Universite de Nantes

Five-Year Project Led by Experts at Cincinnati Children's Opens Doors for Using 'Next-Generation' Intestine Organoids to Improve Outcomes for People with IBD, EoE, Celiac Disease and Many Other GI-Tract Disorders CINCINNATI , Jan. 26, 2023 /PRNewswire/ -- In many ways, our intestines serve as the front gate between our bodies and the world around us. They help digest our food and absorb our medications. They send alarm signals when harmful bacteria, viruses, and allergens invade. When the intestines malfunction, or fail to form properly during development, a wide range of gastrointestinal diseases can occur; such as inflammatory bowel disease (IBD), eosinophilic esophagitis (EoE), and celiac disease. Many infectious diseases, ranging from mild to deadly, also start in the intestine. Continue Reading Findings from Cincinnati Children's Open Doors for Using 'Next-Generation' Intestine Organoids to Improve Outcomes. Tweet this This illustration shows how a next-generation intestinal organoid produced at Cincinnati Children's mirrored how the human body's immune system develops in the intestine, including T/B cell "zonation" and beyond. Now, scientists at Cincinnati Children's report a significant breakthrough in a years-long quest to build a better model for studying gastrointestinal disease. They have succeeded at developing a complex "next-generation" intestinal organoid that includes key elements of a functional immune system. Detailed findings were published online Jan. 26, 2023, in Nature Biotechnology. The co-authors say this is the first in vivo organoid of any type (heart, liver, stomach, etc.) to incorporate a functional immune system. "Not only does the organoid support the migrating immune tissues—rather than rejecting them—but those immune cells and structures go on to improve the development of the intestine itself, specifically its ability to recognize foreign antigens," says corresponding author Michael Helmrath, MD. 5-Year Quest Blends 'Humanized' Mouse and Organoid Tech Many of the experiments that helped confirm the new findings were led by first author Carine Bouffi, PhD, then a member of Helmrath's lab at Cincinnati Children's and now a senior scientist at the pharmaceutical company Boehringer Ingelheim. Overall, the work involved 20 scientists at five institutions. The work started with growing intestine organoids following an innovative process created in 2011 by experts with the Center for Stem Cell & Organoid Medicine (CuSTOM) at Cincinnati Children's. That team was the first in the world to produce a functioning intestine organoid from induced pluripotent stem cells (iPSCs), a type of stem cell made from mature human cells instead of fetal tissue. The center has achieved several milestones since, including producing the world's first esophagus and stomach organoids. After growing for 28 days in a dish, the tiny organoid spheres had reached a few millimeters in size. Then came the next crucial step: transplanting the organoids into an immunosuppressed mouse to avoid rejection of the human tissue. In this study, to investigate the role of the immune system during development, the team used "humanized" mice that had been genetically modified to suppress their own immune systems, which allowed transplanted human immune cells to function instead. Many research centers around the world use similar humanized mice in their projects. The team members performed delicate surgery to transplant the organoids into mice by placing them under a membrane surrounding their kidneys. There, the organoids continued to grow more than 1,000-fold to about 1 cm in diameter (about the size of a pea). At 12, 16 and 20 weeks, the lab team collected organoids to analyze the types of cells they contained. They found that the organoids contained multiple types of human immune cells that migrated from the humanized mice, including CD45+ cells and important cell formations called gut-associated lymphoid tissue (GALT) structures. "We saw that immune cells from the humanized mouse migrated to the organoid," Helmrath says. "We saw the same types of cells, following the same sequences of development, that we see in human development." Importantly, the team further confirmed that functional M cells—a key type of immune signaling cell—were produced only when humanized tissues were exposed to specific bacterial antigens. Achieving this required exposing the inside of the tiny developing intestines to fragments of E. coli bacteria, a microbe normally found in human intestine. This triggered the organoid tissue to secrete antibodies in reaction to the exposure. "When we started this project, we did not know if implanting intestinal organoids in humanized mice would work, since it had never been done before," Bouffi says. "When we got the first results, we saw the infiltration of immune cells in the organoids and I thought that the host mouse was rejecting the organoid. But after further analysis, we found that the immune cells were actually organized and later developed into an immune tissue comparable to a human intestine. Organoids are remarkable." Potential uses for next-gen intestinal organoids The first applications for these improved organoids will likely involve using them as testing platforms to learn more about the many immune-mediated diseases affecting the digestive tract, Helmrath says. Unlike animal models, organoids can be grown to more accurately reflect the genetic conditions of a common