Approved gout therapy colchicine shows promise for Gaucher in lab
Oral anti-inflammatory med reduced fat accumulation in cell model
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Colchicine, an approved anti-inflammatory medication for treating gout, significantly reduced fat accumulation and signs of cellular damage in a cell model of Gaucher disease, according to a new study.
The lab findings suggest that the oral treatment — which was identified for potential use in Gaucher with the aid of computational analyses of large biological datasets — could possibly be repurposed to treat the rare genetic disorder.
“The results demonstrated that colchicine significantly suppressed lipid [fat] accumulation, suggesting its potential as a therapeutic candidate for Gaucher disease,” the researchers wrote, noting that the drug, “an alkaloid extracted from the lily plant Colchicum autumnale, has been used for the treatment of gout for over 2000 years and possesses broad-spectrum anti-inflammatory properties.”
The team noted that the research to date on the medication’s use in Gaucher has been conducted only in a laboratory. As such, “additional investigations are required to further support and validate the drug’s therapeutic effects,” the researchers wrote.
The discovery was detailed in a study titled “A bioinformatics-guided analytical approach for drug repositioning: Colchicine as a candidate for gaucher disease treatment,” which was published in the journal Analytical Biochemistry.
Gaucher is caused by mutations in the GBA1 gene, which provides instructions for the enzyme glucocerebrosidase, known as GCase. This enzyme is needed to break down certain fatty molecules inside cells. When it is missing or abnormal, these substances accumulate abnormally, leading to cell dysfunction and a range of disease symptoms.
People with Gaucher also show a higher incidence of malignant melanoma, the most aggressive form of skin cancer. Additionally, carrying a mutated copy of the GBA1 gene significantly raises the risk of developing Parkinson’s disease, which is also tied to melanoma.
Still, the underlying biological mechanisms linking these conditions remain poorly understood.
Repurposing colchicine for Gaucher could potentially be cheap, quick
Drug repurposing — the process of finding new medical uses for existing drugs — is a promising development strategy because it offers shorter timelines, lower costs, and higher success rates than developing new drugs from scratch. This is in large part because the given treatment’s safe use in humans is already established.
With this in mind, a team at Hoseo University in South Korea sought to identify genes altered in both Gaucher disease and melanoma to find therapeutic targets amenable to existing drugs. To do so, the scientists used bioinformatics, a technique that employs computational tools to analyze large biological datasets.
The researchers first examined patterns of gene activity across thousands of genes, using datasets from GBA-mutated Parkinson’s tissue models and melanoma samples. When gene activity data from the two diseases were compared directly, 121 disease-associated genes overlapped.
Additional computational tools identified 14 hub genes, or those with the highest degree of interconnectivity with other genes. When the team examined gene activity across several independent datasets of melanoma and disorders similar to Gaucher — which also impact enzymes that degrade unwanted cellular components in cellular compartments called lysosomes — only one hub gene, called CCN2, was consistently increased across all datasets.
After screening approved drugs known to be associated with CCN2, eight potential candidates were identified. Among them, dexamethasone and losartan bound with high affinity to the CCN2 protein, but another drug called colchicine showed the most consistent binding to the protein, and was selected for further analyses.
In this study, we used bioinformatics … [and] demonstrated the therapeutic potential of the candidate drug, colchicine.
An anti-inflammatory, colchicine is primarily used to prevent and treat flares of gout, a form of inflammatory arthritis caused by deposits of uric acid crystals in the joints. It’s also approved to reduce the risk of heart attack, stroke, and cardiovascular death.
To evaluate colchicine’s effectiveness, the team used a Gaucher model in which cells were exposed to CBE, a molecule that inhibits GCase activity.
Exposure to CBE increased levels of reactive oxygen species, which cause cell-damaging oxidative stress, a feature of Gaucher. When colchicine was added alongside CBE, oxidative stress was reduced. Colchicine also significantly reduced CBE-induced accumulation of fatty molecules.
“In this study, we used bioinformatics to identify CCN2 as a key common biomarker linking Gaucher disease and melanoma,” and “demonstrated the therapeutic potential of the candidate drug, colchicine,” the team concluded.
