Discovery of the Mechanism for A Rare Autoinflammatory Disease Brings Repurposed Treatment

A global research team led by scientists at Mount Sinai have discovered the underlying biology of a rare autoimmune condition and have also identified an existing U.S. Food and Drug Administration approved class of drug to treat it.

The scientists discovered that a protein that activates the body’s antiviral defenses can cause a rare rheumatoid-like autoinflammatory condition that is treatable with an FDA-approved class of drugs known as TNF (tumor necrosis factor) inhibitors.

The findings appear in the journal Cell.

Though the condition had been known to researchers, it has now been named TBK1 deficiency. The researchers reported that the absence of the protein, known as TBK1 (TANK-binding kinase 1), renders cells vulnerable to a form of programmed cell death in response to TNF, but that this genetic defect can be effectively and quickly addressed by therapeutic agents that block the source of the inflammation.

Homozygous mutations in TBK1, which occur when copies of the aberrant gene encoding the protein are passed on by both parents, are extremely rare. Based on past studies in mouse models and human cell cultures, researchers assumed that these mutations would leave individuals susceptible to a wide range of viral infections. They found instead that none of the four people in the cohort they studied, ages 7 to 32, showed signs of inadequate antiviral immunity. Rather, they all suffered from a systemic autoinflammatory condition that resulted from a dysregulated response to TNF, an important protein involved in controlling inflammation and cell death.

“TBK1 signaling activates the body’s antiviral mechanisms to fight off infection and block different stages of viral replication, as well as control TNF-mediated inflammation,” said lead author Justin Taft, an investigator in the Department of Microbiology at the Precision Immunology Institute and the Center for Inborn Errors of Immunity at the Icahn School of Medicine at Mount Sinai. “But if a mutation prevents expression of the TBK1 gene or disrupts its function, then cells become overly sensitive to TNF. And that can trigger a disproportionate amount of cell death, which sets off a violent cascade of debris from dying cells that inflames surrounding tissue and fuels the inflammation.”

By treating TBK1-deficient individuals with anti-TNF therapeutics, the team confirmed its suspicions about the underlying biology of the genetically driven condition.

“We have essentially defined a new disease and its associated mechanisms of autoinflammation, which previously were managed with steroid treatments, non-steroidal anti-inflammatory drugs, or other non-specific therapeutics clinicians deemed worth trying,” said Dusan Bogunovic, Director of the Center for Inborn Errors of Immunity and senior author of the study. “We were able to target the condition directly and effectively with TNF inhibitors once we knew the causative factors of the inflammation. And the clinical improvement was quick and substantial.”

Photo: Justin Taft, an investigator in the Department of Microbiology at the Precision Immunology Institute and the Center for Inborn Errors of Immunity at the Icahn School of Medicine at Mount Sinai.

Author: Rare Daily Staff