disease state or even to act as "avatars" that mimic organ tissue from a specific patient. "There are broad potential applications to these findings, not just for intestine organoids but for all organs affected by immune-mediated disease," Helmrath says. Longer term, scientists hope to replicate their success in mice with larger animal hosts that can produce larger volumes of human organoid tissue. If successful, lab-started organ tissues eventually might serve as living patches that could help damaged organs heal themselves before people require full-organ transplantation. About this study In addition to Bouffi and Helmrath, Cincinnati Children's co-authors included: Kathryn Wikenheiser-Brokamp, MD, PhD, Praneet Chaturvedi, MS, Nambirajan Sundaram, PhD, Gillian Goddard, MD, Mark Wunderlich, MS, Nicole Brown, MD, Maxime Mahe, PhD, Holly Poling, BS, Simon Vales, PhD, Garrett Fisher, James Mulloy, PhD, Aaron Zorn, PhD, and James Wells, PhD. Collaborators also included researchers from the University of Cincinnati, Johns Hopkins University School of Medicine, the University of Michigan, and the Université de Nantes in France. Funding sources for this work include grants from the National Institute of Diabetes and Digestive and Kidney Disorders (NIDDK) and National Institute of Allergy and Infectious Diseases (NIAID) (U01DK103117); the Cincinnati Digestive Disease Center Award (P30 DK0789392); and philanthropic support from the Farmer Family Foundation. SOURCE Cincinnati Children's Hospital Medical Center

A study of hydroacoustic, acoustic and seismic waves from underwater explosions off the French coast could help guide the disposal of unexploded World War II ordnance (UXO) in those waters, according to a new study. A study of hydroacoustic, acoustic and seismic waves from underwater explosions off the French coast could help guide the disposal of unexploded World War II ordnance (UXO) in those waters, according to a new study published in the Bulletin of the Seismological Society of America. The French Navy Mine Warfare Office routinely destroys this ordnance with countermining -- detonating a charge placed next to the UXO -- to make the sea safe for ships and divers. The countermining charges are located on the seafloor or in a barrel floating in the water column. Even small explosions can trigger effects such as underwater landslides or waves that could potentially damage shoreline and underwater infrastructure such as pipelines and cables, making it important to understand how these detonations behave and to limit their damage. Mickaël Bonnin of the University of Nantes and colleagues had a unique opportunity to observe the effects of countermining explosions in December 2018. The researchers analyzed the seismic records of eight underwater explosions in the Bay of Hyères off the southeastern coast of France in the Mediterranean Sea. The data were recorded on hydrophones, a shock gauge and a dense array of seismic stations located onshore no further than 15 kilometers from the explosions. The explosions themselves were equivalent to 80-680 kilograms of TNT. The most energetic signals recorded by the array were high amplitude, high frequency hydroacoustic or "H" signals. The researchers detected these signals at stations on rocky sites near the shoreline, suggesting they were likely conditioned by the shape of the bay and the sedimentary cover of the seabed. Bonnin said the research team was surprised to be able to observe the H signals at all. "As seismologists rather focused on the study of the crust and the lithosphere, we were first interested in low frequency signals, of less than 50 hertz," he explained. But by configuring the stations to record at high sampling rates, of 200 hertz and up, the team was able to observe the signals at some stations. "These are observations that we would like to investigate further," he added. "In particular, we would like to know if H waves can be observed further inland." The findings may also shed light on whether countermining explosions are less destructive and intrusive when placed on the seabed or in the water column. Placing the explosion in the water column rather than the seabed limits the release of seismic energy, so some experts prefer it to limit potential onshore damage. However, the researchers' observations of the seismic signal of the nearby Saint-Anne bell tower on Porquerolles Island found that even the largest explosion among the detonations did not release enough energy to damage the masonry structure. Explosions in the water column, on the other hand, can cause a noise nuisance that is damaging to sea animals. Bonnin and colleagues found that while explosions in the water column do limit the release of seismic energy between 1 and 10 hertz, an explosion in the water column generates dramatically more energetic H signals than the same TNT-equivalent explosion on the seabed. "We think that limiting the seismic energy release … is probably not necessary in view of the impact than an explosion in the water column can have on aquatic fauna," Bonnin said. "Moreover, we are not entirely sure that the discomfort that may be perceived on shore by the population is due to the seismic waves," he added. "It is possible that it is caused by H waves and perhaps by acoustic waves. These two types of waves see their energy maximized when shooting in the water column." The study is part of a BSSA special section in on seismoacoustics and seismoacoustic data fusion.

