BMP4

Researchers have collaborated to refine a cell culture technology platform that grows genetically identical lung buds from human embryonic stem cells. When we're driving to a new destination, we often turn down the stereo as we follow the directions. What had been music suddenly sounds like noise, and it interferes with our focus. Our understanding of how infectious diseases like COVID affect human lungs has been similarly confounded by noise. Data from patient lung tissues greatly varies from person to person, obscuring the basic mechanisms of how, exactly, SARS-Co-V2 first infects lung cells. It's also an after-the-fact analysis -- as if we're trying to map the route the virus took three states back. Turning down the noise of variability by studying genetically identical tissues from the first moment of infection could light up the route the pathogen takes. Which cells are infected, and when? What is the level of infection, and how does it differ depending on cell type? How does it change in different conditions? And what if it were possible to track thousands of these infections at once? It might revolutionize our understanding of both infections and the drug treatments used to combat them. That's the hope for new advanced tech capable of growing mini organs on microchips. The labs of Rockefeller's Ali Brivanlou and Charles M. Rice collaborated to refine a cell culture technology platform that grows genetically identical lung buds -- the embryonic structures that give rise to our breathing organs -- from human embryonic stem cells (hESCs). Their findings were recently published in Stem Cell Reports. When placed on an array of microchips and carefully dosed with a custom cocktail of signaling molecules, the hESCs rapidly organize themselves into "micro lungs" that have full tissue complexity. These buds can be cultured by the thousands, allowing for an unprecedented high-throughput analysis of lung tissue infection without all the noisy variables. The result is unlimited, fast, and scalable access to lung tissue that has the key hallmarks of human lung development and can be used to track lung infections and identify candidate therapeutics. "These lungs are basically clones," says Ali Brivanlou. "They have the exact same DNA signature. That way we don't have to worry about one patient responding differently from another. Quantification allows us to keep the genetic information constant and measure the key variable -- the virus." Building a better mini lung Embryonic stem cells are the Ur-cells of the human body. They can infinitely divide to create more stem cells or to differentiate into any other tissue. Brivanlou's Laboratory of Synthetic Biology has long explored their potential. Brivanlou joined forces with Rockefeller colleague Charles M. Rice during the COVID pandemic: his lab had the microchip technology to grow lung buds, and Rice's lab had the necessary biosafety clearance required to infect them with SARS-Co-V2 and study the outcome. In 2021, first authors Edwin Rosado-Olivieri, a stem cell biologist in Brivanlou's lab, and Brandon Razooky, then a postdoc in Rice's Laboratory of Virology and Infectious Disease, began coaxing the cells to organize into more specialized forms. Stem cells don't just organize on their own. They need a confined space -- such as a microchip well -- and stimuli to spark change. The stimuli come from four main signaling pathways that induce stem cells to differentiate into specific cell types. After about two weeks, the group's lung cells had formed identical buds whose molecular profiles closely matched those seen in the earliest stages of fetal lung development -- including the formation of airways and alveoli, structures known to be damaged in many people with severe COVID. Identifying a key culprit Since then, they've used the platform to understand how SARS-Co-V2 infects different lung cells. Alveoli are tiny sacs at the end of the lung branches that manage the gas exchange performed with every breath: oxygen in, carbon dioxide out. By studying cloned alveoli cells en masse, the researchers discovered that alveoli were more susceptible to SARS-Co-V-2 infection than airway cells, which are the guardians of the organ -- the first defense against all inhaled threats. If the virus got past them, the alveoli were sitting ducks. Another view of virus particles (blue) infecting alveolar and airway tissues (red). They also hit upon a winning combination of signaling proteins for creating the most robust batches of lung buds -- a mix of keratinocyte growth factor (KGF) and bone morphogenetic protein 4 (BMP4). Both contribute to cell differentiation and growth. Interestingly, the BMP pathway has a downside. When they compared infected lung buds to postmortem tissue of COVID patients, they found that the BMP signaling pathway was induced in both and rendered the tissues more vulnerable to infection. Blocking the BMP pathway made the cells less vulnerable. Beyond COVID The researchers note that the platform can also be used to investigate the mechanisms of influenza, RSV, pulmonary diseases, and lung cancer, among other diseases. Moreover, it can be used to screen for new drugs to treat them. And lungs are far from the only organ of interest. "The broader focus of our work is understanding cellular development to make synthetic organs and tissues that we can use to model diseases and find therapeutic mechanisms," says Rosado-Olivieri. The liver, kidney, and pancreas are all likely next targets. "The platform will also allow us to respond to the next pandemic with much more speed and precision," Brivanlou adds. "We can quickly capitalize on this platform to make a virus visible and develop therapies much faster than we did for COVID. It can be used to screen for drugs, compounds, vaccines, monoclonal antibodies, and more directly in human tissue. This technology is ready to confront all kinds of threats that may hit us in the future."

