes preclinical studies and therapeutic strategies for LCA, including adeno-associated virus-based gene augmentation therapy, 11-cis-retinal replacement, RNA-based antisense oligonucleotide therapy and CRISPR-Cas9 gene-editing therapy. Understanding the gene therapy development for LCA may accelerate and predict the potential hurdles of future therapeutics translation. It may also serve as the template for the research and development of treatment for other IRDs.

Keywords: Leber Congenital Amaurosis; RNA-based antisense oligonucleotide therapy; gene augmentation therapy; gene-editing therapy; inherited retinal dystrophy.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Outline of retinoid metabolism in the visual cycle. The activation of opsin by light triggers a series of conversions starting from 11-cis-retinal to all-trans-retinal. The cycle is completed by recombination of 11-cis-retinal with opsin protein to form the photoactive pigment. IRBP: interphotoreceptor retinoid-binding protein; LRAT: lecithin retinol acyltransferase; RPE65: Retinal pigmented epithelium-specific protein with molecular mass 65 kDa.
Figure 2
Figure 2
Preclinical milestones of establishing the RPE65-based gene therapy.
Figure 3
Figure 3
Overview of Leber Comgenital Amaurosis (LCA) retinal gene therapy. (a) Schematic illustration of subretinal injection and intravitreal injection. (b) Schematic of the retina structure showing the topology of retinal cell types. (c) The most well-established types of gene therapy of LCA include gene augmentation therapy (Luxturna), gene editing therapy (EDIT-101) and RNA antisense nucleotide-based therapy (QR-110). Top panel: gene editing therapy based on AAV-mediated subretinal delivery of CRISPR-Cas9 system that results in excision of intronic IVS26 mutation in the photoreceptor CEP290 gene that causes abnormal splicing and termination of translation due to introduced cryptic exon. Middle panel: therapy based on intravitreal delivery of RNA antisense oligonucleotides targeting intronic mutation if CEP290 gene that causes abnormal splicing. Oligonucleotides act at RNA level directing normal splicing of mutated pre-mRNAs. Bottom panel: gene augmentation aimed to correct the effect of the mutated RPE65 in RPE is based on the delivery of the wild type RPE65 gene by AAV vector to the subretinal area. Thus, normal RPE65 protein is partially restored, resulting in vision function improvement.
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