JAG1

Study led by experts at Cincinnati Children's sheds light at the cellular level on how heart valve tissues form. Findings eventually may improve survival odds for newborns with heart valve defects. CINCINNATI, July 30, 2024 /PRNewswire/ -- Imagine a future where doctors could detect and treat potentially fatal heart valve defects months before a baby is born. While this future is still a few years away, scientists have made significant progress by creating a detailed map of how human heart valves form. This new map, published July 24, 2024, in Nature Cardiovascular Research, will help guide future heart research. Continue Reading Healthy vs. defective heart valve formation: On the left side, representing healthy valve development, unidirectional blood flow induces Jag1 production in valve endothelial cells (VECs), which activates NOTCH2-mediated Notch signaling when these cells contact Elastin-expressing valve interstitial cells (VICs). This process promotes downstream elastogenesis-related gene expressions. On the right side, representing defective development, a lack of APOE in pulmonary stenosis patients suppresses Notch signaling, leading to elastogenesis defects. Emerging blueprint for replacement valves that can grow Heart valves might be small, but they're incredibly important. Doctors have been replacing damaged heart valves in adults for many years, and sometimes they can save newborns with artificial valve transplants. But these artificial valves aren't perfect. They don't have living cells, so they can't form a completely normal valve. They also don't grow with the child, which means the child might need several risky surgeries as they get older. "Engineered human heart valves with the appropriate cell types for transplantation would avoid repeated surgeries in babies and address the donor valve shortage," says corresponding author Mingxia Gu, MD, PhD, an expert in molecular and cardiovascular biology at Cincinnati Children's. "Now, we've achieved an unprecedented understanding of the cellular composition of human heart valves and how fetal heart valve tissue changes over time. This is a crucial first step for future human valve engineering." How do heart valve leaflets form? The human heart has four valves that control the flow of blood through the heart's chambers. Each valve has two or three thin and fragile-seeming leaflets that open and close more than 2.5 billion times across a lifetime. When a baby is growing in the womb, the cells that make up these leaflets change completely. At 14 weeks, the leaflets are mostly made of complex sugars. By 36 weeks, they turn into three-layered tissues with a mix of flexible and stiff fibers. If these leaflets don't form correctly, it can cause serious heart problems. Heart valve birth defects are rare. The most common type, called bicuspid aortic valve, occurs among an estimated 0.5% to 2% of people. This condition occurs when two of the normal three leaflets of the aortic valve stick together. Those affected need life-long monitoring may require valve replacement surgery at some point. Other conditions that can involve defective heart valves include valve prolapse in Marfan syndrome, a narrow pulmonary valve in tetralogy of Fallot, and a missing aortic valve in hypoplastic left heart syndrome. Unexpected role played by the gene APOE The Cincinnati Children's research team studied healthy and faulty heart valves all the way down to the single-cell level. They documented in unprecedented detail how various cell types signal each other to form valve tissues. In a key finding, the team discovered a cell type that expresses high levels of the gene APOE. This gene needs to work in concert with another gene called NOTCH2 to make the elastin fibers essential for heart valve function. The involvement of APOE was surprising because previously the gene had been known only for its role in atherosclerosis and Alzheimer's disease. The paper further describes signaling "crosstalk" among key genes as they instruct developing cells to form the heart valve tissues. This process continues as the fetus grows and continues after birth until the heart reaches its full adult size. "The finding of APOE as the top regulator in modulating elastin formation during early valve formation could yield a new angle for clinicians to understand heart valve underdevelopment," says co-corresponding author Yifei Miao, MBBS, PhD. How can these findings help people with heart valve defects? Researchers will need several more years to figure out how to use these new discoveries to help people. Knowing which genes are key for making the various parts of heart valves—and which ones function incorrectly in babies with heart valve defects—will provide vital clues for creating future gene or cell therapies. One exciting idea is to use the new atlas to engineer a "human valve" for valve replacement therapy. Currently, replacement valves include mechanical devices, biological ones made from cow or pig tissue, and some human valves obtained from donated organs. The new atlas may help scientists build or "grow" human-tissue valves in the lab. "This atlas provides insights into the similarities and differences among the four human valves, enabling more precise valve engineering and deep understanding of the valve-specific phenotypes in patients," Gu says. "The newly