National University of Ireland

Novel surgical option for the treatment of anal fistula, a painful and debilitating colorectal condition Milestone follows recent completion of clinical trial evaluating the safety and efficacy of the device FDA clearance paves the way for BioHealx™ commercialization GALWAY, Ireland--(BUSINESS WIRE)-- Signum Surgical (‘Signum’ or ‘the Company’), a medical technology company developing innovative solutions to treat colorectal diseases, is pleased to announce that its BioHealx™ technology has been granted marketing clearance by the U.S. Food and Drug Administration (FDA), as a first-of-its-kind medical device for the treatment of anal fistula. Anal fistulas are a painful colorectal condition affecting one in 5,000 people worldwide1. In the United States, over 90,000 surgeries are performed annually to treat anal fistulas2. Current treatment options are often unsuccessful, which frequently result in inadequate or slow healing, a high risk of incontinence, and repeat procedures. Developed in collaboration with expert colorectal surgeons, BioHealx™ is a single use, bioabsorbable implant used to treat anal fistula in a minimally invasive procedure. BioHealx™ is designed to close the internal opening of the fistula tract via tissue apposition and dissolve in the body after treatment. The single-operation approach is designed to promote healing, prevent fistula recurrence, and protect patient continence. The De Novo classification and clearance by the FDA, represents a significant milestone for Signum and follows the completion of a single-arm, non-randomized, clinical trial in 2023 designed to evaluate the safety and efficacy of BioHealx™. The multi-centre clinical trial, led by four investigators in Hungary, treated a total of 32 patients (both male and female adults) who had experienced recurrent anal fistula from at least one previous failed treatment. Final follow up assessments have been completed on the 32 patients over a period ranging from 13 to 40 months. Peter Ónody, Colorectal Surgeon and Principal Investigator of the clinical trial, commented: “I am excited at the potential of BioHealx as a novel surgical option for the treatment of anal fistula and, in particular, its ease of use for physicians. This treatment has the potential to eliminate the need for multiple surgeries and substantially reduce surgical trauma and the rate of fistula recurrence, while reducing costs for patients and the overall health care system.” Moshe Zilversmit, Co-Founder and CEO of Signum Surgical, commented: “We are proud to develop BioHealx, now an FDA De Novo cleared medical device for the treatment of anal fistula. This is a significant milestone for our business and an important step to bring this novel treatment to market for the benefit of patients, surgeons, and the healthcare system. We are currently in discussions with potential strategic commercialization partners to explore how to rapidly and efficiently make the BioHealx solution available to patients. FDA clearance for BioHealx™, which is protected by our growing intellectual property portfolio, continues our strong momentum in addressing the unmet clinical need for the treatment of anal fistula.” Dr Bernard Collins, Investor Director, commented: “Signum Surgical’s innovative BioHealx technology addresses a major unmet clinical need in colorectal care and specifically for the significant patient population suffering with anal fistula. In excess of 90,000 surgeries are performed annually in the United States alone to treat this debilitating condition, however current treatment options are often unsuccessful and there is a high risk of repeat procedures. With strong investor interest in Signum Surgical, FDA De Novo clearance is another transformative step for Moshe, Eoin and the team, and marks further progress towards bringing BioHealx to market in the near future for the benefit of patients and physicians.” About Signum Surgical Headquartered in Galway, Ireland, Signum Surgical is an ISO 13485 certified medical technology company focused on developing innovative solutions to treat colorectal diseases, starting with anal fistula, a painful and debilitating condition that severely affects patients’ quality of life. Current treatments often fail to successfully address this condition. With its BioHealx™ device, Signum Surgical has developed a minimally invasive technology that offers a breakthrough for these patients. Having explored gastrointestinal and colorectal care, and identified an unmet need of this patient population, Eoin Bambury and Moshe Zilversmit founded Signum Surgical in 2016 as a spin-out of the National University of Ireland BioInnovate programme. Signum Surgical successfully raised €5.5 million in equity in two investment rounds to support its clinical and regulatory programs. In addition, Signum received €3.6 million in 2019 through two non-dilutive grant funding awards from the European Union Horizon 2020 SME Instrument and Ireland’s Disruptive Technologies Innovation Fund (DTIF). The Company’s equity shareholders include Halo Business Angel Network’s MedTech Syndicate who served as lead investor in both funding rounds, as well as Enterprise Ireland, the Western Development Commission, Rising Tide Europe and other medical device industry angel investors. For more information, please visit About Anal Fistula Anal fistula is a painful colorectal condition that affects one in 5,000 people.1 In most cases, patients will develop an anal fistula, due to an infected anal gland that, when left untreated will abscess and burrow through the patient’s sphincter muscle. Anal fistulas cause a host of unpleasant symptoms that hamper patients’ quality of life, such as swelling and discharge of blood or pus from the anus. Current standard of care treatments, including seton placement or fistulotomy surgery, involve the opening or cutting of the channel to reach the fistula, followed by draining or scraping and flushing out the infected tissue. These treatments are often unsuccessful and can result in inadequate or slow healing, a high risk of incontinence, and repeat procedures. 1 Ommer A et al: Clinical practice guideline: Cryptoglandular anal fistula Deutsches Arzteblatt International 2011; 108(42): 707–13. 2 Zanotti, C., Martinez-Puente, C., Pascual, I. et al. Int J Colorectal Dis (2007) 22: 1459 View source version on businesswire.com: Contacts FTI Consulting Paddy Berkery / Rugile Nenortaite Tel: +353 86 602 5988 / +353 86 277 9905 Email: signumsurgical@fticonsulting.com Source: Signum Surgical View this news release online at:

