Choroideremia is a rare, inherited eye disorder that leads to progressive vision loss, primarily affecting males. This condition gradually diminishes vision, posing challenges for affected individuals. Understanding available and emerging treatments is important. This article explores choroideremia and its current and future therapeutic strategies aimed at preserving and potentially restoring vision.
Understanding Choroideremia
Choroideremia is an X-linked recessive genetic disorder caused by a mutation in the CHM gene on the X chromosome. Males are typically affected, while females are usually carriers and may experience milder symptoms. The CHM gene provides instructions for making Rab Escort Protein-1 (REP-1), a protein involved in intracellular vesicle trafficking, which is important for the function and survival of retinal cells.
The disease begins in childhood with night blindness. As the condition progresses, individuals experience a gradual loss of peripheral vision, often described as “tunnel vision,” followed by a decrease in the ability to see fine details. These symptoms arise from the progressive degeneration of the choroid, the retinal pigment epithelium (RPE), and the photoreceptor cells within the retina. While central vision is often preserved until later stages, most affected individuals experience severe vision loss or blindness by late adulthood.
Current Treatment Strategies
Gene therapy is the most advanced and widely investigated treatment approach for choroideremia. This therapy focuses on delivering a functional copy of the CHM gene to the retinal cells to compensate for the mutated gene. Adeno-associated virus (AAV) vectors are used as carriers to transport the normal CHM gene into the eye, targeting the photoreceptor cells and retinal pigment epithelium.
Clinical trials for choroideremia gene therapy have shown promising results. The first-in-human Phase 1/2 clinical trial, initiated in 2011, demonstrated the safety and some efficacy of injecting an AAV2-REP1 vector under the retina. This procedure involves a vitrectomy followed by a subretinal injection of the AAV vector. Initial outcomes indicated sustained visual benefits for some patients, with reports of subjective improvements in dim light vision and gains in reading lines on eye charts.
Subsequent studies, including a Phase 2 trial and an international Phase 3 trial, have continued to evaluate the long-term safety and effectiveness of this gene therapy. The Phase 3 trial, involving 170 participants, is the largest gene therapy trial for an inherited retinal disease. While there has been variability in visual acuity improvements across different trials, with a median gain of approximately 1.5 to 5.5 ETDRS letters reported in Phase 1/2 trials, the overall findings suggest the potential to slow or stabilize vision loss. Beyond gene therapy, supportive care measures are also important, including the use of low vision aids, vision rehabilitation programs, and genetic counseling for families.
Future Treatment Possibilities
Research into choroideremia treatment extends beyond current gene therapy applications. Gene-editing technologies, such as CRISPR/Cas9, represent a significant area of focus. These techniques aim to directly correct the specific genetic mutation in the CHM gene rather than simply adding a new copy. While still in early research stages, successful gene editing could potentially restore normal REP-1 protein function more precisely and permanently.
Optogenetics is another area of investigation, which involves introducing light-sensitive proteins into surviving retinal cells. This strategy aims to make cells that are not typically light-sensing capable of responding to light, thereby restoring some visual function, particularly in individuals with advanced degeneration where many photoreceptors have been lost.
Stem cell therapy also holds promise for choroideremia. This involves transplanting healthy retinal cells, such as retinal pigment epithelium (RPE) or photoreceptor cells, to replace those lost due to the disease. Induced pluripotent stem cells (iPSCs) derived from choroideremia patients are being used to create miniature retinal structures, known as organoids, to study the disease and test potential treatments. Scientists are also working on developing iPSC-derived photoreceptor and RPE cell patches for surgical implantation.
Neuroprotection strategies are also being explored, focusing on preserving the remaining retinal cells from further degeneration. These approaches may involve the use of compounds like antioxidants or other agents designed to protect cells from damage. While some studies, such as those involving oral lutein supplementation, have not shown measurable benefits in choroideremia patients, the broader concept of neuroprotection remains an active area of investigation in retinal diseases.