Ocular gene therapy is a medical approach for treating genetic eye diseases by delivering a functional copy of a gene directly to cells in the eye. This process corrects a genetic defect, addressing the root cause of the condition.
The eye is a suitable candidate for this treatment for several reasons. Its small, compartmentalized structure allows for localized doses, minimizing effects on the rest of the body. The eye is also easily accessible and possesses immune privilege, meaning it has a reduced immune response. This quality lowers the likelihood of the body rejecting the therapeutic intervention.
How Gene Therapy Works in the Eye
The primary mechanism for delivering genetic material involves a modified virus known as a vector. The most common is the adeno-associated virus (AAV), chosen for its safety and ability to enter retinal cells without causing disease. Scientists disable the AAV, remove its genetic contents, and load it with a healthy copy of the faulty gene. This repurposed virus then acts as a delivery vehicle to carry its therapeutic payload into the target cells.
Different AAV serotypes are chosen based on their affinity for specific cell types within the retina, like RPE cells or photoreceptors. The process begins when the vector attaches to a target cell, which engulfs it. Once inside, the vector releases its genetic cargo into the cell’s nucleus.
Inside the nucleus, the new gene remains separate from the cell’s DNA as a stable piece of genetic material called an episome. This gene provides the correct instructions for the cell to produce the protein it was previously unable to make. Restoring this protein production can halt cellular damage and improve the function of retinal cells, leading to potential vision gains.
Eye Conditions Targeted by Gene Therapy
Ocular gene therapy focuses on inherited retinal diseases (IRDs) caused by single-gene mutations. The most prominent success is the treatment for Leber congenital amaurosis (LCA) from mutations in the RPE65 gene, which causes severe vision loss in early childhood. The FDA-approved therapy, Luxturna, delivers a working copy of the RPE65 gene to retinal cells. This allows the cells to produce an enzyme needed for the visual cycle, which can halt or reverse vision loss.
Beyond LCA, researchers are investigating gene therapies for other IRDs in clinical trials. Retinitis pigmentosa (RP), a disease causing progressive photoreceptor death that leads to night blindness and tunnel vision, is a target. Another condition being studied is choroideremia, a degenerative disease affecting the retina and choroid.
Research is also extending to complex eye diseases not caused by a single gene, like wet age-related macular degeneration (AMD) and diabetic retinopathy. For these conditions, gene therapy aims to enable the eye to produce its own therapeutic proteins long-term from a single injection. This could reduce the need for frequent treatments, such as anti-VEGF injections, and transform the management of leading causes of blindness in adults.
The Patient Treatment Process
A patient’s journey begins with genetic testing to confirm a diagnosis and identify the specific gene mutation causing their inherited retinal disease. The results determine if a patient is a candidate for an available therapy. Current treatments are designed to correct defects in particular genes.
The treatment is administered through a surgical procedure called a vitrectomy, performed by a retinal surgeon. The surgeon removes the vitreous, the gel-like substance filling the eye, to access the retina. This is followed by a subretinal injection, where a tiny cannula delivers a droplet of fluid containing the AAV vector under the retina. This places the vector in direct contact with the target photoreceptor and RPE cells.
Following the procedure, patients enter a recovery period requiring careful management. Post-operative care is necessary to monitor healing, check for complications, and evaluate the therapy’s effectiveness. This care involves:
- Wearing an eye patch for a period of time
- Maintaining a specific head position to help the retina settle
- Using steroid eye drops to manage inflammation
- Restricting physical activity
- Attending regular follow-up appointments
Evaluating Success and Potential Complications
The success of ocular gene therapy is measured by improvements in functional vision rather than a complete restoration of sight. A primary assessment is the multi-luminance mobility test, which measures a patient’s ability to navigate a maze in varying low-light conditions. Other metrics include enhanced light sensitivity, an expanded visual field, and halting the progression of the disease.
The long-term durability of these treatments is a subject of ongoing study. Current data suggests the positive effects can be stable for several years because the vector enables sustained protein production. As this is a new field, researchers continue to collect data to understand the full duration of the benefit and if retreatment may be necessary.
Potential complications can arise from the surgical procedure or the therapy itself. Surgical risks are similar to those of other intraocular surgeries and can include:
- Inflammation
- Elevated eye pressure
- Cataract formation
- Retinal tears or detachment
Risks associated with the vector include an inflammatory response, which is managed with corticosteroids. The severity of this inflammation can be dose-dependent, with higher vector doses sometimes leading to more significant reactions.