SQS

Clarifying the cause of a skin disease led to the discovery of a new disease-causing gene, a new category of diseases, and new perspectives for both counseling and therapy. The discovery is the first time that epigenetic silencing, the 'switching off' of an otherwise intact gene, has been recognized as the cause for a skin disease. Clarifying the cause of a skin disease led to the discovery of a new disease-causing gene, a new category of diseases, and new perspectives for both counseling and therapy. The Kobe University discovery is the first time that epigenetic silencing, the "switching off" of an otherwise intact gene, has been recognized as the cause for a skin disease. Porokeratosis is a skin disease that leads to the development of annular or circular, red and itchy lesions. In some individuals, these develop all over the body, in some localized in lines, and in some only in one or very few spots. Kobe University dermatologist KUBO Akiharu previously discovered that patients need "two hits" to one of the four genes that, when damaged, were known to cause the disease. Kubo explains: "We get one set of genes from each of our parents, which means that, for all genes relevant to this disease, we have two copies. However, patients had one deficient copy in all of their cells, which means that they inherited that from one of their parents. But they also had later mutations in the other copy in those areas of the skin where the disease developed." After that discovery, over fifty patients visited Keio University Hospital and Kobe University Hospital to get screened by Kubo, and among these they found eight patients who didn't have deficiencies in any of the four genes known to cause the disease, and they also had slightly different symptoms. "I was convinced that there is a yet unknown cause of porokeratosis, and so my graduate student at Keio University, SAITO Sonoko, started to search for it." In The American Journal of Human Genetics, they now report that they identified a new gene, called FDFT1, that when damaged will cause porokeratosis. But while those patients who had lesions all over the body had one deficient copy inherited from one of the parents and one later mutation in the affected cells, which is similar to what is known for other causative genes, those with more localized lesions did not have such an inherited damaged copy. Kubo says, "These observations led to the hypothesis that not genetic, but epigenetic changes in FDFT1 are hidden as the first hits." Epigenetic changes don't affect the DNA sequence that constitutes the gene but refer to molecular tags a cell can add to DNA to indicate whether or not to produce proteins from the gene, depending on the tag. "And that is exactly what we found. Epigenetic silencing of FDFT1 during early embryonic development in a cell that will give rise to skin cells is the first hit in this type of porokeratosis." The whole picture therefore is that, in order to develop the disease, people need two damaged copies of the gene, "two hits." One they acquire either from their parents or through epigenetic silencing early in their fetal development. This predisposes them to developing the disease but in itself is not symptomatic. In the case of epigenetic silencing, individuals are mosaics of predisposed cells, which derive from the one where the silencing occurred, and unaffected cells. A second defect in the other copy of the gene leads to the development of the disease: Similar to the previously known causative genes, the protein produced from FDFT1 is involved in the production of cholesterol and with both copies of the gene deficient, toxic by-products accumulate in the cells. These results have many fascinating implications. First, the knowledge of the affected gene allows doctors to prescribe a treatment. "We conducted a therapeutic evaluation of atorvastatin (a blocker of cholesterol production) and cholesterol ointment in three individuals with FDFT1-deficient porokeratosis. All individuals exhibited reduced skin redness and thickening, pruritus (itchiness), and scaling within 4-12 weeks of treatment initiation, and no relapse was observed with continued use of the ointment," the researchers write in the paper. Second, when counseling patients, for those who didn't inherit a deficient gene from their parents it is reassuring news that they will also not pass the predisposition to the illness on to their children. And third, "This is the first skin disease caused by early-development epigenetic silencing of a particular gene. Among all diseases, a fully comparable mechanism is only known in Lynch syndrome. We thus expect that epigenetic causes are hidden not only in these but also in other diseases, suggesting the existence of a category of diseases associated with the silencing of genes," the researchers explain.