Blood stem cells -- key to transplants that are used as life-saving treatments for blood cancers and blood and immune disorders -- have the capacity to self-renew, but quickly lose their ability to do so in a lab dish. Scientists have identified a protein that not only enables blood stem cells to self-renew in a lab dish, but also allows these expanded cells to function effectively after being transplanted into mouse models. The findings could help make blood stem cell transplants available to more people and improve the accessibility and safety of gene therapies that use these cells. UCLA scientists have identified a protein that plays a critical role in regulating human blood stem cell self-renewal by helping them sense and interpret signals from their environment. The study, published in Nature, brings researchers one step closer to developing methods to expand blood stem cells in a lab dish, which could make life-saving transplants of these cells more available and increase the safety of blood stem cell-based treatments, such as gene therapies. Blood stem cells, also known as hematopoietic stem cells, have the ability to make copies of themselves via a process called self-renewal, and can differentiate to produce all the blood and immune cells found in the body. For decades, transplants of these cells have been used as life-saving treatments for blood cancers such as leukemia and various other blood and immune disorders. However, blood stem cell transplants have significant limitations. Finding a compatible donor can be difficult, particularly for people of non-European ancestry, and the number of stem cells available for transplant can be too low to safely treat a person's disease. These limitations persist because blood stem cells that have been removed from the body and placed in a lab dish quickly lose their ability to self-renew. After decades of research, scientists have come achingly close to solving this problem. "We've figured out how to produce cells that look just like blood stem cells and have all of their hallmarks, but when these cells are used in transplants, many of them still don't work; there's something missing," said Dr. Hanna Mikkola, senior author of the new study and a member of the Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research at UCLA. To pinpoint the missing piece that prevents these blood stem cell-like cells from being fully functional, Julia Aguade Gorgorio, the paper's first and co-corresponding author, analyzed sequencing data to identify genes that are silenced when blood stem cells are placed in a lab dish. One such gene, MYCT1, which encodes a protein by the same name, stood out as being essential to these cells' self-renewal capacity. They found that MYCT1 regulates a process called endocytosis, which plays a key role in how blood stem cells take in the signals from their environment that tell them when to self-renew, when to differentiate and when to be quiet. "When cells perceive a signal, they have to internalize it and process it; MYCT1 controls how fast and how efficiently blood stem cells perceive these signals," said Aguade Gorgorio, an assistant project scientist in the Mikkola lab. "Without this protein, the signals from the cells' environment turn from whispers into screams and the cells become stressed out and dysregulated." The researchers compare MYCT1 to the sensors in modern cars that monitor all nearby activity and selectively relay the most crucial information to drivers at the right time, aiding decisions like when to safely turn or change lanes. Without MYCT1, blood stem cells resemble anxious drivers who, used to relying on these sensors, suddenly find themselves lost without their guidance. Next, the researchers used a viral vector to reintroduce MYCT1 to see if its presence could restore blood stem cell self-renewal in a lab dish. Restoration of MYCT1, they found, not only made the blood stem cells less stressed and enabled them to self-renew in culture but also allowed these expanded cells to function effectively after being transplanted into mouse models. As a next step, the team will investigate why the silencing of the MYCT1 gene occurs, and then, how to prevent this silencing without the use of a viral vector, which would be safer for use in a clinical setting. "If we can find a way to maintain MYCT1 expression in blood stem cells in culture and after transplant, it will open the door to maximize all these other remarkable advances in the field," said Mikkola, who is a professor of molecular, cell and developmental biology in the UCLA College and a member of the UCLA Health Jonsson Comprehensive Cancer Center. "This would not only make blood stem cell transplants more accessible and effective but also improve the safety and affordability of gene therapies that utilize these cells." This work was supported by the National Institutes of Health, the Swiss National Science Foundation, the European Molecular Biology Organization, the UCLA Jonsson Cancer Center Foundation, the James B. Pendleton Charitable Trust, the McCarthy Family Foundation, the California Institute for Regenerative Medicine, the UCLA AIDS Institute, the Board of Governors Regenerative Medicine Institute at Cedars-Sinai Medical Center, the Royal Society, the Wellcome Trust and the UCLA Broad Stem Cell Research Center Stem Cell Training Program.

