Choroideremia: from genetic and clinical phenotyping to gene therapy and future treatments

Abstract

Choroideremia is an X-linked inherited chorioretinal dystrophy leading to blindness by late adulthood. Choroideremia is caused by mutations in the CHM gene which encodes Rab escort protein 1 (REP1), an ubiquitously expressed protein involved in intracellular trafficking and prenylation activity. The exact site of pathogenesis remains unclear but results in degeneration of the photoreceptors, retinal pigment epithelium and choroid. Animal and stem cell models have been used to study the molecular defects in choroideremia and test effectiveness of treatment interventions. Natural history studies of choroideremia have provided additional insight into the clinical phenotype of the condition and prepared the way for clinical trials aiming to investigate the safety and efficacy of suitable therapies. In this review, we provide a summary of the current knowledge on the genetics, pathophysiology, clinical features and therapeutic strategies that might become available for choroideremia in the future, including gene therapy, stem cell treatment and small-molecule drugs with nonsense suppression action.

Synonymous Variant in the CHM Gene Causes Aberrant Splicing in Choroideremia

“…At this time, the visual acuity deteriorates. [1][2][3][4][5] Choroideremia is a progressive disease, which explains the latest stage of the disorder of the current 58-yearold Brazilian patient compared with the 34-year-old Cuban descendent.…”

“…4 Until now, according to the literature, there has not been any genotype-phenotype correlation in choroideremia. 1,[15][16][17][18][19] Sanger sequencing of all CHM exons and exon/intron boundaries found only one synonymous variant (c.1359C>T, p.(Ser453=)). This variant was considered to have a high likelihood of being disease-causing, via the observed skipping of CHM exon 11 reported here.…”

“…retinal degeneration that affects approximately 1:50,000 males. 1,2 The symptoms include early nyctalopia with progressive constriction of peripheral visual fields. 3 The central vision is preserved until approximately 40 years of age, when the central vision loss usually starts.…”

“…4,5 Pathogenic variants in the CHM gene are related to choroideremia. [1][2][3][4][5] According to the Human Gene Mutation Database, more than 280 variants in the CHM gene have already been associated with choroideremia, 6 but only 1 silent/synonymous variant (c.1359C>T; p.(Ser453=)) has been reported. 7 Until now, there has been no substantial molecular evidence that this variant actually affects the correct splicing process.…”

Fluorescence Lifetime Imaging Ophthalmoscopy (FLIO) in Patients with Choroideremia

“…3 In addition, REP1 is heavily involved in intracellular trafficking of proteins, small substrates, and various organelles. 4 Mutations in the CHM gene subsequently alter the function of REP1, causing degeneration in cellular structure, transport, and stability. The mechanism of disease pathophysiology remains unclear, as it is uncertain whether the RPE, choroid, or photoreceptor layers are affected first or simultaneously; however, it has been suggested that the RPE may be affected first, leading to retinal disturbances and to the formation of retinal tubulations.…”