CAMBRIDGE, Mass.--(BUSINESS WIRE)-- Nimbus Therapeutics, a biotechnology company designing breakthrough medicines through structure-based drug discovery and development, today published research in the Proceedings of the National Academy of Sciences describing the structural basis for isoform-specific inhibition of human CTPS1 (CTP synthase 1). Selective inhibition of CTPS1 is a promising approach for the treatment of autoimmune and other T cell-driven diseases, but little is known about the mechanisms underlying selective versus non-selective inhibition. Nimbus scientists, in partnership with researchers from the University of Washington and Schrödinger, used cryo-electron microscopy (cryo-EM) to characterize the activity of CTPS inhibitors in binding to, inhibiting and distinguishing between CTPS1 and its isoform CTPS2. The cryo-EM research was funded by Nimbus and led by professor Justin Kollman at the University of Washington. “We’re proud to have conducted this impactful research in partnership with our valued colleagues at University of Washington and Schrödinger, further building on Nimbus’ long history of fruitful academic collaborations,” said Peter Tummino, Ph.D., Chief Scientific Officer at Nimbus. “The insights we have published will be instrumental in our efforts to develop selective inhibitors of CTPS1 that can potentially offer a powerful new means of treating autoimmune diseases and T cell-driven cancers.” “A defining feature of Nimbus’ structure-based drug discovery approach is our use of leading-edge computational technology, including cryo-EM, to characterize drug targets in unprecedented detail,” said Scott Edmondson, Ph.D., Senior Vice President and Head of Chemistry at Nimbus. “The discoveries made in this research, together with Nimbus’ expertise in computational chemistry, molecular sciences and disease biology, will inform our ongoing development of highly selective small-molecule CTPS1 inhibitors.” The paper, entitled “Structural basis for isoform-specific inhibition of human CTPS1,” published online in the Proceedings of the National Academy of Sciences this week: . About Nimbus Therapeutics Nimbus Therapeutics designs breakthrough medicines. Utilizing its powerful structure-based drug discovery engine, Nimbus designs potent and selective small molecule compounds targeting proteins that are known to be fundamental drivers of pathology in highly prevalent human diseases and which have proven difficult for other drug makers to tackle. Nimbus is headquartered in Cambridge, Mass.

The search for better T and B cell therapies have absorbed billions in R&D funds from some of the biggest drugmakers in the world. A French biotech thinks it could have a hyper-focused approach to T and B cell malignancies, and it’s taking home a decent-sized check to race to the clinic. Step Pharma has bagged $41.5 million in funding to take its lead CTPS1 inhibitor into clinical trials for T cell malignancies by the first quarter of 2022, the French biotech said Wednesday. The company’s science was based on the work of French immunologist Alain Fischer, who identified a genetic connection between the CTP synthase 1 enzyme and the inability of normal B and T cells to proliferate in patients. The company was initially seeded in 2015, and current CEO Andrew Parker stepped in about 18 months ago to help drive the company into Phase I studies. Step believes its focus on the CTPS1 enzyme can offer a hyper-targeted approach to spur T cells and B cells to target aggressive tumors. “The genetics told us that if you block CTP synthase 1, you’ve got this very specific effect on T and B cells,” Parker said. “That’s what really gives this a very targeted approach to inhibit proliferation of B cells and T cells and spare other cell types.” The initial Phase I, scheduled to enroll in the EU given the company’s established presence in France, will operate as a five-arm “basket study,” Parker said, with three arms focusing on T cell hematologic malignancies and two arms focusing on B cell conditions. If any arm shows clinical promise, the biotech plans to expand enrollment up to 35 patients in Phase II proof-of concept studies. In T cell lymphomas, Step believes a 35-patients study in the Phase II setting could be enough for a breakthrough designation and fast track, Parker said. Meanwhile, the B cell arms would likely require Phase III studies as they would apply to third-line-or-later patients. With the EU equivalent of an IND set for early 2022 — in the January or February range, by Parker’s count — Step is planning to expand its small team of five to around 10 as it enters the clinic. The round was co-led by new investors Hadean Ventures and Sunstone Life Science Ventures, which joined existing investors Kurma Partners, Pontifax and Bpifrance, which reinvested through its Innovative Biotherapies and Rare Diseases fund and InnoBio 2 fund. As part of the financing, Jacob L. Moresco from Sunstone Life Science Ventures and Walter Stockinger from Hadean Ventures will join the board.