Blocking Key Immune Pathway May Halt Severe Effects of Sickle Cell Disease

Sickle cell disease can cause a dangerous complication called acute chest syndrome (ACS), yet the biological processes behind it have remained unclear. Now, researchers at Mass General Brigham have uncovered a surprising culprit—an ancient immune pathway that becomes highly active in patients with ACS and plays a central role in driving the condition (1^✔ ✔Trusted Source
Complement is activated in patients with acute chest syndrome caused by sickle cell disease and represents a therapeutic target

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FDA-Approved Drugs Show Promise for Sickle Cell ACS

In preclinical models, the team demonstrated that blocking this pathway with existing FDA-approved drugs significantly reduced the severity of ACS symptoms. These findings, published in Science Translational Medicine, open the door to new therapeutic approaches that could dramatically improve outcomes for patients with sickle cell disease.

“Despite ACS being the leading cause of mortality in patients with sickle cell disease, we can currently only offer supportive care to our patients,” said corresponding author Sean Stowell, MD, PhD, of the Department of Pathology at Brigham and Women's Hospital, a founding member of the Mass General Brigham healthcare system. “Our study offers potential targets for therapeutic intervention for this devastating condition.”

Sickle Cell Disease: Unraveling the Complement System's Role in Acute Chest Syndrome

Sickle cell disease occurs due to an inherited mutation in hemoglobin that causes the destruction of red blood cells (RBCs), or hemolysis. This, in turn, can block blood vessels, injure the lungs, and eventually progress into ACS—a condition that includes shortness of breath, chest pain and wheezing that can quickly progress and turn fatal. Prior research has suggested that hemolysis can activate the complement system — a group of immune proteins that trigger a cascade of events to eliminate pathogens. However, it has been unclear how the complement system contributes to ACS and disease progression.

The research team analyzed blood samples from 27 patients with sickle cell disease and detected higher baseline levels of complement activation when compared to healthy controls. They also observed increased complement activation in patients experiencing ACS. Using a mouse model of sickle cell disease, the investigators found that the complement pathway helped cause the breakdown of red blood cells, indicating that factors other than mutated RBCs may be contributing to the symptoms of sickle cell disease.

They also found that the breakdown of red blood cells caused by complement activation created a cycle of even more activation, which led to ACS. By removing certain complement proteins or using existing drugs to block them, researchers were able to reduce the breakdown of red blood cells and prevent ACS in their studies with animal models.

The authors propose that randomized clinical trials could be conducted to see if complement inhibitors that target different parts of the pathway could be effective in patients with ACS.

Reference:

1. Complement is activated in patients with acute chest syndrome caused by sickle cell disease and represents a therapeutic target - (https://www.science.org/doi/10.1126/scitranslmed.adl4922)

Source-Eurekalert