The search for the root cause of neurodegenerative diseases like multiple sclerosis (MS) has turned up many suspects, but one central to many research efforts is a type of immune cell called microglia. The dysfunction of these key cogs in the central nervous system has prompted a wide-ranging search for drugs that can alter their activity, but new research suggests we might already have one such drug at our disposal, with an existing drug delivering significant therapeutic effects on experimental models of MS.
Microglia are key to the body's ability to clear out harmful agents such as pathogens or cancerous cells, and find themselves at the heart of many research efforts aimed at curtailing chronic neurodegenerative diseases. This stems from a growing body of evidence tying infections of the central nervous system to disorders ranging from Alzheimer's to Parkinson's and MS, with studies continuing to demonstrate how understanding microglia behavior could lead to next-generation treatments for such diseases.
This includes how microglia that are missing key proteins can drive both Alzheimer's and MS, how microglia can heal damaged neurons to prevent seizures in Parkinson's and how microglia's role in disease might be mediated by our gut bacteria. The potential for new therapeutics that tweak microglia activity is vast, but scientists at Sweden's Karolinska Institutet tapped into modern screening methods to make sure existing candidates weren't being overlooked.
“The data-mining of open access databases is an approach that is both time and economically efficient, and there is so much data available nowadays,” says first author Keying Zhu. “We were lucky to identify four compounds with the properties we wished for, and one of these proved to be promising for our continued investigations, ultimately demonstrating significant therapeutic effect in our experimental model of MS.”
The compound in question is an inhibitor of the topoisomerase 1 (TOP1) gene, and its analog topotecan (TPT) is an FDA-approved treatment for small cell lung cancer. The team first showed that TOP1 was highly expressed in the inflamed tissues from MS patients and in mouse models. The scientists then crafted a new drug delivery system consisting of DNA origami (MyloGami) coated in naturally-occurring polysaccharides, which can be loaded with TPT (Topogami) to specifically target microglia. This system was demonstrated in in vitro cultures and also in in vivo experiments on mouse models of MS, where it significantly suppressed inflammatory response in microglia, and mitigated progression of the disease.
“The biotechnology industry has realized the potential for microglia-targeting strategies, and at least 20 new companies have started during recent years,” says study author Professor Bob Harris.“Compared to novel drug discovery programs that can take 20 years before a new medicine is approved, using existing prescribed drugs can halve that time.”
The research was published in the journal EMBO Reports.
Source: Karolinska Institutet