Inherited Retinal Disease Therapies Targeting Precursor Messenger Ribonucleic Acid

Abstract

Inherited retinal diseases are an extremely diverse group of genetically and phenotypically heterogeneous conditions characterized by variable maturation of retinal development, impairment of photoreceptor cell function and gradual loss of photoreceptor cells and vision. Significant progress has been made over the last two decades in identifying the many genes implicated in inherited retinal diseases and developing novel therapies to address the underlying genetic defects. Approximately one-quarter of exonic mutations related to human inherited diseases are likely to induce aberrant splicing products, providing opportunities for the development of novel therapeutics that target splicing processes. The feasibility of antisense oligomer mediated splice intervention to treat inherited diseases has been demonstrated in vitro, in vivo and in clinical trials. In this review, we will discuss therapeutic approaches to treat inherited retinal disease, including strategies to correct splicing and modify exon selection at the level of pre-mRNA. The challenges of clinical translation of this class of emerging therapeutics will also be discussed.

Stargardt disease and progress in therapeutic strategies

“…Antisense oligonucleotide (AONs) mediated splice modulation is gaining increasing attention as a strategy to overcome several specific disease-causing mutations. AONs are short (8-50 nucleotide) single-stranded nucleic acids or nucleic acid analogues, complementary to the target sequence, according to the Watson-Crick base pairing principle (162). The use of AONs has been expanded to invoke various mechanisms to modify gene expression at the mRNA level, including 1) induce exon skipping to bypass nonsense mutations and mutations that cause reading frame shift; 2) block cryptic splice sites that are abnormally activated; 3) impede splice silencers located near exons in such a way as to enhance exon recognition (237).…”

“…With the advances in retinal imaging techniques, non-invasive examination and functional assessment allow safe and repeated measurements of disease progression and therapeutic effects. Additionally, the relative isolation of the compartment and modified immune privilege make it possible to maintain effective therapeutic drug concentration, minimize systemic immune exposure and reduce potential toxicity to other organs that are not targeted (162). This section will highlight therapeutics for ABCA4-STGD1 undergoing clinical trials.…”

“…With the broad aim of introducing therapeutic nucleic acids into targeted cells, gene therapy approaches can be classified into (1) gene replacement that introduces a functional copy of the causative gene into affected cells, without addressing the mutation itself and is generally applicable for diseases caused by loss-of-function mutations (194; 2) gene editing utilizes highly specific nucleases to repair the pathogenic mutation in the endogenous affected allele, with the aim of restoring the wild-type DNA sequence and functional protein expression (195; 3) splice modulation that induces alternatively spliced transcripts via administration of antisense oligonucleotides or specialized small molecules. By targeting selected splicing motifs as needed, a disrupted reading frame due to mutations can be restored, or exons carrying disease-causing mutations can be removed during pre-mRNA splicing process, with the aim to generate functional protein (162).…”

A Review of Gene, Drug and Cell-Based Therapies for Usher Syndrome

“…ASO treatment has been widely investigated for retinal disease therapies (Huang et al, 2017 ). Recently, up to nine antisense-oligonucleotide variants were identified for the treatment of Stargardt disease caused by the intronic c.4539 + 2001G >A mutation in the large ABCA4 gene (Garanto et al, 2019 ).…”

Novel Therapeutic Approaches for the Treatment of Retinal Degenerative Diseases: Focus on CRISPR/Cas-Based Gene Editing

“…Furthermore, some promising therapies with small molecules are moving from in vitro studies to clinical trials. In the case of IRDs caused by an aberrant splicing process, antisense oligonucleotides can be used to avoid the recognition of cryptic splice sites and the inclusion of pseudoexons ( Collin et al, 2012 ; Huang et al, 2017 ). For other retinal disorders (e.g., retinitis pigmentosa or Leber congenital amaurosis), a pharmacological approach targeting signaling pathways is being envisioned.…”