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

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.

Structural Differences Across Multiple Visual Cortical Regions in the Absence of Cone Function in Congenital Achromatopsia

“…Using gene therapeutic interventions, such as those well established in Leber’s Congenital Amaurosis, visual and behavioural outcomes have also been variable (for review see: Chiu et al, 2021 ). However, evidence that cortical plasticity is still possible later in life was provided by an fMRI study reporting increased responses in visual cortex following gene therapy when participants with Leber’s Congenital Amaurosis were treated in adulthood ( Mowad et al, 2020 ).…”

Gene Therapy: Recent Advancement and Challenges

“…The function of around 6,000 of the over 20,000 human genes is currently unknown. Furthermore, instead of focusing on the genes themselves, more research can be done on non-coding regions of DNA, which account for roughly 98% of the human genome and hold epigenetic regulators that are responsible for over 90% of susceptibility for common diseases [23]. Altering gene expression by editing a gene regulatory element rather than the genetic mutation itself can be a very useful approach.…”

CRISPR Approaches for the Diagnosis of Human Diseases

“…Since its identification, functional description [6][7][8], and subsequent design to make it programmable and efficient to edit the genome [9], CRISPR/Cas has become a revolution in the biotechnology field. Genome editing, gene therapy, epigenetic regulation, and library construction are only a few of the uses of CRISPR [10][11][12][13]. The fact that nucleic acids are effective biomarkers for many diseases, together with the ability of the CRISPR/Cas system to recognize specific nucleotide sequences, and the discovery of new Cas protein effectors (Class 2, type V; Cas12 and Cas13) has opened the door to new tools that offer cost-effective and portable diagnostics through nucleic acid screening (Figure 1).…”