The Ocular Gene Delivery Landscape

Abstract

The eye is at the forefront of developing therapies for genetic diseases. With the FDA approval of the first gene-therapy drug for a form of congenital blindness, numerous studies have been initiated to develop gene therapies for other forms of eye diseases. These examinations have revealed new information about the benefits as well as restrictions to using drug-delivery routes to the different parts of the eye. In this article, we will discuss a brief history of gene therapy and its importance to the eye and ocular delivery landscape that is currently being investigated, and provide insights into their advantages and disadvantages. Efficient delivery routes and vehicle are crucial for an effective, safe, and longer-lasting therapy.

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

“…Over the past years, increasing efforts have been focused to develop treatment solutions to restore normal gene function by gene therapy in vision and hearing disorders (Delmaghani and El-Amraoui, 2020;Kleinlogel et al, 2020;Omichi et al, 2020;Maguire et al, 2021;Sahu et al, 2021). The first applications of gene therapy were focused on gene replacement (or gene supplementation) therapy where a healthy copy of a defective gene is brought into the cells bearing the mutation using viral vectors.…”

“…For all viral and non-viral gene therapies, the specific delivery to ocular or auditory target cells requires appropriate use of vectors and routes of administration to ensure safety, efficacy and specificity (Nyberg et al, 2019;Yu and Wu, 2021;Sahu et al, 2021). Here below, we detail cell-specific delivery attempts for auditory and ocular disorders.…”

“…The eye and ear are particularly suitable organs for a wide range of therapeutic interventions because: 1) there is a minimal risk of therapeutic agents diffusing to unwanted tissues or organs upon local delivery, due to the confined environment of the compartments concerned, 2) these organs have a fluidic composition, favoring dissemination to target cell; and 3) the two organs are unique zones of immune privilege, thanks to a blood-organ barriers impeding movement of cells and molecules into and out of the sensory epithelia (Bucher et al, 2020). 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).…”

“…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).…”

“…The capsid serotype and promoter in front of the transgene are key parameters determining expression in a given cell type. Novel AAV capsids, and cis-regulatory elements (such as short promoters, enhancers, polyadenylation sequences) are being continuously improved to further expand the utility of AAV mediated gene therapy in ocular and auditory disorders (Planul and Dalkara, 2017; Sahu et al, 2021). One note-worthy method for improving capsid proteins has been directed evolution generating optimized AAV capsids for specific gene therapy applications (Zinn et al, 2015;Byrne et al, 2020).…”