Inherited retinal diseases (IRDs) naturally emerge as prime candidates for gene therapy. So far, there have been no effective treatment options for these blinding disorders, which significantly reduce patients’ quality of life and constitute a major socioeconomic burden (Ng et al. 2024). Additionally, many of these conditions are caused by mutations in a single gene, and these genetic defects have been identified. The research in this area, which is very extensive and exceeds the scope of this article, has been summarized in comprehensive reviews (Hu et al. 2021; Georgiou et al. 2021; Chiu et al. 2021; Brar et al. 2024). While the majority of ocular gene therapy research focuses on IRDs, the potential for treating other eye diseases is equally promising and exciting.

Glaucoma is the main cause of blindness in industrialized countries due to progressive optic neuropathy, commonly associated with elevated IOP. Unfortunately, current treatments that focus on lowering IOP are often unsuccessful or insufficient. Gene therapy offers several innovative approaches. Firstly, reducing IOP by decreasing aqueous humor production or enhancing outflow via genetic modulation may prove more effective than using currently available pharmaceuticals. Secondly, gene therapy strategies that provide neuroprotection for retinal ganglion cells (RGCs) could be particularly beneficial for patients who experience disease progression despite controlled IOP (Moreno-Montañés et al. 2014; Sulak et al. 2024).

Three gene therapy products targeting glaucoma have reached clinical trials. The first, bamosiran (SYL040012), is an siRNA molecule that inhibits the synthesis of the β2-adrenergic receptor when administered topically, leading to a significant reduction in IOP. Bamosiran (SYL040012) shows a good tolerability and safety profile (Moreno-Montañés et al. 2014; Gonzalez et al. 2016). The second, QPI-1007, delivered through a single intravitreal injection, is an siRNA that inhibits the pro-apoptotic protein caspase-2, therefore preventing RGC death. The results of this clinical trial have not been reported (Jiang et al. 2021).

In June 2024, a clinical trial began evaluating CRISPR/Cas9 instantaneous gene editing therapy in patients with primary open-angle glaucoma (POAG) who have elevated IOP and a myocilin (MYOC) gene mutation (ClinicalTrials.gov: NCT06465537). MYOC gene mutations, associated with approximately 4% of adult-onset POAG cases and over 10% of juvenile-onset cases, cause toxic myocilin accumulation in trabecular meshwork cells, impairing aqueous humor outflow and raising IOP (Kwon et al. 2009).

Previous studies in a POAG mouse model using an adenovirus carrying CRISPR (Ad5-crMYOC) administered through intravitreous injection, successfully disrupted the MYOC gene and its aberrant function, lowered IOP, and protected against further glaucomatous changes (Jain et al. 2017). The ongoing clinical trial will assess a similar system—CRISPR/Cas9 Instantaneous Gene Editing Therapy (BD113 virus-like particle)—for its safety, tolerability, and preliminary efficacy in POAG patients with MYOC mutations. Participants will receive a single intracameral injection, with follow-up evaluations over 1 year (ClinicalTrials.gov: NCT06465537).

AMD is a leading cause of severe vision loss globally, with its prevalence expected to rise in the coming years. The disease exists in two forms: neovascular AMD (nAMD) and dry AMD. Intravitreal injections of anti-VEGF agents are the standard treatment for nAMD, but despite the significant improvements these therapies offer, they are not without drawbacks.

Frequent clinic visits and repeated intravitreal injections place a substantial burden on patients and healthcare systems, in addition to increasing the risk of adverse events. Additionally, some patients show limited response to treatment (Blasiak et al. 2024; Rowe and Ciulla 2024). Numerous clinical trials are investigating gene therapy for nAMD. While these therapies continue to target VEGF, they aim to improve treatment response and maintain visual gains through prolonged expression, thereby reducing the frequency of treatments and easing patient burden. These options could become available in the near future, thanks to ongoing research and advanced trials (Trincão-Marques et al. 2024; Blasiak et al. 2024; Rowe and Ciulla 2024).

Dry AMD is characterized by RPE dysfunction, photoreceptor loss, and retinal degeneration, with the late stage known as geographic atrophy (GA) (Schultz et al. 2021). Pathways involving the complement system, oxidative stress, and lipid metabolism are implicated in AMD pathogenesis. The first treatments, recently approved in 2023, include pegcetacoplan and avacincaptad pegol, which inhibit the complement cascade via regular intravitreal injections. However, these treatments are limited and insufficient as they have not consistently demonstrated significant improvement in visual acuity, require frequent invasive administrations, and carry potential safety risks and side effects, including the risk of conversion to the neovascular form of the disease (Trincão-Marques et al. 2024; Rowe and Ciulla 2024).

