Nature releases new treatments for rare genetic diseases
An international research team scientist presented in the February 22 issue of Nature: Blocking causes Gauchers disease (GD) and other lysosomal storage disease (LSD) inflammation and organ damage The molecule can be used as a treatment, which is less expensive than current treatments.
The research team's report data was obtained from a mouse model of lysosomal storage disease and blood samples donated by patients with Gaucher disease.
Current methods of treating Gaucher disease and other lysosomal storage diseases include enzyme replacement therapy or substrate reduction therapy. These methods break down or prevent the accumulation of certain fat molecules and other waste particles that block cells to cause inflammation, damage to cells and organs, and in some cases lead to death. LSD patients lack enzymes that break down waste proteins and other waste particles. If the cells flow out of these wastes, the body will not function properly.
LSD is considered to be rare among 50 genetic diseases. According to the National Institutes of Health, their birth frequency is one in every 8,000 cases, making LSD a major challenge for the health care system. Researchers emphasize the need for new treatments.
"Current enzyme replacement and substrate reduction therapies are expensive and still associated with inflammation, with increased risk of malignant tumors and Parkinson's disease," said Dr. Manoj Pandey, a researcher at the first human author, Syndicate's Child Genetics Division. “We recommend targeting a molecule called C5aR1 that can be a viable treatment option for patients with Gaucher disease and other LSD patients.â€
Find the target
Through a study of laboratory mouse models and human cells, the team showed that C5aR1 is a key molecular pathway driving the inflammatory process of Gaucher disease. The inflammatory process of Gaucher disease is initiated by a genetic mutation in GBA1. GBA1 encodes the lysosomal enzyme glucocerebrosidase (GCase), which degrades the fatty molecule glucosylceramide (GC). C5aR1 is a small peptide (protein component) receptor from the complement system called C5a (part of the immune system) that drives inflammation in several different types of immune cells.
The disease process begins with a GBA1 mutation that drives the extensive accumulation of glucosylceramide in immune cells. Prior to the current study, the molecular processes linking glucose ceramide accumulation with inflammation, and the role of inflammation in disease progression, are unknown.
In the Gaucher mouse model, Pandey and colleagues showed that inflammatory glucosylceramide accumulation in spleen, liver, lung and bone marrow immune cells drives the induction of autoantibodies to glucosylceramide that forms immune complexes. These immune complexes promote the production of C5a and the activation of its receptor C5aR1.
In organ tissues from diseased mouse models, the researchers found evidence that C5aR1 catalyzes the accumulation of glucosylceramide by controlling enzymes that produce fat molecules. C5aR1 activation is a reminder of the balance between glucosylceramide formation and its degradation.
The researchers also found similar evidence for C5aR1 and related pro-inflammatory molecules in cells from blood samples donated by Gaucher patients.
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