Novel Therapeutic Strategy Identified for Crohn's Disease
- Some patients with Crohn's disease have a genetic risk factor: mutations in a chromatin reader known as speckled protein 140 (SP140), which is expressed only in macrophages and other immune cells
- This study sought to determine the normal function of SP140 as well as how alterations in the protein affect chromatin structure and can eventually lead to immune disease
- SP140 was found to be a negative regulator of topoisomerases 1 and 2 (TOP1/2), chromatin-remodeling enzymes that have a key role in DNA replication
- Mice with SP140 and humans with SP140 mutations exhibited uncontrolled TOP activity and impaired macrophage function; conversely, in a mouse model of Crohn's disease, TOP inhibition reduced markers of intestinal inflammation
- Some TOP inhibitors are already FDA-approved for cancer treatment, and this study provides a rationale for clinical trials to investigate them as targeted therapies for patients with Crohn's disease who have SP140 mutations
Chromatin—the collection of DNA, RNA, and associated proteins that form chromosomes—is compressed within cell nuclei to control DNA replication and gene expression. Proteins called chromatin "readers" help maintain proper chromatin structure, often in response to environmental cues.
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Dysregulation of chromatin readers is a key event in cancer, and increasing evidence implicates altered chromatin readers in immune disorders as well. Mutations in a chromatin reader known as speckled protein 140 (SP140) have been associated with chronic lymphocytic leukemia as well as Crohn's disease, multiple sclerosis, and susceptibility to tuberculosis.
Hajera Amatullah, PhD, a research fellow in the Center for the Study of Inflammatory Bowel Disease in the Division of Gastroenterology at Massachusetts General Hospital, Kate L. Jeffrey, PhD, a scientist at the Center and associate professor of Medicine at Harvard Medical School, and colleagues recently discovered how SP140 directly contributes to Crohn's disease. In Cell, they explain their findings may lead to a novel therapeutic approach to Crohn's and other immune diseases.
A Critical Functional Role
SP140 is expressed only in immune cells such as macrophages. The researchers found it normally represses and shields topoisomerases 1 and 2 (TOP1/2), chromatin-remodeling enzymes that help DNA untangle during replication. In this way, SP140 maintains the cytokine and bacterial killing functions of macrophages, preventing Crohn's disease and other inflammatory conditions.
Conversely, loss of SP140 in humans and mice resulted in uncontrolled TOP activity and impaired macrophage function. In a mouse model of Crohn's disease, inhibition of either TOP1 or TOP2 restored macrophage function and reduced markers of intestinal inflammation.
Laying the Groundwork for Novel Therapies
A number of TOP inhibitors for cancer treatment, such as topotecan, irinotecan, and etoposide, were approved years ago by the FDA, and others are in clinical trials. They produce cytotoxic effects by interfering with DNA replication.
This study provides a rationale to conduct clinical trials of FDA-approved TOP inhibitors for targeted treatment of patients with Crohn's disease who have SP140 mutations.
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