discovered APOE+ valve cell type could be crucial for seeding onto an engineered valve scaffold to mediate elastin fiber formation, which is essential for valve remodeling and function." About the study Cincinnati Children's co-authors also included Ziyi Liu, MD, Yu Liu, PhD, Zhiyun Yu, PhD, Cheng Tan, MD, Nicole Pek, BSc, Anna O'Donnell, BS, MBA, Minzhe Guo, PhD, Katherine Yutzey, PhD, and David Winlaw, MBBS, MD, (now at Lurie Children's Hospital). Co-authors also included experts with the Stanford School of Medicine, the University of Michigan, the University of Washington, and the Icahn School of Medicine at Mount Sinai, New York. Funding sources for this study include support from Additional Ventures (1019125), an Endowed Scholar Award from Cincinnati Children's, two grants from the Chan Zuckerberg Initiative (CZF2019-002440 and CZF2021-237566), and two American Heart Association Predoctoral Fellowship grants (1013861 and 906513). This research was further supported by the Cincinnati Children's Heart Institute Biorepository, the Discover Together Biobank, the Division of Pulmonary Biology, and core research facilities in Pathology and Confocal Imaging. SOURCE Cincinnati Children's Hospital Medical Center

BOSTON, MA / ACCESSWIRE / March 27, 2024 / Pieris Pharmaceuticals, Inc. (NASDAQ:PIRS) provided a corporate update today announcing a strategy to maximize its ability to capture the potential milestones from its 4-1BB bispecific Mabcalin® (antibody-Anticalin fusion) protein immuno-oncology assets partnered with Pfizer (formerly Seagen), Boston Pharmaceuticals, and Servier. After considering an extensive range of options, the Company's Board of Directors decided to implement this new strategy along with relevant cost-saving measures that are expected to extend the Company's cash runway into 2027. The Company's strategic review process has focused on maximizing stockholder value, which includes the preservation of potential milestone and royalty payments the Company is eligible to receive. Management and the Board of Directors evaluated a broad spectrum of potential options, including asset in-licensing, out-licensing, royalty monetization, strategic transactions (including reverse mergers, strategic mergers, and sale), and liquidation. With the assistance of the Company's retained strategic advisor, Stifel, Nicolaus & Company, more than 500 companies were contacted regarding a strategic transaction, and the Company underwent a robust process to identify and negotiate with a select number of final candidates. The Company entered into extended exclusivity with one party contemplating a strategic merger, which centered on that party's interest in developing the Company's clinical-stage asset cinrebafusp alfa, but after extensive diligence and negotiations, that counterparty was unable to secure adequate capitalization and offer acceptable terms. The Company ultimately determined that the Company's planned repositioning offers the best opportunity to maximize stockholder value. "After an extensive review of strategic alternatives, our Board has determined that retaining the value of future milestone and royalty potential, which could result in up to $75 million of milestone payments during the next several years, as well as potential significant downstream milestones and royalty economics is key to maximizing value for our shareholders," said James Geraghty, Chairman of the Board of Directors. "Implementing a lean business model with substantially reduced operating expenses results in an expected cash runway into at least 2027, while offering risk-mitigated diversification with high quality partners. Finally, on behalf of the full board, I want to express our gratitude to our employees for all their contributions and express to our investors our commitment to maximize shareholder value going forward." In support of optimizing potential milestones and royalties, the Company's strategic repositioning includes: A plan to maintain strategic capability by maintaining a lean and experienced Board and management pro actively pursue the Company's strategy and consider strategic options; The discontinuation of all the Company's research and development efforts, which is expected to be completed by the middle of 2024; A workforce reduction that affects additional employees and the executive leadership team, expected to be implemented in the second quarter; A plan to reduce the size of the Company's Board of Directors, to be better aligned with the nature of the Company's continuing operations, also expected to be implemented in the second quarter; "A compelling feature of this new strategy is its planned self-funded nature, offering the opportunity to capture meaningful future milestones and royalties through multiple partnered programs that are fully funded by third parties," commented Stephen Yoder, President and Chief Executive Officer. Mr. Yoder continued, "The new strategy will also facilitate the potential to pursue milestone and royalty monetization agreements with third parties to possibly accelerate cash distributions to shareholders." Since initiating the strategic review in July 2023, the Company implemented several steps, including scaling back operational costs, inclusive of associated headcount reductions, ceasing development of PRS-220 and PRS-400 within its respiratory