The Landscape of Non-Viral Gene Augmentation Strategies for Inherited Retinal Diseases

Abstract

Inherited retinal diseases (IRDs) are a heterogeneous group of disorders causing progressive loss of vision, affecting approximately one in 1000 people worldwide. Gene augmentation therapy, which typically involves using adeno-associated viral vectors for delivery of healthy gene copies to affected tissues, has shown great promise as a strategy for the treatment of IRDs. However, the use of viruses is associated with several limitations, including harmful immune responses, genome integration, and limited gene carrying capacity. Here, we review the advances in non-viral gene augmentation strategies, such as the use of plasmids with minimal bacterial backbones and scaffold/matrix attachment region (S/MAR) sequences, that have the capability to overcome these weaknesses by accommodating genes of any size and maintaining episomal transgene expression with a lower risk of eliciting an immune response. Low retinal transfection rates remain a limitation, but various strategies, including coupling the DNA with different types of chemical vehicles (nanoparticles) and the use of electrical methods such as iontophoresis and electrotransfection to aid cell entry, have shown promise in preclinical studies. Non-viral gene therapy may offer a safer and effective option for future treatment of IRDs.

Biomaterial‐based gene therapy

“…Gene therapies for eyes have been widely explored as a therapeutic route to target diseases of the cornea, retina, and RPE 268 . Nonviral gene therapy can provide safer and more effective options for treating IRDs 269 . Vicente‐Pascual et al 270 .…”

“…268 Nonviral gene therapy can provide safer and more effective options for treating IRDs. 269 Vicente-Pascual et al 270 used protamine, dextran, and HA and formulated a nonviral vector based on solid LNPs and PVA as a gene delivery system for the induction of IL-10 expression. Eye drops developed in this study may be of use in the treatment of corneal inflammation.…”

Progress in Gene Editing Tools and Their Potential for Correcting Mutations Underlying Hearing and Vision Loss

“…Over the years, different vectors and delivery routes have been tested, and their efficiency validated in the two sense organs (Delmaghani and El-Amraoui, 2020;Sahu et al, 2021;Nyberg et al, 2019;Yu and Wu, 2021;Valentini et al, 2020;Wang et al, 2019; see also Figure 4). Details on viral and non-viral delivery vehicles, routes of administration approaches into the eye and the inner ear can be found in recent reviews (Nyberg et al, 2019;Wang et al, 2019;Delmaghani and El-Amraoui, 2020;Valentini et al, 2020;An and Zha, 2020;Sahu et al, 2021;Yu and Wu, 2021;Toualbi et al, 2021).…”

Efficient workflow for validating homology-independent targeted integration-mediated gene insertion in rod photoreceptor cells to treat dominant-negative mutations causing retinitis pigmentosa

“…Recessive mutations occur when the gene or protein expressed by the mutated gene allele is nonfunctional but does not influence the function of the wild-type (WT) gene allele. In individuals harboring a recessive mutation, gene therapy, also known as replacement therapy, is frequently used to introduce a normal gene from an external source 12 . On the other hand, dominant mutations constitute a type of inheritance (heterozygous) in which a mutation in one of the two alleles precipitates disease development.…”