Use of Gene Therapy in Retinal Ganglion Cell Neuroprotection: Current Concepts and Future Directions

Abstract

We systematically reviewed published translational research on gene-based therapy for retinal ganglion cell (RGC) neuroprotection. A search was conducted on Entrez PubMed on 23 December 2020 using the keywords “gene therapy”, “retinal ganglion cell” and “neuroprotection. The initial search yielded 82 relevant articles. After restricting publications to those with full text available and in the English language, and then curating for only original articles on gene-based therapy, the final yield was 18 relevant articles. From the 18 papers, 17 of the papers utilized an adeno-associated viral (AAV) vector for gene therapy encoding specific genes of interest. Specifically, six of the studies utilized an AAV vector encoding brain-derived neurotrophic factor (BDNF), two of the studies utilized an AAV vector encoding erythropoietin (EPO), the remaining 10 papers utilized AAV vectors encoding different genes and one microRNA study. Although the literature shows promising results in both in vivo and in vitro models, there is still a significant way to go before gene-based therapy for RGC neuroprotection can proceed to clinical trials. Namely, the models of injury in many of the studies were more acute in nature, unlike the more progressive and neurodegenerative pathophysiology of diseases, such as glaucoma. The regulation of gene expression is also highly unexplored despite the use of AAV vectors in the majority of the studies reviewed. It is also expected that with the successful launch of messenger ribonucleic acid (mRNA)-based vaccinations in 2020, we will see a shift towards this technology for gene-based therapy in glaucoma neuroprotection.

Glaucoma Heritability: Molecular Mechanisms of Disease

“…For example, in 2020, Wu et al described an application of a gene therapy injectable to disrupt the aquaporin 1 locus in the ciliary body to reduce aqueous humor production and, therefore, reduce IOP to prevent retinal ganglion cell loss [71,72]. Similarly, it has been suggested that gene therapy may be used for retinal ganglion cell neuroprotection [73]. However, to this point, therapies targeted specifically at genes leading to POAG endophenotypes and, therefore, increased risk of POAG have not been identified.…”

Cell-Based Neuroprotection of Retinal Ganglion Cells in Animal Models of Optic Neuropathies

“…However, because of short half-life times and the inability to cross the blood-retina barrier, significant long-term protection was only observed when these proteins were administered locally and continuously [ 14 , 43 , 44 ]. While a virus-mediated gene transfer of NTFs is the most frequently used delivery strategy, other strategies have also been successfully employed, such as a non-viral gene transfer or intraocular implantations of NTF-loaded slow-release devices [ 14 , 32 , 42 , 44 , 117 , 118 ]. Intraocular transplantations of cells genetically modified to overexpress NTFs represent another strategy to continuously administer NTFs to dystrophic retinas ( Table 1 ).…”

“…Diverse treatment strategies are being tested for their efficacy tin rescuing RGCs from cell death, such as dietary modifications, electrical stimulation therapy, immunomodulatory strategies or gene therapy [ 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 ]. At late stages of the disease, the only treatment option is a functional replacement of the lost RGCs.…”

Topical Administration of a Nanoformulation of Chitosan-Hyaluronic Acid-Epoetin Beta in a Rat Model of Glaucoma

“…The principal risk factor is high intraocular pressure (IOP), and current glaucoma therapy is focused on managing it by increasing aqueous humor outflow and decreasing its production, in an attempt to delay the disease’s progression [ 2 ]. However, research in ophthalmology is shifting towards neuroprotection as a complementary approach to glaucoma treatment, and several neuroprotective strategies are under study, such as the use of progesterone, neurotrophic factors [ 3 ], asiatic acid [ 4 ], and gene therapy [ 5 ].…”