JNJ-1887, delivered intravitreally, uses an AAV2 vector to increase the expression of a soluble form of CD59, an anti-inflammatory protein in the complement pathway, which is under-expressed in retinal cells in the course of GA (Trincão-Marques et al. 2024; Heier et al. 2024; Rowe and Ciulla 2024). OCU410, based on AAV delivery of the RORA gene via subretinal injection, addresses both lipid metabolism (reducing lipofuscin deposits and oxidative stress) and the complement system (providing anti-inflammatory effects) (Rowe and Ciulla 2024). GT-005, also delivered subretinally, induces the expression of complement factor I, a natural inhibitor of the complement system, using an AAV2 vector (Trincão-Marques et al. 2024).

Non-infectious uveitis is primarily treated with corticosteroids, though systemic immunomodulatory therapy, including TNF inhibitors, may be necessary in some cases. A strategy for local administration could achieve therapeutic effects while minimizing the risk of adverse events. A novel gene therapy approach for non-infectious uveitis involves the use of a clinical-grade plasmid DNA, pEYS606, which encodes a fusion protein with high affinity for human TNF-α. This DNA is transduced into ciliary muscle cells via electrotransfer, resulting in the secretion of therapeutic proteins into ocular fluids. The treatment significantly reduced ocular inflammation in two rat models of uveitis, granting advancement to a phase I/II clinical trial (Touchard et al. 2018).

Gene therapy holds promise for treating and potentially curing both inherited and acquired corneal disorders, as well as metabolic diseases affecting the cornea (Klausner et al. 2007). Research has yielded promising results in the prevention and treatment of corneal diseases, as thoroughly reviewed by Amador et al. (2022) and Di Iorio et al. (2019).

The cornea is an attractive target for gene therapy due to its accessibility for agent delivery, the ability to conduct noninvasive examinations, and its relative immune privilege (Amador et al. 2022; Mohan et al. 2024). Various gene delivery strategies, including viral and non-viral vectors, have been explored to address corneal diseases.

Viral vectors, such as AAVs and adenoviruses, are widely used for their high gene transfer efficiency. For example, AAV5 has shown promise for delivering genes into the corneal stroma, while lentiviral vectors are also under investigation (Amador et al. 2022; Mohan et al. 2024). In contrast, non-viral vectors, such as nanoparticles and naked plasmid DNA, offer advantages like lower immunogenicity and ease of manufacturing (Amador et al. 2022).

Advances in gene editing have further expanded therapeutic possibilities. CRISPR-Cas9 is being investigated for genetic corneal dystrophies, enabling precise gene deletion, replacement, or correction. Studies have demonstrated the feasibility of CRISPR/Cas9-mediated editing to repair disease-causing mutations in corneal cells (Taketani et al. 2017). Additionally, antisense oligonucleotides and siRNAs are being explored for targeting specific mutations in dystrophies like Fuchs endothelial corneal dystrophy (Amador et al. 2022).

Beyond genetic disorders, gene therapy is also being developed to modulate corneal fibrosis, wound healing, immune response, and neovascularization. Targeting TGF-β signaling with Smad7, bone morphogenic protein-7, and decorin has shown promise in reducing corneal scarring in animal models (Gupta et al. 2017; Mohan et al. 2024). In rabbits, combination gene therapy with AAV5-DCN and AAV5-PEDF significantly reduced corneal fibrosis (Mohan et al. 2024). Moreover, gene therapy involving c-Met and hepatocyte growth factor has been explored to enhance corneal epithelial wound healing, particularly in diabetic corneas (Amador et al. 2022).

Immunomodulatory gene therapy is also an emerging strategy for prolonging corneal allograft survival. Gene transfer of interleukin-10 and CTLA4-Ig has been investigated for this purpose (Amador et al. 2022). A notable study by Gilger et al. (2024) demonstrated that delivering a chimeric anti-vascularization immunomodulator via AAV8 ex vivo to corneal grafts effectively reduced inflammation and neovascularization in a high-risk corneal transplant model.

Anti-angiogenic gene therapy has also shown potential in inhibiting corneal neovascularization. Genes such as decorin, PEDF, angiostatin, and vasohibin-1, delivered through various vectors, have demonstrated efficacy in suppressing abnormal blood vessel formation (Amador et al. 2022; Mohan et al. 2024). In a chemically injured rabbit cornea model, simultaneous delivery of decorin and PEDF genes via AAV5 significantly reduced both corneal fibrosis and neovascularization while being well tolerated by the ocular tissue (Mohan et al. 2024).

Emerging research is also exploring gene therapy for NK and HSK. In vivo CRISPR gene editing using HELP offers a promising strategy for severe refractory HSK, as it directly targets and reduces the HSV-1 virus in the cornea with an acceptable safety profile (Wei et al. 2023). In another study, Cong et al. (2024) investigated a single intrastromal injection of AAV carrying the NGF gene in various mouse models of NK, including those induced by capsaicin, HSK, type II diabetes, and alkali burns. The researchers found that this approach efficiently transduced corneal nerve fibers and was transported back to the trigeminal ganglion, leading to enhanced corneal nerve repair, accelerated epithelial healing, reduced corneal swelling, and improved corneal sensitivity across all tested NK models (Cong et al. 2024).