Forcefield Therapeutics presents positive preclinical data at the 2022 Scientific Sessions of American Heart Association Preclinical data outlining the mechanisms of three proteins shown to restore heart function following acute myocardial infarction (heart attack) presented at AHA Proteins were identified by FunSel technology and developed by Forcefield London UK, 7 November 2022 – Forcefield Therapeutics (“Forcefield”) Ltd, a pioneer of best-in-class therapeutics to protect heart function by arresting the loss of cardiomyocytes following myocardial infarction, has presented positive preclinical data on three proteins identified by the FunSel platform which have potential to preserve heart function following a heart attack. The paper, Novel Recombinant Cardioprotective Factors Against Myocardial Infarction Selected in vivo from an AAV Secretome Library, was presented on Sunday November 6th at the 2022 Scientific Sessions of American Heart Association (AHA) in Chicago by Dr Mateusz Tomczyk, Research Associate at King’s College London. The paper presented preclinical data outlining the mechanisms of three proteins identified by FunSel, Forcefield’s protein ‘search engine’. FunSel is ‘gene agnostic’: unconstrained by genetics and does not rely on knowledge of which factor is causing a disease. It allows ‘functional selection’ of therapeutic factors for disease phenotype correction. FunSel contains a library of thousands of AAV vectors encoding secreted proteins. Results presented at AHA show that, after two rounds of iterative selection in mice, the three proteins identified by FunSel preserved cardiomyocyte viability, sustained cardiac function and prevented pathological remodelling. In both neonatal cardiomyocytes and adult hearts, all three factors reduced apoptosis and induced protective macro-autophagy. In particular, Chrdl1 exerted its protective activity by binding and inhibiting extracellular bone morphogenetic protein 4 (BMP4), which resulted in protection against cardiomyocyte death and induction of autophagy in cardiomyocytes after myocardial infarction. In addition, it was found that two variants optimised for clinical development demonstrate preliminary efficacy when administered using the anticipated clinical route and time of administration in a myocardial infarction model. The work developing FunSel originated at the International Centre for Genetic Engineering and Biology (ICGEB) and the University of Trieste, Italy. It has been further developed by Mauro Giacca, Professor of Cardiovascular Sciences at King’s College London and co-founder of Forcefield Therapeutics and supported by the British Heart Foundation. Forcefield Therapeutics, a pioneer of best-in-class therapeutics to retain heart function via protection of cardiomyocytes was launched in 2022 backed by leading healthcare investor Syncona and is undertaking the development work to enable clinical trials in patients in the future. Professor Mauro Giacca commented: “While early stage, these data support our conviction in the importance of the three proteins we have identified. These can be administered immediately after a heart attack to minimise cardiac damage and therefore have the potential to revolutionise treatments for patients at risk of heart failure. “These findings reveal a method for the systematic, in vivo selection of tissue protective factors and disclose novel potential cardiac therapeutics, and we’re very excited about their potential.” - ENDS - Notes to Editors About Forcefield Therapeutics Ltd. Forcefield Therapeutics Ltd (Forcefield Tx) is a pioneer of best-in-class therapeutics to retain heart function via protection of cardiomyocytes. Forcefield Tx was founded by scientists, industry experts and investors with a shared purpose to revolutionise treatment following acute myocardial infarction (AMI). Forcefield’s unique approach can both retain and protect heart cells, minimising the impact of AMI and preventing the cascade of events that may lead to subsequent heart failure. Forcefield Tx is led by a proven team with a record of success from discovery to commercialisation. It launched in April 2022, backed by leading FTSE 250 healthcare company, Syncona with an initial investment of £5.5 million. For more information please visit: forcefieldtx.com. About FunSel FunSel is a proprietary in vivo ‘gene therapy search engine’ developed by Purespring Therapeutics’ co-founder Professor Mauro Giacca, Professor of Cardiovascular Sciences at King’s College, London. FunSel is ‘gene agnostic’: unconstrained by genetics and therefore does not rely on knowledge of which gene is causing a disease. It allows ‘functional selection’ of therapeutic factors for disease phenotype correction. FunSel contains a library of thousands of AAV vectors encoding secreted proteins. Because it is gene agnostic, FunSel offers potential to allow the application of gene therapy to non-monogenic disorders and treat much broader patient populations. The platform has already been instrumental in the creation of Purespring Therapeutics and sister company Forcefield Therapeutics, a pioneer of best-in-class therapeutics to protect heart function and has broad potential for researchers developing gene therapy in many disease areas. It provides Purespring with opportunities to support industry peers through partnering and potential collaborations. About the British Heart FoundationIt is only with donations from the public that the BHF can keep its life saving research going. Help us turn science fiction into reality. With donations from the public, the BHF funds ground-breaking research that will get us closer than ever to a world free from the fear of heart and circulatory diseases. A world where broken hearts are mended, where millions more people survive a heart attack, where the number of people dying from or disabled by a stroke is slashed in half. A world where people affected by heart and circulatory diseases get the support they need. And a world of cures and treatments we can’t even imagine today. Find out more at bhf.org.uk. Contacts: Forcefield Therapeutics Richard Francis, CEOcontact@forcefieldtx.com+44 (0)20 3855 6324Consilium Strategic CommunicationsAmber Fennell, Jessica Hodgson, Genevieve Wilsonforcefield@consilium-comms.com+44 (0)203 709 5700