franchise, and suspending investments associated with co-development of partnered assets. The Company has also eliminated its material long-term obligations through the previously disclosed termination of its lease obligation in Germany, while simultaneously continuing to improve its cash position through the sale of its laboratory and office equipment. As previously disclosed, the Company remains eligible to receive contingent milestone and royalty payments across its partnered 4-1BB bispecific Mabcalin protein franchise resulting from its partnerships with Pfizer, Boston Pharmaceuticals, and Servier. More specifically: All partnered programs are fully funded by the respective partner, and there are no further discovery or development obligations for the Company; The Company may be entitled to aggregate milestones of up to $20 million upon first patient dosed in the phase 2 trials for SGN-BB228, S095012 (formerly PRS-344) and BOS-342, which are all currently in phase 1 clinical development; The Company may be entitled to aggregate milestones of up to $55 million upon first patient dosed in pivotal clinical trials for SGN-BB228, S095012 (formerly PRS-344) and BOS-342; Two additional discovery programs with Pfizer that would entitle the company to additional milestones if brought forward into IND-enabling activities; Total development milestone potential from the three clinical stage assets in single, primary indications could be up to $275 million. Total commercial milestone potential on the same assets, if they are approved, could amount to more than $500 million. A potential additional aggregate amount of up to $160 million in both developmental and commercial milestones exists if these programs are developed in additional indications; and In addition to the milestone potential, all programs are eligible for royalties from commercial sales ranging from mid-single digits to low double digits. In addition to alliance management activities for the partnered programs above, the Company remains committed to trying to obtain value for its products in prior development, including cinrebafusp alfa, as well as proprietary platform capabilities by pursuing potential out-licensing or sale transactions. In addition to pursuing possible monetization of the projected royalty and milestone payments at attractive valuations, the Company may also, from time-to-time, opportunistically consider other options that it believes may increase stockholder value. We can provide no assurance that the Company will receive any potential milestone or royalty payments or on the timing of any such milestone or royalty payments that may become due, or that any potential strategic transactions will occur. As of December 31, 2023, the Company had $26.4 million in cash and investments. The Company does not expect to have any future financing requirements to achieve the near-term milestone potential of its partnered programs. The Company may consider cash dividends as and when milestone or other payments are received if the Company determines there is sufficient cash and investments to achieve the Company's near and long-term objectives. About Pieris Pharmaceuticals: Pieris is a biotechnology company based in Boston, Massachusetts that could potentially be entitled to receive development, regulatory, and sales-based milestones from its 4-1BB bispecifics immuno-oncology assets partnered with Pfizer (formerly Seagen), Boston Pharmaceuticals, and Servier. In addition to the milestone potential, Pieris would be eligible for sales royalties on the same partnered programs if they ultimately are approved for commercialization. The Company is seeking potential acquirers for its remaining preclinical and clinical assets. For more information, visit . Forward-Looking Statements: This press release contains forward-looking statements as that term is defined in Section 27A of the Securities Act of 1933, as amended, and Section 21E of the Securities Exchange Act of 1934, as amended. Statements in this press release that are not purely historical are forward-looking statements. Such forward-looking statements include, among other things statement relating to, our expected cash runway and our belief that the Company's strategy is fully funded; any potential future cash dividend; statements relating to the strategy being self-funded; statements relating to potentially considering strategic opportunities; anticipated timing, achievement, and receipt of milestone and/or royalty payments provided for in our collaboration agreements; the potential size of potential milestones and royalties; the timing, impact, and extent of reductions in our workforce and the size of our Board of Directors; the cost-saving potential of our strategic reprioritization and restructuring; the potential for us to out-license or sell our products in prior development, including cinrebafusp alfa, and our proprietary platform capabilities; and the possible monetization of milestone and royalties. Actual results could differ from those projected in any forward-looking statement due to numerous factors. Such factors include, among others, expectations for achievement of contractual milestones; availability of funding sufficient for the Company's foreseeable and unforeseeable operating expenses; our cash runway may be reduced by unanticipated liabilities or decisions