Gene therapy is rapidly advancing as a potential solution for treating vision loss caused by a range of retinal diseases. These innovative therapies introduce genetic material into cells to replace defective or missing genes, offering hope for conditions previously considered untreatable. The accessibility of the retina and the presence of ocular barriers that limit immune responses make it an ideal target for gene therapy.
Targeting Inherited Retinal Diseases
Inherited retinal diseases, caused by mutations in over 300 genes, are a primary focus of gene therapy research. These diseases can result from either recessive or dominant genes, requiring different therapeutic strategies. For recessive genes, gene therapy introduces a functional copy of the mutated gene. For dominant genes, silencing the mutated gene or correcting the mutation using CRISPR gene editing is necessary.
Early successes in gene therapy targeted Leber congenital amaurosis (LCA) caused by mutations in the RPE65 gene. A phase III clinical trial demonstrated that introducing a functional RPE65 gene using an adeno-associated virus led to sustained improvements in visual function in LCA patients. Currently, around 200 clinical trials are underway to examine the safety and effectiveness of gene therapy for other inherited retinal diseases.
Recent phase 1/2 clinical trials have reported promising results for retinal dystrophies caused by recessive mutations in the GUCY2D and RLBP1 genes. The GUCY2D gene encodes the retinal guanylyl cyclase 1 (RETGC-1) protein, crucial for photoreceptor adaptation to darkness. The study showed that subretinal delivery of a functional GUCY2D copy resulted in a 100-fold improvement in visual sensitivity in low-light environments. Similarly, a trial involving individuals with RLBP1-associated retinal dystrophy demonstrated that subretinal administration of a functional RLBP1 copy led to faster adaptation to darkness and improved daily activities.
Addressing Acquired Retinal Diseases
Gene therapy is also being explored for acquired retinal diseases, such as age-related macular degeneration and diabetic retinopathy. These conditions often involve common pathways, like the vascular endothelial growth factor (VEGF) pathway, which promotes abnormal blood vessel growth in the retina. Current treatments involve frequent anti-VEGF injections, but gene therapy offers the potential for more durable suppression of VEGF.
Approaches under investigation include using adeno-associated viruses to deliver genes encoding anti-VEGF antibody fragments, gene silencing techniques, and gene editing using CRISPR. However, gene therapy for acquired retinal diseases must demonstrate superior benefits compared to existing treatments to gain regulatory approval.
Gene Therapy for Glaucoma
Glaucoma, a leading cause of irreversible blindness, is another target for gene therapy. Current treatments involve daily eye drops or surgical procedures, which can be variable and have side effects. Gene therapy approaches aim to provide a durable alternative, potentially requiring only a single intervention.
One approach involves reducing intraocular pressure by disrupting the aquaporin 1 gene, which is involved in the production of aqueous fluid. Studies in mouse models have shown that disrupting this gene using CRISPR-Cas9 can lower intraocular pressure and mitigate the loss of retinal ganglion cells. Another approach focuses on modulating the expression of genes underlying the loss of retinal ganglion cells, such as those involved in cell death, energy metabolism, and oxidative stress. A recent study in a mouse model of glaucoma demonstrated that delivering a gene involved in energy metabolism prevented the loss of retinal ganglion cells and improved visual function.
Challenges and Future Directions
Despite the progress, challenges remain in the development and application of gene therapies for retinal diseases. These include concerns about the efficacy and safety of long-term gene expression, the large-scale manufacture of vectors, and the accessibility and cost of treatments. Additionally, gene therapy requires viable target cells, making it less effective in advanced stages of retinal diseases.
Researchers are also exploring modifier gene therapies that target shared pathways in rare inherited retinal diseases, as well as optogenetics, which involves administering a gene called opsin to make cells light-sensitive. With numerous clinical trials underway, more gene therapies for retinal diseases are expected to be approved in the near future, offering new hope for individuals with vision loss.
