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New method to develop therapeutics for autoimmune diseases

Posted: 30 November 2023 | | No comments yet

A technique that can sort millions of CRISPR-edited cells based on their secretion patterns has been developed to treat autoimmune diseases.

inflammatory diseases

An international team of scientists have developed a novel method, known as Secretion-Enabled Cell Ranking and Enrichment (SECRE) that could help in the discovery and development of new therapeutics for numerous globally prevalent autoimmune diseases.

Conditions such as lupus, rheumatoid arthritis, and inflammatory bowel disease (IBD), as well as failures within transplanted cells, are all caused by altered cytokine secretion of immune cells within the human body. To discover treatments for these diseases, researchers must identify the genetic regulators of the secretion to investigate the most effective ways of inhibiting them. The research is the result of a project lasting around four years between scientists in the UK, US, and Canada, led by Dr Shana Kelley, President of the Chan-Zuckerberg Institute and Professor at Northwestern University.

This method has been shown to be accurate in sorting hundreds of millions of CRISPR-edited cells based on their secretion patterns and recognising the genetic regulators of cytokine secretion in an autoimmune condition.  Also, the method accounts the detailed profiles of approved treatments, and those under development, to establish if therapies already in existence can be reapplied in new ways.

Dr Mahmoud Labib, Lecturer in the University of Plymouth’s Peninsula Medical School, and the main inventor of the approach said: “This is an incredibly novel approach that can potentially deliver huge benefits for patients, clinicians and the drug companies working to establish new treatments. It gives us the ability to sort large number of cells based on their secretion patterns and identify therapeutic targets that could be applied to help those with conditions for which there are currently few therapeutic options.”

He continued: “Through our existing work, we have demonstrated there is the potential for it to help identify ways of treating various autoimmune conditions, but my work is also now extending to types of cancer including some of the most aggressive types of brain tumours.”

 Inflammatory bowel disease

The long-term health condition inflammatory bowel disease (IBD), characterised by chronic inflammation of the digestive tract, is estimated to affect about seven million people worldwide. Currently, there is no known cure.

The researchers, as part of their work to validate their approach, examined the effect of several kinase inhibitors on CD4+ T cells, which are known to produce interferon gamma, a protein widely involved in several autoimmune diseases including IBD. The inhibitors studied included XMU-MP1, a small molecule that has been explored previously as a treatment for heart failure, hair loss and several other medical conditions.

For this study, the team used XMU-MP1 to treat mice with a form of colitis that has a similar cell secretion profile to that found in humans with IBD. The mice experienced significantly less weight loss and reduced colitis symptoms, while their colons remained virtually normal in appearance and did not show any significant loss of intestinal stem cells.

Based on these findings, the results indicate that using XMU-MP1 to inhibit interferon gamma production in the gut may represent an ideal means to control IBD. The researchers say it provides a promising future strategy for the therapeutic molecular targeting of the condition, although extensive clinical trials would be required before it could be considered as a treatment.

The SECRE technique

The SECRE technique captures the secreted cytokine on the surface of the cell. Then, these cytokines are labelled with magnetic nanoparticles and sorted at high resolution within a microfluidic device, fabricated using scaled three-dimensional (3D) printing.

This technique allows for rapid and high throughput sorting of cells based on their secretion patterns, making it amenable to large-scale functional genetic screens. This method also links the functional signature of the cell with its phenotype, enabling selective sorting of specific subsets of immune cells on the basis of specific cell-surface markers as well as the secretion specific factors. 

This study was published in Nature Biomedical Engineering.

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