Cyprus is in search of new treatment options for rare kidney diseases, which is now on the map of international scientific research, while the ALP-RARE program it coordinates will be presented during a research symposium taking place these days in Budapest.
Specifically, the European project ALP-RARE, which is coordinated by the biobank.cy Center of Excellence of the University of Cyprus, aims to accelerate the development of therapeutic approaches for Alport spectrum disorders, a group of rare hereditary kidney diseases.
As the coordinator of the program, Dr. Grigoris Papagrigoriou, told "F", ALP-RARE secured competitive funding through the new European Partnership for Rare Diseases, ERDERA, with the University of Cyprus taking over the coordination of the international consortium.
This is a three-year preclinical research program. Pharmaceutical substances and their combinations will be tested in animal and other experimental models that reproduce basic characteristics of human disease. The aim is to gather reliable data for possible future clinical trials.
"ALP-RARE has a special connection with Cyprus, as it utilizes experimental models that carry pathogenic variants with increased frequency in Cypriot patients with Alport spectrum disorders and have already been developed by researchers at the biobank.cy Center of Excellence. In the preclinical stage we need to find out not only if a therapeutic approach presents a benefit, but also if the result is confirmed in different models and by different research groups. Only approaches that gather sufficient and consistent evidence will be able to proceed to further development," explained Dr. Papagrigoriou.
What Alport disorders cause
Alport spectrum disorders are linked to genetic variants that affect collagen IV, a material necessary to support kidney filters. The damage can allow proteins and red blood cells to pass into the urine and gradually lead to a loss of kidney function. Some patients also have hearing or vision problems.
Diagnosis can be difficult, as patients with the same genetic disease do not always experience the same symptoms or the same course.
"The diagnosis of rare diseases is not based on a single symptom or a completely standard clinical picture. It requires the synthesis of clinical, laboratory and genetic data, as well as the comparison of the findings with cases that have been recorded internationally," said Dr. Papagrigoriou. "Each new diagnosis can expand our knowledge of the disease and help identify patients who would previously remain without a clear diagnosis. The rarity of a disease, possibly, means that we have not yet found all the people affected so that we have more data for a more accurate diagnosis."
The Cypriot genetic footprint
Some rare hereditary diseases occur with an unusually high frequency in specific areas of Cyprus. A typical example is Mucoprotein 1 Kidney Disease, for which more than 160 people with a genetic diagnosis have been recorded, mainly in the province of Paphos.
The high concentration of cases does not mean that the disease is absent from other countries, but it may indicate that it remains underdiagnosed elsewhere.
The systematic study of hereditary kidney diseases in Cyprus began in the early 1990s at the Cyprus Institute of Neurology and Genetics, with the decisive contribution of Professor Konstantinos Delta and his colleagues.
"In Cyprus we have been systematically studying hereditary kidney diseases for almost four decades. Continuing the work founded by Professor Konstantinos Deltas, we seek not only to record their genetic causes, but also to understand in depth the natural course of the disease, the factors that affect its progression and the ways in which new technologies can improve the diagnosis and monitoring of patients," said Dr. Papagrigoriou.
An important advantage is the possibility of close and repeated monitoring of patients, which is facilitated by the small geographical area of Cyprus and the cooperation between researchers and nephrologists. "Our geographical proximity and cooperation with clinicians allow us to maintain close contact with patients with rare kidney diseases and record the progression of the disease in real time," he said. "With their consent, patients can be re-examined two or three times a year, offering valuable insights into the natural course of the disease and the changes that occur over time."
The importance of genetic diagnosis
Genetic analysis is a key tool for diagnosing hereditary kidney diseases. In some cases, it can limit or prevent the need for a biopsy, while also contributing to a safer assessment of relatives who are considered as potential living transplant donors.
"Molecular diagnosis offers nephrologists an important tool to more accurately identify the cause of a disease, while in transplantation it contributes to a safer assessment of potential donor relatives," he explained. "Genetic diagnosis does not only inform us about the cause of the disease. Combined with clinical data, it can help us better assess its likely course, adjust follow-up and, where there is sufficient evidence, determine the most appropriate therapeutic approach," said Dr. Papagrigoriou.
Three therapeutic directions
The program examines three possible therapeutic approaches, each targeting a different mechanism of the disease.
4-PBA is being studied to see if it can help IV collagen get the right shape and better position itself in the membrane that supports the kidney's filters.
Fenerenone will be evaluated for its potential effect against inflammation and scarring in the kidneys, while specific peptides will be examined for whether they can protect cells from damage.
In a previous study, genetically modified mice that received 4-PBA showed improvement in the membrane structure of renal filters. Related lesions were reduced by about 54%, while fibrosis and scarring in the kidney filters were reduced.
"We are looking at three therapeutic approaches that target different mechanisms of the disease. We'll test them both separately and in combinations, to see if they can provide more benefit when used together. The goal of ALP-RARE is to create a portfolio of promising treatment options, supported by robust and reproducible preclinical data. Thus, the most effective approaches will be able to proceed with evaluation by the relevant regulatory authorities and the design of future clinical trials in humans," explained Dr. Papagrigoriou.
The consortium includes universities, hospitals, research institutes, a biotechnology company and patient organizations. "Meaningful patient participation is now a key element of modern research and is taken seriously by both funding agencies and regulators," Dr. Papagrigoriou pointed out. "Patients are informed about the progress of the program, ask questions and help us understand which symptoms and what effects of the disease burden them the most."
