RP2-RP
RP2-associated
Retinitis pigmentosa
RP2-associated retinitis pigmentosa (RP2-RP) is an X-linked inherited retinal dystrophy and therefore predominantly affects boys and men. Within the spectrum of retinitis pigmentosa, it is typically associated with a particularly early onset of disease. Mutations in the RP2 gene account for approximately 10–15% of X-linked retinitis pigmentosa cases. Based on current epidemiological estimates, RP2-RP is considered an ultra-rare inherited retinal disorder with an estimated prevalence of roughly 1 in 150,000 to 1 in 400,000 individuals.
In brief: What is RP2-RP?
RP2-associated retinitis pigmentosa (RP2-RP) is a rare inherited retinal disease. It usually starts in childhood and often leads to progressive visual loss. The condition arises because light-sensitive cells in the retina – photoreceptors – gradually lose their function. The underlying cause is a disease-causing variant in the RP2 gene located on the X chromosome. As a result, RP2-RP primarily affects boys and men, while women carrying an RP2 variant frequently show milder or no symptoms.
Early complaints typically include night blindness, i.e. markedly reduced vision in dim light or darkness. Already in childhood, patients often develop visual field constriction and a gradual decline in central vision. Fundus examination frequently reveals typical signs of retinitis pigmentosa at an early stage. Many affected individuals are highly myopic, and some develop early cataract. Because the disease often begins early and progresses over time, regular ophthalmic follow-up is important.
At present, no approved disease-modifying therapy is available for RP2-RP. However, modern gene therapy approaches appear particularly promising. Here, a functional copy of the RP2 gene is introduced into the retina to improve impaired cellular function. First experimental data are encouraging. In addition, further novel therapeutic approaches are being investigated, including genome editing using so-called “gene scissors” and optogenetic techniques that aim to render remaining retinal cells directly light-sensitive.
RP2-RP
Disease course and clinical management
RP2-RP usually manifests in childhood and is characterized by rapid loss of visual function and early macular involvement. In published cohorts, the mean age at onset lies within the first decade of life, with the majority of patients developing symptoms before the age of 16 years. The most frequent initial symptom is progressive difficulty seeing under dim light or at night as a consequence of early rod photoreceptor loss. As the disease advances, patients develop peripheral visual field constriction and a decline in central visual acuity due to increasing cone photoreceptor involvement.
Electrophysiology typically shows a severe rod–cone dystrophy with markedly reduced or non-recordable ERG responses. Best-corrected visual acuity is often already substantially reduced in childhood or adolescence and continues to deteriorate over time. Optical coherence tomography (OCT) reveals rapid thinning of the outer retina, early loss of the ellipsoid zone and pronounced macular involvement. Fundus autofluorescence and colour fundus imaging show a variable but usually bilaterally symmetric pattern of progressive retinal degeneration. Additional ophthalmic features frequently include high myopia and, in a relevant proportion of patients, early-onset cataract. Despite some clinical variability, the overall course is typically severe, with early onset and a progressive trajectory.
Given the early onset and rapid progression, structured clinical monitoring is essential. Baseline assessment should include best-corrected visual acuity, OCT, fundus autofluorescence, ERG and widefield fundus photography. Follow-up examinations should be scheduled regularly and adapted to disease stage and progression.
RP2-RP
Genetics and genotype – phenotype correlation
The RP2 gene is located on the long arm of the X chromosome, comprises five exons and encodes a 350-amino-acid protein. Numerous disease-causing variants have been described, including frameshift, nonsense, missense and splice-site variants as well as larger deletions. Current data suggest that most clearly pathogenic variants result in loss of RP2 function, whereas variants of uncertain significance are more often missense changes, non-canonical splice variants or variants in untranslated regions.
To date, no consistent genotype–phenotype correlation has been demonstrated in affected males. In female carriers, the clinical spectrum is broad. While the majority remain asymptomatic, a subset develops clinical signs of a retinal dystrophy. In addition, subclinical changes have been reported on multimodal imaging and functional testing.
RP2-RP
Molecular mechanisms
RP2 is a ubiquitously expressed, membrane-associated protein that is particularly enriched in the retina at the ciliary apparatus, the basal body and periciliary membranes. RP2 is also involved in vesicular transport processes linked, among other compartments, to the Golgi apparatus. N-terminal myristoylation and palmitoylation are critical for membrane association and correct subcellular localization of the protein.
Functionally, RP2 acts as a GTPase-activating protein (GAP) for the small GTPase ARL3 and participates in ciliary and vesicular transport processes that are essential for the directed trafficking of proteins to photoreceptor outer segments. Loss of RP2 leads to persistently increased ARL3 activity and, via this mechanism, contributes to mislocalization of phototransduction proteins and structural damage to photoreceptors. Beyond this, there is evidence that RP2 is involved in actin cytoskeleton organization and additional cellular processes. The full functional spectrum of RP2 and its relevance for different retinal cell types are not yet fully understood and are the subject of ongoing research, including work within our group.
RP2-RP
Therapeutic perspectives
At present, AAV-mediated gene therapy is the most advanced disease-specific therapeutic strategy. In this approach, a functional copy of the RP2 gene is delivered to the retina via viral vectors with the aim of partially restoring the missing gene function. In RP2 knockout mouse models and human retinal organoids, restoration of RP2 expression has been shown to partially improve structural and functional disease features. These findings make RP2-associated retinopathy a promising candidate for future gene augmentation approaches, which are being further explored within the InsightRP2 project.
In addition to gene augmentation, other strategies are under investigation. These include read-through approaches for specific nonsense variants, which aim to promote production of a full-length RP2 protein despite a premature stop codon in the DNA. Genome editing is also discussed as a potentially relevant future therapeutic option. Such techniques seek to correct disease-causing variants directly at the DNA level, for example using CRISPR-based tools; in contrast to gene augmentation, this could directly address the underlying genetic defect. However, no clinically established genome editing therapies currently exist for RP2-associated disease.
Furthermore, gene-agnostic strategies that act independently of the underlying mutation are being explored. Examples include neuroprotective approaches that aim to preserve photoreceptors. For advanced disease stages, in which few or no photoreceptors remain, optogenetic techniques may become relevant in the future, enabling residual retinal cells to be rendered light-sensitive.