Lipid nanoparticle technology-mediated therapeutic gene manipulation in the eyes

Abstract

Millions of people worldwide have hereditary genetic disorders, trauma, infectious diseases, or cancer of the eyes, and many of these eye diseases lead to irreversible blindness, which is a major public health burden. The eye is a relatively small and immune-privileged organ. The use of nucleic acid-based drugs to manipulate malfunctioning genes that target the root of ocular diseases is regarded as a therapeutic approach with great promise. However, there are still some challenges for utilizing nucleic acid therapeutics in vivo because of certain unfavorable characteristics, such as instability, biological carrier-dependent cellular uptake, short pharmacokinetic profiles in vivo (RNA), and on-target and off-target side effects (DNA). The development of lipid nanoparticles (LNPs) as gene vehicles is revolutionary progress that has contributed the clinical application of nucleic acid therapeutics. LNPs have the capability to entrap and transport various genetic materials such as small interfering RNA, mRNA, DNA, and gene editing complexes. This opens up avenues for addressing ocular diseases through the suppression of pathogenic genes, the expression of therapeutic proteins, or the correction of genetic defects. Here, we delve into the cutting-edge LNP technology for ocular gene therapy, encompassing formulation designs, preclinical development, and clinical translation.

Keywords: LNP technology; MT: Delivery Strategies; lipid nanoparticles; nucleic acid-based drugs; ocular diseases; ocular gene therapy.

Graphical abstract

Figure 1

Eye structure Diagram of anatomical components (A), physiological barriers (B), and corneal layers (C) in ocular tissues. (B) Schematic representation of four physiological barriers, which include the tear film barrier, corneal barrier, blood-aqueous barrier (BAB), and blood-retinal barrier (BRB). (C) Schematic representation of the corneal layers with additional Bowman’s layer and Descemet’s membrane detailed.

Figure 2

Schematic of representative inherited retinal degeneration or dystrophy and the related gene mutations The schematic on the left illustrates the major IRDs, which include X-linked juvenile retinoschisis (XLRS), LCA10, LCA2, PDE6B-associated retinal pigmentosa (PDE6B-RP), MERTK-associated retinal pigmentosa (MERTK-RP), LCA1, X-linked retinal pigmentosa (XLRP), and Leber hereditary optic neuropathy (LHON). The schematic on the right illustrates the major cell types of the retina and the RPE, including rod and cone PRs, bipolar cells (BCs), horizontal cells (HCs), amacrine cells (ACs), RGCs, and Müller glial cells (MCs). The cell types in the schematic are aligned with the corresponding affected cells in the immunohistochemically labeled retina.

Figure 3

LNP components, assembly and characterization methods Schematic representation of different types of lipid nanocarriers and the common lipids (A) used to assemble them, as well as the manufacturing and characteristic process of LNPs (B).

Figure 4

Mechanisms by which LNPs encapsulate nucleic acids and its life cycles

Figure 5

Schematic representation of gene therapies including gene replacement, gene silencing, and gene editing in the application of ocular disease

Figure 6

Representative research on LNP-based gene therapeutics in ocular diseases (A) Schematic diagram of DSPE-PEG-Trf micelles based on pDNA therapies, which was drawn according to the outline of experiments reported by Lajunen et al. (B) Schematic diagram for mRNA-loaded lipid-based carrier-induced gene therapies, which were drawn according to the outline of experiments reported by Devoldere et al. (C) Schematic of peptides conjugated LNP-mRNA formulation.

Figure 7

Representative research on LNP-based mRNA in ocular diseases and the distribution of delivered mRNA after intravitreal or subretinal injection