Ocular Barriers and Their Influence on Gene Therapy Products Delivery

Abstract

The eye is formed by tissues and cavities that contain liquids whose compositions are highly regulated to ensure their optical properties and their immune and metabolic functions. The integrity of the ocular barriers, composed of different elements that work in a coordinated fashion, is essential to maintain the ocular homeostasis. Specialized junctions between the cells of different tissues have specific features which guarantee sealing properties and selectively control the passage of drugs from the circulation or the outside into the tissues and within the different ocular compartments. Tissues structure also constitute selective obstacles and pathways for various molecules. Specific transporters control the passage of water, ions, and macromolecules, whilst efflux pumps reject and eliminate toxins, metabolites, or drugs. Ocular barriers, thus, limit the bioavailability of gene therapy products in ocular tissues and cells depending on the route chosen for their administration. On the other hand, ocular barriers allow a real local treatment, with limited systemic side-effects. Understanding the different barriers that limit the accessibility of different types of gene therapy products to the different target cells is a prerequisite for the development of efficient gene delivery systems. This review summarizes actual knowledge on the different ocular barriers that limit the penetration and distribution of gene therapy products using different routes of administration, and it provides a general overview of various methods used to bypass the ocular barriers.

Ocular Delivery of Therapeutic Proteins: A Review

“…Collagen fibers from the hydrophilic stroma also limit the penetration of therapeutic proteins, which usually takes place via pinocytosis or endocytosis (active transport mechanism) [ 55 , 56 ]. The tight junctions present in the cornea, sclera, and retina significantly prevent the diffusion of hydrophilic large macromolecules [ 56 , 57 ].…”

“…Collagen fibers from the hydrophilic stroma also limit the penetration of therapeutic proteins, which usually takes place via pinocytosis or endocytosis (active transport mechanism) [ 55 , 56 ]. The tight junctions present in the cornea, sclera, and retina significantly prevent the diffusion of hydrophilic large macromolecules [ 56 , 57 ]. The tight junctions in the conjunctival epithelium are usually wider than those in the corneal epithelium but are still unable to provide penetration of large molecules [ 58 , 59 ].…”

“…Similarly, lipophilicity or hydrophobicity can also be increased by covalent conjugation with hydrophobic moiety or by noncovalent interactions with any hydrophobic compound. Solubility improvements can also be achieved using a conjugation with cyclodextrin and PEG, eliminating enzymatic degradation [ 39 , 40 , 56 , 75 ]. Thus, the pharmacokinetic properties of therapeutic proteins can be optimized, keeping in mind these changes must not affect their biological efficacy.…”

Stimulus-Responsive, Gelatin-Containing Supramolecular Nanofibers as Switchable 3D Microenvironments for Cells

“…However, an increasing number of studies have shown that the behavior of cells on two-dimensional (2D) substrates is distinctly different from that on three-dimensional (3D) ECMs in vivo. Moreover, type I collagen and fibronectin, two major classes of ECM proteins, are fibrous and form “mesh-like” 3D microenvironments [ 5 , 6 , 7 ].…”

Formulation and Evaluation of Polymer‐Based Nanoparticles for Intravitreal Gene‐Delivery Applications

“…This method is less invasive and relatively safe while potentially providing widespread gene transfer throughout the entire retinal surface area (Duncan et al., 2018). One caveat is that a relatively high gene therapy dose would be needed due to the presence of a series of delivery barriers encountered in this administration route, such as the vitreous gel and inner limiting membrane (ILM) (Leclercq, Mejlachowicz, & Behar‐Cohen, 2022; Mains & Wilson, 2013; Zhang & Johnson, 2021a). This aspect is of particular concern for virus‐based gene‐delivery platforms (e.g., AAV) as the necessity of large viral doses creates significant issues of safety, immunogenicity, and economic burden (Timmers et al., 2020).…”