Translational research yields new approaches to treatment for rare diseases

Rare diseases – sometimes referred to as “orphan diseases” – get left behind in the development of new treatments because of their low prevalence: because patient numbers are small, clinical studies are difficult to conduct and the pharmaceutical industry has no commercial interest in the issue. What can help here is close cooperation between publicly funded research and industry at international level. ANCA-associated vasculitis is one such rare disease. The standard treatment for it reduces mortality but has serious side effects. A few years ago, the research group led by Prof. Ralph Kettritz at the Experimental and Clinical Research Center (ECRC) – which is operated by the MDC and the Charité – identified an essential key element in the disease process, the complement receptor C5a. This receptor is a suitable target for a new and more specific drug. The development of an agent that blocks the receptor has now reached the stage of testing on patients. The multicentric phase II study is being conducted at clinics in North America and Europe, including the Department of Nephrology at the Charité.

From patients …

ANCA-associated vasculitis is a systemic disease in which an immune reaction to autologous structures in the white blood cells triggers inflammation in small blood vessels. If untreated, the disease leads to organ failure and death. The classical treatment involves suppressing the immune system by administering corticosteroids and cytostatic drugs – a powerful method that halts progression of the illness but can nevertheless end fatally for the patient on account of the severe side effects. According to Prof. Kettritz, there has been no real advance in treatment for the last 50 years. A new treatment that targets B lymphocytes is effective, but has also undesirable side effects, he says.

Prof. Kettritz is senior physician in the Department of Nephrology at the Charité in Berlin. ANCA-associated vasculitis frequently affects the intricate capillaries of the kidneys, the renal corpuscles, and results in kidney failure in many of his patients. The group of researchers at the ECRC is therefore interested in the exact details of the chain of events in the human organism that leads to this disease.

through research …

The disease is triggered by antibodies that target autologous proteins. Antibodies normally bind highly specifically to proteins of foreign invaders, marking them for immune defence. The ANCA (Anti-Neutrophil Cytoplasmic Autoantibodies), by contrast, attach themselves to components of the white blood cells, such as the myeloperoxidase. This activates these immune cells, which release oxygen radicals and highly active enzymes, thereby – as the research group has shown – switching on the complement system in the blood serum. The complement system usually defends the body against micro-organisms by releasing cytotoxins that attack the invaders in a strictly regulated cascade reaction. Cell culture studies conducted by the group at the ECRC have shown that proteins in the complement system, C5a and its receptor C5aR, are essential to the ANCA-induced immune activation.


Necrotizing inflammation of a glomerulus in a patient with ANCA vasculitis.

The researchers have also developed a mouse model. They bred genetically modified mice that lacked myeloperoxidase. To induce ANCA-associated renal vasculitis, these mice are first injected with myeloperoxidase. They then form autoantibodies. To trigger the ANCA-associated vasculitis, a further step is necessary. The mice that lack autologous myeloperoxidase – which means that the autoantibodies have not yet caused any damage – are given a transplant of bone marrow from a normal wild-type mouse. The animals now develop white blood cells that contain myeloperoxidase and are therefore targeted by the ANCA. After a short time, the mice thus treated develop the typical symptoms such as blood and protein in the urine and scarring and necrosis of the renal corpuscles. However, if the mice receive bone marrow from mice with no C5a receptor, almost no lesions are found in the tissue samples. These mice appear to be protected against the disease.

… to the drug

These findings, published as a basic research paper in the Journal of the American Society of Nephrology in 2009, inspired the company ChemoCentryx to look for ways to suppress the C5a receptor. Such inhibitors have potential as a therapeutic agent. After toxicology studies and tests of efficacy in animals, the company announced clinical trials for the agent CCX168 as a drug for ANCA-associated renal vasculitis. The first phase involves testing tolerance in healthy humans. In the second phase, CCX168 is administered to patients to identify its efficacy in humans. According to ChemoCentryx, the initial results are very positive. David Jayne, the principal investigator of the study, explains: “These Phase II data show encouraging signs that treatment with CCX168 both enabled a reduction in glucocorticoid exposure, and improved the speed and quality of remission.”

What particularly fascinates Prof. Kettritz is the successfully travelled route from hospital to laboratory and then to industry in order to find a highly promising agent that could in the near future bring patients a real improvement in their treatment: “The MDC has embraced translation – and our example is really translational.”


Adrian Schreiber, Hong Xiao, J. Charles Jennette, Wolfgang Schneider, Friedrich C. Luft, and Ralph Kettritz. C5a Receptor Mediates Neutrophil Activation and ANCA-Induced Glomerulonephritis (2009), J Am Soc Nephrol. doi: 10.1681/ASN.2008050497

The research group at the MDC’s Experimental and Clinical Research Center (ECRC):