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Clinical research on genotype-phenotype correlations in retinitis pigmentosa (RP) are in preparation for gene therapy studies.

Researchers based at the University of Tübingen, Germany have published a clinical study on retinitis pigmentosa (RP) showing that detailed clinical and genetic findings may be amenable for gene therapy studies in the future.  The study was focused on biallelic variations in the PDE6A gene, caused by RP, which appears to account for less than 4% of families with the autosomal recessive disorder.  A consortium of researchers (RD-CURE) has built a collaborative initiative for the clinical translation of gene therapy in preparation for an upcoming gene supplementation trial.  Currently, three registered natural history studies of patients with PDE6A will be hugely important in the development of subsequent gene therapy trials, not least of all to collect accurate prognoses and prognostic information.


Inherited retinal diseases (IRDs) are reported for 271 genes, comprising >12,000 mutations, including inheritance patterns of dominant, recessive, di-genic, polygenic, X-linked, sex-linked, mitochondrial and de novo cases.  Research identifying RP genes alone, was published around the 1990s and has led to 89 genes being catalogued to this day. One gene, PDE6A, encodes the alpha subunit of the rod photoreceptor cyclic guanosine monophosphate (cGMP) phosphodiesterase and this was identified as the seventh RP locus, on chromosome 5q31.2-q34 in 1995.  The gene encodes an enzyme to hydrolize the intracellular cytoplasmic cGMP level, causing the closure of cyclic nucleotide-gated channels, an essential step for phototransduction.  The RD-CURE consortium’s aim is to prepare the necessary groundwork required to have the relevant data available in order to recruit the RP patient cohorts.


In the current study, the researchers recruited 57 RP patients from the University of Tübingen and 12 collaborating European tertiary referral centers. Seventeen of the PDE6A variants found in these patients appeared to be novel, while findings showed that disease “was highly symmetrical between the right and left eyes and visual impairment was mild or moderate in 90% of patients, providing a window of opportunity for gene therapy”.  A brief summary of the data showed that thirty patients were homozygous for disease-causing alleles while twenty-seven patients were heterozygous for 2 different PDE6A variants each. The mean (SD) best-corrected visual acuity was 0.43 (0.48) logMAR and the median visual field area with object III4e was 660 square degrees (5th and 95th percentiles, 76 and 11,019 square degrees; 25th and 75th percentiles, 255 and 3923 square degrees). This and further data will be extremely valuable when gene therapy outcomes become available.  These data outcomes will be important to analyse and may be critical to combine different types of endpoints using real world data.