MST2

Although periodontitis is an extremely prevalent disorder, it is challenging to conduct detailed and comprehensive analyses of its progression at the cellular level. Recently, researchers developed an improved periodontitis mouse model that simplifies the collection and analysis of multiple periodontal tissue types. Using this model, they clarified the role of an important signaling pathway in the inflammatory response of periodontal tissue, paving the way for better diagnostic and therapeutic strategies for periodontitis. Periodontal disease, represented by periodontitis, is the leading cause of tooth loss and affects close to one in five adults worldwide. In most cases, this condition occurs as a result of an inflammatory response to bacterial infection of the tissue around teeth. As the condition worsens, the gums begin to pull away, exposing teeth roots and bone. Notably, the incidence of periodontitis becomes more prevalent with age and with populations worldwide living longer, developing a solid understanding of its underlying causes and progression is important. In a study recently published in Nature Communications on March 28, 2024, researchers from Tokyo Medical and Dental University (TMDU) found a way to achieve this by improving upon a widely used animal model to study periodontitis. Studying periodontitis directly in humans is challenging. As a result, scientists often resort to animal models for preclinical research. For instance, the "mouse ligature-induced periodontitis model," since its inception in 2012, has enabled researchers to study the cellular mechanisms underlying this condition. Simply put, with this model, periodontal disease is artificially induced by ligating silk threads onto the molars of mice models, which induces plaque accumulation. While convenient and effective, this model, however, fails to capture the complete picture of periodontitis. "Even though the periodontal tissue is composed of gingiva, periodontal ligament, alveolar bone, and cementum, analyses are usually performed exclusively on gingival samples due to technical and quantitative limitations," remarks lead author Mr. Anhao Liu. "This sampling strategy limits the conclusions that may be drawn from these studies, so methods that allow for the simultaneous analysis of all tissue components are needed." To address this limitation, the research team developed a modified ligature-induced periodontitis model. Instead of the classic single ligature, they used a triple ligature approach on the upper left molar of male mice. This strategy expanded the range of bone loss without causing severe bone destruction around the second molar, increasing the yield of the different types of periodontal tissue. "We isolated the three main tissue types and evaluated the RNA yield between the two models. The results showed that the triple-ligature model effectively increased the yield, achieving four times the yield of normal peri-root tissue and supporting the high-resolution analysis of different tissue types," explains senior author Dr. Mikihito Hayashi. After confirming the efficacy of their modified model, the researchers proceeded to investigate the effects of periodontitis on gene expression among the different tissue types over time, focusing on genes related to inflammation and osteoclast differentiation. One of their main findings was that the expression of the Il1rl1 gene was markedly higher in peri-root tissue five days after ligation. This gene encodes the protein ST2 in both receptor and decoy isoform, which binds to a cytokine called IL-33 that is involved in inflammatory and immunoregulation processes. To gain further insights into the role of this gene, the team induced periodontitis in genetically modified mice that lacked the Il1rl1 or Il33 genes. These mice exhibited accelerated inflammatory bone destruction, highlighting the protective role of the IL-33/ST2 pathway. Further analysis of cells containing the ST2 protein in its receptor form, mST2, revealed that most of them were of macrophage lineage. "Macrophages are typically classified into two main types, pro-inflammatory and anti-inflammatory, based on their activation process. We found that mST2-expressing cells were unique in that they expressed some markers of both types of macrophages simultaneously," comments senior author Dr. Takanori Iwata. "These cells were present in the peri-root tissue before inflammation was triggered, so we named them 'periodontal tissue-resident macrophages.'" Together, the findings of this study showcase the power of this modified animal model to study the full scope of periodontitis in greater detail, right down to the biomolecular level. "We suggest the possibility that a novel IL-33/ST2 molecular pathway regulating inflammation and bone destruction in periodontal disease, alongside specific macrophages in peri-root tissue, is deeply involved in periodontal disease. This will hopefully lead to the development of new treatment strategies and prevention methods," concludes senior author Dr. Tomoki Nakashima.

Noam Galai/Getty Images This week began with four biopharma companies announcing intentions to become publicly traded companies and it’s ending with three companies making their debut on the Nasdaq. This morning, two of those companies, Ikena Oncology and Design Therapeutics, join Edgewise Therapeutics by trading on the exchange. Design Therapeutics Carlsbad, Calif.-based Design Therapeutics begins trading on the Nasdaq under the ticker symbol DSGN. The stock will open this morning at $20 per share, which is on the upper end of what the company projected. Design said it expects to raise approximately $240 million from the IPO, a little bit higher than the $228 million the company previously anticipated. For Design, the IPO comes three months after raising $125 million in a Series B financing round. Finances from the IPO, as well as the cash from the Series B, will be used to develop treatments for nucleotide repeat expansion disorders, including its lead program in Friedreich ataxia, which is expected to enter clinical development in the first half of 2022. Other disorders the company will target with its GeneTac platform will include myotonic dystrophy type-1, and other indications that have yet to be publicly announced. The company is developing a platform of gene-targeted chimera small molecules for the treatment of serious degenerative disorders caused by inherited nucleotide repeat expansions. Ikena Oncology Ikena Oncology, a company focused on developing cancer therapies targeting key signaling pathways that drive the formation and spread of cancer, begins trading on the Nasdaq at $16 per share. The stick will trade under the ticker symbol “IKNA.” Boston-based Ikena said it expects to raise $125 million from the IPO. In January, the company secured $120 million in a Series B financing round. Funds from the IPO and the Series B will support development of the company’s oncology pipeline. Ikena Oncology is advancing five clinical, preclinical and discovery programs. In January, Ikena announced IK-930, a TEAD inhibitor targeting the Hippo signaling pathway, has entered IND-enabling studies. Ikena plans to IND in the second half of 2021 and to initiate a Phase I clinical trial evaluating single-agent IK-930 in biomarker-enriched patient populations, such as those with Hippo pathway-altered tumors. Other assets in development include a lead optimization-stage KRAS signaling program dubbed IK-175; an AHR antagonist known as IK-412; a kynurenine-degrading enzyme; and IK-007, an EP4 receptor antagonist. Ikena has entered into a global strategic collaboration with Bristol Myers Squibb on the IK-175 and IK-412 programs. Edgewise Therapeutics Boulder, Colo.-based Edgewise Therapeutics will also begin selling its common stock this morning on the Nasdaq under the ticker symbol “EWTX.” The stock will begin trading at $16 per share and are expected to net the company about $176 million from the IPO. Like the other two companies, Edgewise Therapeutics recently conducted a financial raise. In December, Edgewise raised $95 million in a Series C financing round. Funds from that round, as well as the IPO, will be used to advance the company’s muscular dystrophy program, as well as other indications. Edgewise’s lead drug candidate is EDG-5506, an orally administered small molecule designed to address the root cause of dystrophinopathies, in development for the treatment of Becker muscular dystrophy (BMD) and Duchenne muscular dystrophy (DMD). EDG-5506 is currently being assessed in a Phase I study. Other biopharma companies will soon make their debut on stock exchanges. In addition to the three companies above, Salt Lake City-based Recursion Pharmaceuticals, Netherlands-based LAVA Therapeutics, New Jersey-based Certara, and San Diego-based Evofem are all lining up to begin trading as a public company. Each of these companies announced their intentions this week.