Targeting a cell-death regulator to treat autoimmune diseases

3D medical background with DNA strand
Two groups of scientists identified mutations in RIPK1 that cause a previously unknown human autoinflammatory disease. (kirstypargeter/iStock/Getty Images Plus/Getty Images)

GlaxoSmithKline recently rolled back a RIPK1 inhibitor, GSK2982772, from phase 2 studies in ulcerative colitis, rheumatoid arthritis and psoriasis. But if two Nature studies are correct, the British pharma may want to take a second look at RIPK1 in autoinflammatory diseases.

A research team led by scientists at the Walter and Eliza Hall Institute of Medical Research in Australia and the National Institute of Health’s (NIH's) National Human Genome Research Institute identified three families whose members suffered from similar autoimmune symptoms and discovered that they all had irregularities in RIPK1, a gene that makes a key protein in the mediation of cell death and inflammation. By examining the patients’ exomes, which are the protein-encoding regions of the genome, the team found the seven patients showed different mutations but at the exact same location of RIPK1, according to one of the Nature studies.

Autoimmune diseases occur when the immune system attacks normal cells, which can cause fever, inflammation and damage to vital organs. The Eliza Hall-led team discovered that the members of the families they studied actually had a new autoimmune disease, which the team called CRIA syndrome. They suffered from episodic fevers and swollen lymph nodes, as well as several other inflammatory symptoms, beginning in early childhood and continuing throughout adulthood.

RIPK1 activation plays a key role in programmed cell death, too much of which can lead to inflammation. Normally, cells maintain a proper balance by cleaving RIPK1 with an enzyme called caspase-8. “In this autoinflammatory disease, the mutations are preventing the molecule from being cleaved into two pieces, resulting in uncontrolled cell death and inflammation,” John Silke, the study’s co-senior author, explained in a statement.

RELATED: Denali and Sanofi to press forward with RIPK1 drug in Alzheimer’s and other brain diseases

In a separate Nature study, a group led by researchers from Zhejiang University (ZJU) in China and Harvard Medical School described the same phenomenon in two families.

The ZJU-Harvard team also found that RIPK1 promotes not just cell death, but also the production of pro-inflammatory cytokines such as IL-6. Interestingly, five patients in Silke’s study and one in the ZJU-Harvard study showed significant reduction of symptoms when treated with Roche’s IL-6 inhibitor Actemra (tocilizumab). However, some had to discontinue the treatment due to side effects.

Silke and colleagues also studied the effect of RIPK1 mutations in mice. Mice with mutations in the same location that caused CRIA syndrome in humans showed a similar exacerbation of cell death and inflammation, the researchers reported.

RIPK1 has been linked to various disorders, including neurodegenerative diseases and metastatic cancer. But drug development focused on irregularities in the gene hasn't quite panned out. In addition to abandoning GSK2982772, GSK recently terminated the development of another RIPK1 inhibitor, GSK095, in pancreatic cancer.

Last year, Sanofi put down $125 million for two RIPK1 inhibitors by Denali Therapeutics. One of the drugs, DNL747, is being studied in early-stage clinical trials for Alzheimer’s disease and amyotrophic lateral sclerosis.

The discovery of CRIA syndrome could enhance the effort to target RIPK1 with drugs, said Daniel Kastner of the NIH’s National Human Genome Research Institute, a pioneer in inflammatory disorders and co-senior author of the study alongside Silke. “Understanding the molecular mechanism by which CRIA syndrome causes inflammation affords an opportunity to get right to the root of the problem,” Kastner said.

“RIPK1 inhibitors may be just what the doctor ordered for these patients,” he added. “The discovery of CRIA syndrome also suggests a possible role for RIPK1 in a broad spectrum of human illnesses, such as colitis, arthritis and psoriasis.”

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