InsightRP2
Establishment of new therapeutic approaches for RP2-associated retinitis pigmentosa
Retinitis pigmentosa (RP) refers to a group of hereditary retinal diseases characterized by progressive degeneration, particularly of the photoreceptors. RP affects approximately 1 in 4,000 people worldwide and can be caused by changes in many different genes. Mutations in the RP2 gene are responsible for a significant proportion of X-linked retinitis pigmentosa (XLRP).
InsightRP2 is a multimodular, interdisciplinary project in which the Wollnik research group is investigating the genetic causes, disease mechanism, and new therapeutic approaches for RP2-associated retinitis pigmentosa (RP2-RP). Our project consists of several components:
Registry
The InsightRP2 Registry is the first global registry specifically for patients with retinitis pigmentosa caused by changes in the RP2 gene. It collects clinical and genetic information about the causes, medical history, progression of visual impairment, and treatment of the affected person. We also collect image data, e.g., images of the back of the eye (funduscopy; optical coherence tomography, OCT), and analyze how the retina changes over the course of the disease. The registry helps clinicians and researchers to better understand the genetic basis and disease progression of RP2-associated retinitis pigmentosa and to focus their research and the development of future treatment concepts accordingly. In this way, we want to find out which types of mutations in the RP2 gene occur frequently and how individual mutations affect the age of onset and progression of the disease. We also want to learn how the disease progresses from the perspective of those affected and whether there are additional associated health problems, such as a tendency to rheumatic complaints. The registry helps to identify patients with this specific form of retinitis pigmentosa in order to facilitate their access to new information and, if applicable, future therapy studies. The registry is based at the Institute of Human Genetics and uses a secure REDCap-based database hosted at Göttingen University Medical Center.
People (m, f, d) of any age with a proven causal change (pathogenic variant or mutation) in the RP2 gene are eligible to participate. Unfortunately, people with other forms of retinitis pigmentosa cannot participate. However, they can register in the patient registry of the patient association for people with retinal diseases, PRO RETINA, for example.
Wenn Sie Fragen haben oder weitere Informationen über die Studie wünschen, wenden Sie sich bitte per E-Mail an die Studienkoordinatorin, Frau Dr. Nina Bögershausen: insight.rp2(at)med.uni-goettingen.de
Contact
If you have any questions or would like further information about the study, please contact the study coordinator, Ms. Dr. Nina Bögershausen: insight.rp2(at)med.uni-goettingen.de
Retinal AI imaging analysis
In the InsightRP2 registry, we use image data such as fundus images and optical coherence tomography (OCT). We evaluate this data in cooperation with Prof. Peter Krawitz's team at the Institute for Genomic Statistics and Bioinformatics in Bonn using specially programmed artificial intelligence (AI). Our goal is to determine morphological parameters of the disease progression.
A key advantage of AI in image analysis is its ability to detect even subtle changes in the retinal structure at an early stage. For example, AI algorithms can identify a decrease in photoreceptor density or changes in the retinal pigment epithelium (RPE) layer with high precision. We want to use these capabilities to describe the disease progression of RP2-associated RP at the image morphological level using objective criteria. In the future, this should help simplify clinical diagnosis and progression monitoring and enable improved individual prognoses. In addition, we want to use AI image analysis in the development of new therapies by applying it to assess the effectiveness of treatment approaches.
Research into molecular disease mechanisms
The RP2 gene encodes the ubiquitously expressed RP2 protein, which consists of 350 amino acids. RP2 is expressed throughout the human retina and is particularly localized in the ciliary apparatus of photoreceptor cells, where it is essential for maintaining ciliary structure and function. RP2 is known to function as a GTPase-activating protein (GAP) for the small GTPase ARL3, a ciliary protein that plays a crucial role in the transport of proteins to the outer segments of photoreceptors.
To better understand the precise function of RP2 in different retinal cell types, we collaborated with the team of Dr. Lukas Cygenek (Head of the Stem Cell Unit – Göttingen (SCU) at UMG) to use CRISPR/Cas9 technology to introduce several mutations, which also occur in patients, into induced pluripotent stem cells (iPSCs). From these stem cells, we differentiate various retinal tissues and organoids, which we examine in more detail using modern high-throughput and OMICS technologies (e.g., single-cell transcriptomics, proteomics, metabolomics) as well as cell biological and molecular methods. Integrative OMICS data analyses are used for this purpose. The results obtained should provide additional insights into the disease mechanism of RP2-associated RP at the molecular level.
Development of gene therapy & genome editing therapy
The findings we gain from our molecular studies are used to develop new therapeutic approaches based on gene replacement and/or genome editing. Gene therapy offers promising approaches for the treatment of degenerative retinal diseases. Gene therapy can replace the defective gene, helping those affected to stabilize or even improve their vision. A well-known example of this is Luxturna®, a gene therapy that has been successfully used in patients with RPE65 mutations. Preclinical studies have shown that gene therapy can also be used to replace the RP2 gene, thereby largely restoring the function of retinal cells in models. These results suggest that gene therapy could also be a significant therapeutic option for RP2-associated retinitis pigmentosa, especially since the RP2 gene is a “small” gene and can therefore be more easily introduced into the target cells. We would like to pursue these approaches further in order to develop a clinically applicable gene therapy for RP2-associated retinitis pigmentosa.
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