About four years after closing its Series B round the first time, Horama is adding another $25.1 million to its coffers for its work on a next-gen gene therapy that could treat retinitis pigmentosa patients not covered by Roche’s Luxturna — and it’s sporting a new name to boot. The French biotech, now called Coave Therapeutics, has expanded its Series B round, bringing its total raise to $39 million, CEO Rodolphe Clerval announced early Wednesday morning. The latest round was led by Seroba Life Sciences, with a hand from Théa Open Innovation, eureKARE, Fund+, Omnes Capital, V-Bio Ventures, Kurma Partners, Idinvest, GO Capital, and Sham Innovation Santé/Turenne. Why the name change? Coave stands for “conjugated AAV vectors,” which is exactly what the company intends to make, Clerval told Endpoints News. Horama launched in 2015 based on work from the University of Nantes in the west of France. The company’s core technology — dubbed the AAV Ligand Conjugate, or ALIGATER platform — is designed to enhance the delivery and efficiency of AAV vectors by binding AAVs to ligands, similar to the way scientists would link an antibody to a payload to form an antibody-drug conjugate. “It’s a technology that is inspired from, for instance, antibody drug conjugates, where people are taking chemical components and using chemistry to bind them on proteins,” Clerval said. “This is exactly what we are doing, but we are taking the entire AAV… and we are developing specific ligands and we are binding covalently those ligands onto the surface of the capsid.” By doing so, Clerval says the scientists are able to make three key changes: improving the biodistribution of the capsid (how it’s able to travel through the tissue of an organ), improving transduction efficiency (its ability to transfer the payload inside the cell), and preventing the capsid from being neutralized by the body’s immune response. The company’s lead program, CTx-PDE6b, is currently in a Phase I/II trial for PDE6b inherited retinal dystrophies, including retinitis pigmentosa. Luxturna — which was developed by Spark Therapeutics before it was bought out by Roche in 2019 — is currently approved to treat mutations in the RPE65 gene. Retinitis pigmentosa caused by PDE6b mutations often leads to blindness by midlife, and is characterized by the progressive loss of photoreceptors. “Those patients basically will lose some photoreceptors, lose their vision, starting by the periphery vision to a shrinkage of their visual field,” Clerval said. Last August, Ocugen received orphan drug designation for its own gene therapy, OCU400, to treat PDE6b-associated retinal diseases. That candidate’s currently in IND-enabling stages, according to the company’s website. To date, 15 of 17 patients are enrolled in Coave’s Phase I/II trial, and Clerval expects to read out data in 2022. In addition to advancing that program toward pivotal trials, the 12-person team also has multiple preclinical programs in the works for rare CNS and ocular diseases, including CTx-GBA1 for Parkinson’s disease and Gaucher Disease and CTx-ABCA4 for Stargardt’s disease.