Introduction

Choroideremia is a hereditary retinal dystrophy. It has a prevalence of 1 in 50,000 patients, making it an extremely rare condition. It is most commonly observed in males due to its X-chromosome linkage. The defect is characterised by a progressive deterioration of the outer retina, retinal pigment epithelium and inner choroid.It is a recessive inherited disorder due to a mutation in the CHM gene.¹

Pathophysiology

Although there is evidence that states that the choroid region of the eye is the most affected, studies tend to say that the RPE cells or photoreceptors are primarily affected. Inflammation is most commonly prevalent in patients with this disorder. The presence of lymphocytic infiltration in the choroid marks the early stages of choroideremia.¹

Symptoms

People suffering from the disorder often complain about night blindness during adolescence, which gradually progresses towards a severe peripheral vision loss during adulthood. Peripheral visual field loss progresses, and it usually culminates in loss of central vision in their fifth or sixth decade of life.¹

Diagnosis¹

• Utility of cell‑free fetal DNA in combination with next‑generation sequencing (NGS)
• Non-invasive prenatal testing for Y chromosome determination
• Fundus examination:  Peripheral pigmentary changes may characterise the retina of affected patients. At a later time, distinct regions of chorioretinal atrophy are usually visible
• Fundus autofluorescence (FAF): Essential biomarker for disease progression in CHM. The evaluation of disease progression by estimating the rate of autofluorescence shrinkage can be achieved using fundus autofluorescence
• Optical coherence tomography (OCT): The test revealed a trend that patients who later suffered from choroideremia had increased central macular thickness in early childhood

Therapeutic possibilities¹

• Gene Therapy: Adeno-associated virus (AAV) vector-based gene therapies have been used in the CHM treatment. Gene therapy is a promising treatment option for choroideremia because it is caused by a single faulty gene and can often be diagnosed early. Gene therapy is an effective option for the eye as there is a low risk of immune reaction and systemic penetration
• Stem cell therapy: It is a potential option for therapy in patients with different advanced retinal dystrophies. Before using stem cells, defining the most suitable tissue to be regenerated (RPE cells or photoreceptors) and the best stem cell category to use is important
• Small molecules: Small-molecule drugs may be helpful by promoting ribosomal read-through of premature stop codons and thus bypassing abnormal termination signals. In the nonsense-mediated zebrafish model of choroideremia, this approach was shown to be effective in determining an increase in RPE1 expression
• Retinal prosthesis systems: It provides long-term retinal stimulation in cases with advanced stages of outer retinal dystrophies.

What is CRISPR

Scientists have understood the effects of a single change in the nucleotides or a specific gene could result in devastating changes and could result in incurable diseases. The solution to this is, scientists have developed target genome editing tools. The RNA-guided CRISPR-Cas nuclease systems are one of them.² CRISPR-Cas systems work by guiding small RNAs that engage in Watson-Crick base pairing with the target DNA to introduce double-strand breaks (DSBs) at specific sites for correction. The CRISPR gene editing tool can be used as a probable emerging therapy as the therapeutic approach as correcting the genomic copy of the gene, may provide greater assurance of achieving and maintaining the desired level of gene expression. This is because the gene would be subject to regulation by its normal transcriptional regulation and epigenetic environment. This approach could offer more stable and long-term results, as the repaired gene remains regulated by the body’s natural mechanisms. However, this approach requires further elucidation due to concerns regarding the potential for harm due to unintended off-target effects from the ubiquitously expressed Cas9 protein. This approach could offer more stable and long-term results, as the repaired gene remains regulated by the body’s natural mechanisms.³

Summary

The duration of current choroideremia trials is five years or less. Given that the treatment’s objective is to halt further deterioration, and since the natural history of choroideremia is of an extremely slow degeneration, it may be suggested that patients ought to be monitored for at least 10 years to observe a significant outcome. This could therefore be an issue for cholioderemia. While CRISPR gene editing may not yet replace gene augmentation as the leading treatment, it holds promise, especially for certain patient subgroups with specific mutations. The limitations of current therapies, such as variable outcomes in advanced-stage patients and regulatory setbacks, underscore the need for newer approaches. CRISPR’s ability to precisely correct genetic defects at their source offers a novel and potentially curative solution. With further research focused on improving editing accuracy, optimising delivery systems, and selecting ideal candidates, CRISPR could become a powerful tool in the future of choroideremia treatment.³