Introduction

Choroideremia is a rare eye condition that can cause serious vision problems over time. It affects the outer layers of the retina and was first recognised in the 1800s.¹ This condition leads to gradual vision loss because the body does not produce enough of a protein called Rab-escort protein 1 (REP1).² Choroideremia is passed down through generations in an X-linked recessive pattern, meaning it mostly affects people assigned male at birth. Despite this, people who are assigned female at birth can carry the gene and sometimes have mild symptoms.¹ It usually starts with problems seeing in low light during childhood or teenage years. Over time, vision gradually worsens, and people who are assigned male at birth with this condition lose most of their sight by middle age.¹ Choroideremia affects about 1 in 50,000 people of European ancestry and is more common in certain regions, such as northern Finland. In the UK, it is thought that over 500 people assigned male at birth are affected, and about 3,000 across Europe.¹ Eye doctors can often suspect choroideremia based on the appearance of the retina. The diagnosis is usually confirmed with genetic testing to detect mutations in the CHM gene.¹ Even though researchers have studied choroideremia for decades, there is currently no treatment proven to stop or slow the disease down. However, because of how the disease functions and progresses, it is considered a good candidate for gene therapy, a treatment that could replace the missing or faulty gene.¹ This article will look at what gene therapy is, the promising results so far and the challenges researchers face.

What Is Gene Therapy?

Gene therapy for the retina is an exciting new treatment approach that could help with many causes of blindness.² Gene therapy aims to deliver the healthy CHM gene to the RPE.³ Early experiments used lentivirus vectors in mice, but these were not significantly effective in retinal cells. Later, adeno-associated virus (AAV) vectors were shown to successfully restore REP1 protein function in both cell cultures and animal models. These studies paved the way for human clinical trials.⁴

The surgery itself is challenging. It temporarily detaches the retina in areas that are already thin and fragile, which would normally make vision worse.⁵ Yet, findings support the safety of this therapy. Even though choroideremia patients have delicate retinas and may be at higher risk for certain complications like macular holes, surgery was generally successful in restoring the anatomy of the eye when needed.⁵ There are various forms of gene therapy being studied for this disease, the most successful so far has been gene supplementation which is adding a working copy of the missing or faulty gene. When people have this condition, the goal is to try and keep as much vision for as long as possible, not try to drastically improve vision. Choroideremia is rare but has a big impact on quality of life and healthcare access so it important to find ways to help people that are living with it.⁵

Progress So Far

Recent studies are helping to build a better picture of how gene therapy may benefit people with choroideremia. One clinical trial found that patients who received gene therapy could read two more lines on a vision chart compared with those who did not have the surgery.⁶

Researchers are also testing different ways to measure whether gene therapy is working. One approach is to monitor the “smooth zone”, an area of the retina that still contains healthy retinal pigment epithelial (RPE) cells, which have not yet been damaged by the disease. Tracking whether this area remains stable, increases, or decreases in size over time could help doctors assess how well the treatment is slowing the disease. A UK-funded trial called Regenerate found that in younger patients, the smooth zone often remained intact after gene therapy. This suggests it could be a useful marker in early-stage disease. Since gene therapy repairs certain cell functions in surviving RPE and light-sensing cells, focusing treatment on areas with a healthy smooth zone may give the best results.⁵ In another study, doctors delivered the REP1 gene under the retina in 14 people with choroideremia. Overall, the treated eyes had better vision than the untreated eyes.² Even in advanced cases where vision loss would usually be rapid, gene therapy appeared to help maintain or improve eyesight. Some participants were able to read three or more lines on the eye chart, and the treatment was generally found to be safe over the two-year trial.

What Are The Challenges Of Gene Therapy?

Gene therapy has offered hope for treating inherited retinal diseases, but results have been mixed. Some therapies, like those for rod–cone dystrophies, have been approved by the FDA and European Medicines Agency. Early trials in patients with RPE65 mutations showed encouraging improvements, even in patients with severe vision loss. In some cases, visual improvements lasted for at least four years. However, other studies showed that despite initial improvements, gene therapy did not stop the underlying retinal degeneration after a few years.⁷ Treating other inherited retinal diseases carries the possibility of losing useful central vision. As a result, treatment outcomes for most inherited retinal diseases are expected to be more modest. Trials are more likely to slow disease progression rather than produce dramatic vision gains, especially in choroideremia, where even end-stage patients may retain small areas of central retina that provide good vision.⁷ Early gene therapy trials often target the central retina because it is crucial for sharp, detailed vision. However, this also carries a risk to the remaining healthy vision. Retinal surgery techniques continue to improve in order to reduce trauma and avoid complications or stimulate immune reactions. Currently, we do not yet know the long-lasting effects of gene replacement therapy of choroideremia or most other inherited retinal diseases.⁷

Looking To The Future

Research is now focusing on how to make gene therapy for choroideremia more effective, longer lasting, and safer for people at different stages of the disease. Phase I/II trials have shown that the treatment is generally safe and can improve vision in some patients, but many participants had advanced disease with only small areas of healthy retina remaining, which limits potential benefit.³ Large natural history studies have helped researchers understand how vision and retinal health decline over time. Future trials aim to test the therapy in younger patients with more healthy retinas to see if it can preserve structure, as well as to confirm visual improvements.⁴ Scientists are also working to improve how the gene is delivered by increasing expression in target cells, exploring alternative viral vectors for better delivery to photoreceptors, and refining vector design to safely maximise benefit. Results so far show small improvements in vision, but responses vary, so optimising surgical techniques, managing inflammation, and identifying the best timing for treatment may help improve outcomes. The smooth zone is being considered as a main measure of treatment success because it is easier to track in early disease and reflects eye health.⁵ Subretinal injections, which place the gene directly onto target tissue in the eye’s immune-protected environment, require delicate surgery that temporarily detaches the retina, posing challenges in advanced disease where the retina is fragile. In the future, robotic-assisted surgery may improve precision and reduce risk by allowing slow, controlled delivery of the gene, and early results from the first human trials of this approach are promising.⁷

Summary

Gene therapy for choroideremia has advanced from experimental animal studies to promising human trials, offering hope for a condition that has long lacked effective treatment. Clinical results show that delivering a healthy CHM gene can be safe and, in some cases, improve or preserve vision, even in advanced disease. While outcomes vary, early interventions particularly in patients with healthier retina may yield greater benefits. Significant challenges still remain. The surgical delivery method is complex, the long-term durability of benefits is uncertain, and risks such as retinal damage or immune reactions must be managed. Advances in surgical precision, including robotic-assisted techniques, and improved viral vectors may help overcome these barriers. Future randomised, controlled trials in well-selected patient groups will be key to confirming effectiveness and guiding clinical use. Although current therapies are more likely to slow progression than restore lost vision, the progress in choroideremia gene therapy represents an important step toward targeted genetic treatments for inherited retinal diseases. With continued refinement, it may one day preserve vision for many at risk of blindness.