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.

Keywords: inherited retinal disease; nanoparticles; non-viral gene therapy; photoreceptors; plasmid DNA; retinal pigment epithelium; transfection.

Figure 1

Retinal non-viral gene therapy. (A) Plasmid DNA vectors are designed to ensure cell-specific, long-lasting, and safe expression of the transgene of interest. (B) Different physical or chemical strategies can be applied to aid DNA transfection in the necessary cells (C) Different routes of administration can be used depending on the gene delivery strategy and the targeted cells. CDS: coding sequence; GCL: ganglion cell layer; INL: inner nuclear layer; ONL: outer nuclear layer; SLNs: solid-lipid nanoparticles; UTMD: ultrasound-targeted microbubble destruction (Created with BioRender.com (accessed on 1 February 2021)).

Figure 2

Key nanoparticles of interest for retinal non-viral gene therapy. Several chemical vehicles have been developed as plasmid DNA carriers, such as nanoparticles based on liposomes, solid lipids, niosomes, polymers, and lipopeptide (Created with BioRender.com (accessed on 1 February 2021)).