According to a recent article in Pharma Tutor, researchers at NHGRI, a division of the National Institute of Health, identified the biological cause of a newly-discovered autoinflammatory disease they named the CRIA syndrome.
They identified an error at a location where a DNA letter was changed incorrectly and discovered that the disease they were tracking was the result of a genetic mutation of the RIPK1 gene. The RIPK1 gene encodes for the RIPK1 protein that has a significant role in cell death pathways.
Symptoms of CRIA,
Dr. Daniel Kastner, the scientific director of NHGRI and his associates, were responsible for the discovery of CRIA.
Its symptoms include but are not limited to swollen lymph nodes, abdominal pain, fever, problems associated with various gastrointestinal disorders, and enlarged liver and/or spleen.
People with suspected autoimmune diseases are advised to “be patient” as it takes a long time to diagnose these complex diseases. In fact, seven people who have been treated every few weeks for a fever of unknown origin have finally been diagnosed by researchers, who discovered that the cause of their symptoms is CRIA syndrome.
CRIA appears to mimic a typical autoinflammatory disease in that the patient’s immune system is activated without an obvious trigger.
CRIA does not appear to be life-threatening. However, serious and painful symptoms follow the patients throughout their lives.
Finding RIPK1
A total of 554 people were examined who exhibited symptoms of unknown origin such as continuous fever and swollen glands. These examinations were followed by random studies of databases containing profiles of 250,000 people to find evidence of the RIPK1 mutation. They did not.
To the scientists, this was clear evidence that “they were on to something.”
About the RIPK1 Protein
Normal cells are protected from an action by RIPK1 to promote cell death through another protein that “cuts” RIPK1 in the protein sequence.
Dr. Kastner’s team, while observing CRIA patients, saw that mutations occurred at the exact location where the RIPK1 protein gets cut.
This was evidence that they could control inflammation and cell death by cutting RIPK1. The disorder was named CRIA (cleavage-resistant RIPK1-induced autoinflammatory) syndrome.
Collaborating With the Australian Team
In order to study the molecular mechanisms involved, Dr. Kastner contacted doctors Laloui and Silke at an Australia medical institute. The doctors created mouse models that had RIPK1 mutations similar to those found in CRIA patients.
Doctors Laloui and Silke found that mouse models with two RIPK1 mutations suffered cell death which was proof that RIPK1 must be cut.
But mice that had one normal copy and one mutated copy of RIPK1, as in the CRIA syndrome, were responsive to inflammatory stimuli. The researchers believe that in some way these reactions may provide clues to the origin of various human diseases.
Finding A Therapy For CRIA
The Kastner team treated several patients with the anti-inflammatory drugs etanercept and anakinra with little success.
A third drug, tocilizumab, proved to be somewhat more successful, as it can suppress the immune system. In the case of CRIA, tocilizumab reduced the frequency and severity of its symptoms.
RIPK1 inhibitors are now being developed for CRIA syndrome and in an effort to relieve symptoms of other inflammatory disorders.