to opportunistically pursue strategic opportunities; our ability to be successful in exploring and consummating one or more licensing or other transactions on attractive terms if at all for our proprietary platform capabilities or our products in prior development; our ability to maintain a lean and capable management team and board over time; our actual reductions in spending as compared to anticipated cost reductions; including in collaboration with other parties, the inherent uncertainties associated with developing new products or technologies, such as Anticalin based compounds, our partners' ability to develop, complete clinical trials for, obtain approvals for and commercialize any of our partnered product candidates; our partners ability to achieve expected market share if the drugs are approved and commercialized; uncertainty of overall market size of any of our partnered product candidates; competition in the industry in which we operate; the possibility that our partners may decide not to prioritize or further pursue the programs that we hope to receive milestone and royalty payments under; the fact that data and results from clinical studies may not necessarily be indicative of future results; we may face challenges in continuing to comply with Nasdaq listing standards, such as those relating to minimum price and operating company status; delays or disruptions due to geopolitical issues, including the conflict in Ukraine and the Middle East; and overall market conditions. These forward-looking statements are made as of the date of this press release, and we assume no obligation to update the forward-looking statements, or to update the reasons why actual results could differ from those projected in the forward-looking statements, except as required by law. Investors should consult all of the information set forth herein and should also refer to the risk factor disclosure set forth in the reports and other documents we the Securities and Exchange Commission, or the SEC, available at including, without limitation, the Company's most recent Annual Report on Form 10-K, the Company's Quarterly Reports on Form 10-Q, and subsequent filings with the SEC. Investor Relations Contact: Pieris Pharmaceuticals, Inc. Investors@pieris.com SOURCE: Pieris Pharmaceuticals, Inc. View the original press release on accesswire.com

Researchers have used DNA origami, the art of folding DNA into desired structures, to show how an important cell receptor can be activated in a previously unknown way. The result opens new avenues for understanding how the Notch signalling pathway works and how it is involved in several serious diseases. Researchers at Karolinska Institutet in Sweden have used DNA origami, the art of folding DNA into desired structures, to show how an important cell receptor can be activated in a previously unknown way. The result opens new avenues for understanding how the Notch signalling pathway works and how it is involved in several serious diseases. The study is published in Nature Communications. Notch is a cell receptor that is of great importance to a wide range of organisms and plays a crucial role in many different processes, including early embryonic development in both flies and humans. Notch regulates the development of stem cells into different cell types in the body. Defects in this signalling pathway can result in serious diseases, including cancer. The prevailing view of the receptor's function has so far been that it is activated purely mechanically, by a neighbouring cell pulling on it, meaning that signalling only occurs as a result of direct communication between cells. However, researchers at Karolinska Institutet now report that the activation of Notch can also be achieved 'on demand' with the help of a protein called Jag1. The researchers placed the protein on a DNA structure created by so-called DNA origami, a technique that makes it possible to build structures of any shape at the nanoscale using DNA as a building material. In this case, the DNA structure was moulded into a nano-sized stick that can carry the protein to the cell surface. "This is a technique that allows us to place molecules of the Jag1 protein at very small distances from each other in different patterns, and then we have exposed these patterns to stem cells with Notch receptors," says Björn Högberg, professor at the Department of Medical Biochemistry and Biophysics, Karolinska Institutet, who led the study together with KI researcher Ioanna Smyrlaki at the same department. The results show that the Notch receptor can be activated to different degrees, depending on the shape of the pattern and the local concentration of the protein. However, several questions remain about how exactly this signalling takes place. "We are now collaborating with other researchers to see if we can make this method work in vivo as well, i.e. in a mouse model and not just in test tubes," says Björn Högberg. "This is basic research, but Notch is an important component in several diseases, including a form of leukaemia and the developmental disorder Alagille Syndrome. We therefore hope that the results will also lead to a better understanding of these diseases." The research was mainly funded by the Knut and Alice Wallenberg Foundation, the Swedish Research Council and the European Research Council (ERC).