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Analysis of choroideremia gene (CHM) mutations highlight CpG mutation clusters and support gene replacement approaches

Researchers studying the genetic basis of choroideremia have published results highlighting a clustering of lesions around 5 CpG sites within the CHM gene located on the X-chromosome. According to the ocular research group, based at the Nuffield Laboratory of Ophthalmology, University of Oxford, the majority of point mutations occurred at the only 5 CpG sites that would code for a stop codon as the result of a C>T transition. Given the inherent genomic instability at CpG sites within the human genome, the researchers predicted that similar mutations may be found with increased frequency in future generations. The research also recorded the prevalence of null mutations within the CHM gene, and the rate of detection of mutations by sequencing, given their relevance to assessing the potential for gene replacement therapy in patients with the disorder.


Choroideremia is estimated to affect in 1 in 50,000 males, arising from mutations in the CHM gene coding for the rab-escort protein 1 (REP1), critical for intracellular trafficking within the eye. The UK researchers established a cohort of 79 patients diagnosed with the disorder. 74 of the 79 patients (94%) were shown to harbour causative mutations (via sequencing) and the majority of the mutations identified led to null proteins. Analyzing the spectrum of mutations from the cohort showed that 47% of the patients had insertions and deletions, 18% had splice junction mutations, and 35% had single point mutations. 62% of the pedigrees analyzed had single point mutations with C to T transitions at C-phosphate-G (CpG) dinucleotides. The C to T mutations were located in 5 of 24 CpG di-nucleotides spread across the CHM gene. From their study, the researchers concluded that the majority of CHM mutations appeared to be null and therefore potentially suitable for gene replacement therapy.


At present, at least three clinical studies are addressing the development of a gene therapy treatment for choroideremia: “NCT01461213” (, sponsored by the University of Oxford, aims to deliver the AAV-REP1 vector at two different doses to the retina of 12 patients with a diagnosis of choroideremia; “NCT02077361”, sponsored by the University of Alberta, represents an open label study using an AAV2 vector, also carrying the Rab-escort Protein-1 (estimated 6 patients) and finally, “NCT02341807”, sponsored by Spark Therapeutics in the US, are conducing a phase 1/2 study using AAV2 to deliver the normal human CHM gene to the retina of 15 patients. The studies are scheduled to complete, respectively, in June 2017, December 2018, and January 2019. The Oxford CHM mutational analysis provides further under-pinning to each trial for the rationale of pursuing a gene replacement therapy.