Researchers can use the light naturally thrown off by biological specimens to better study the different states of stem cells in the nervous system, thanks to a tool brightening their chances for studying the way stem cells age. Researchers can use the light naturally thrown off by biological specimens to better study the different states of stem cells in the nervous system, thanks to a tool developed at the University of Wisconsin-Madison, brightening their chances for studying the way stem cells age. The UW-Madison team combined autofluorescence -- that natural light emission -- and sequencing genetic material in single cells to study the behavior of neural stem cells. Autofluorescence is often considered a hindrance, as it can obscure the glowing labels researchers use to track specific signals within a cell. In their new technique, however, the researchers found the signatures of autofluorescence can be used to study stem cells' dormant state, known as quiescence. They published their findings recently in the journal Cell Stem Cell. "The quiescent state is very important, because the exit from quiescence is the rate-limiting step in making newborn neurons in the adult brain. Aging and neurological diseases limit this exit from quiescence, so we have a great need to study adult neural stem cells in their different cell states," says Darcie Moore, the senior author on the study, a professor of neuroscience and member of UW-Madison's Stem Cell and Regenerative Medicine Center. "Our goal was to create a new tool that could identify if an adult neural stem cell was quiescent and its different substates (dormant or resting quiescence), or if the cell is activated, entering into the cell cycle." Moore partnered with Melissa Skala, a UW-Madison biomedical engineering professor, Morgridge Institute for Research investigator and member of the Stem Cell and Regenerative Medicine Center whose lab has been developing fluorescence lifetime imaging to study the autofluorescent signatures associated with single cells. When cells shift from active to quiescent states, the presence and abundance of certain proteins important to metabolism change. These molecules alter the way light is absorbed and emitted back out of the cell. By focusing on light emitted by parts of the cell that change in key ways with quiescence, the researchers identified the light "signature" that matches a target cell state. "These natural signals within the cell can reliably identify cell function and identity," Skala says. "It's like nature is trying to tell us all the secrets of life." By sequencing RNA -- a kind of working copy of DNA used to produce the proteins that make things happen in cells -- in the mouse neural stem cells they studied, the researchers confirmed matches between cell state and light signatures. By identifying and decoding these autofluorescence signatures, Moore and Skala have developed a tool that can aid in studying adult neurological diseases and aging, but potentially also expand beyond neuroscience. They've already begun working with Colin Crist, a professor of human genetics at McGill University, to investigate the unique autofluorescent signatures present in muscle stem cells. "Now that we've discovered that this research created not only a tool but gave us unique insight to cellular processes that are different between quiescent and activated neural stem cells, I feel even more strongly that identifying a cell based on how they act versus how they express one protein will shift studies from studying static systems to dynamic systems," says Moore. "That we can study these cells as they change throughout time without destroying them -- while also seeing how these functional measures change -- is very exciting." This research was supported in part by grants from the National Institutes of Health (P30 CA014520, 1S10RR025483-01, T32GM008688 and 1DP2OD025783) as well as the Vallee Foundation, Morgridge Institute for Research and Retina Research Foundation.