MUC5B

- Funding secured from CF Foundation and current investors for SPL84 Phase 2 study - - Two additional early-stage candidates expected to commence Phase 1-2a studies over the next 12 months – JERUSALEM, April 3, 2024 /PRNewswire/ -- SpliSense, a clinical-stage biotechnology company focused on the development of transformative RNA-based therapies for pulmonary diseases including cystic fibrosis (CF), muco-obstructive diseases like COPD, asthma, non-CF bronchiectasis (NCFB) and idiopathic pulmonary fibrosis (IPF), today announced that the U.S. Food and Drug Administration (FDA) cleared the Investigational New Drug (IND) application for the initiation of a Phase 2 study for SPL84 in CF. SPL84 is the Company's lead antisense oligonucleotide (ASO) product for the treatment of people with CF carrying the 3849+10 kilobase (Kb) C->T splicing mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. The IND Clearance for the Phase 2 study initiation was granted following SPL84's favorable safety profile, supported by Phase 1 and preclinical toxicological and pharmacological data demonstrating the potential for full restoration of CFTR protein and activity, based on clinically predictive CF models. The Company has also announced today that it has secured funding from the CF Foundation and other existing investors to support the SPL84 Phase 2 study and additional pulmonary programs. This represents the CF Foundation's third investment in SpliSense's SPL84 program. "We are excited to initiate the Phase 2 study for SPL84 in CF with the support of the CF Foundation and other existing investors," said Gili Hart, PhD, Chief Executive Officer of SpliSense. " Although currently available CF therapies have managed to significantly increase life expectancy over the past few decades, there is still a significant unmet medical need for disease modifying treatments. Our lead product, SPL84, has been shown to fully restore CFTR activity in the CF gold standard pharmacological model. With the recent FDA IND clearance, we hope to be able to deliver, a life-changing treatment for people with CF carrying the 3849+10 Kb C->T mutation and expand our unique technology to additional CF mutations where there is a significant unmet need." "In addition, SPL84 serves as proof-of-concept for our platform for the treatment of additional pulmonary diseases, including muco-obstructive diseases and IPF, which are expected to enter the clinic over the next 12 months," added Dr. Hart. About Cystic Fibrosis (CF) CF is a genetic multisystem disorder that originates from various mutations in the CFTR gene, which is responsible for the production of the CFTR protein, a chloride channel expressed in the lungs as well as in other tissues. The past decade has seen a dramatic change in CF care with the approval of new CFTR modulators. However, approved CFTR modulators do not support all people with CF and do not offer a cure for the disease. Thus, new strategies of therapeutic development are essential to address partially responsive and non-responsive people with CF, specifically those carrying the 3849+10 Kb C->T splicing mutation. About SPL84 SpliSense utilizes short, precisely targeted proprietary RNA stretches called Antisense Oligonucleotides (ASOs) to modulate specific mRNA sequences or correct various mutations in the target mRNA. SPL84 binds specifically to the mutated CFTR RNA in the targeted sequence, leading to the modulation of the mutated region in the mRNA, potentially allowing the cell to produce fully functional CFTR proteins. SPL84 is administered directly and preferentially to the lungs via inhalation where it is designed to be taken up by the lung cells and to drive the production of corrected CFTR mRNA and eventually fully functional CFTR proteins. About SPL5AC (Muco-Obstructive Diseases) and SPL5B (IPF) SpliSense is advancing two preclinical ASO assets for the treatment of additional pulmonary diseases, including muco-obstructive diseases and IPF. Patients with muco-obstructive lung disease are susceptible to severe mortality and morbidity, creating an unmet need for the development of an effective and potent agent in the treatment of mucin induced lung disease. SPL5AC is an ASO that specifically lowers the level of MUC5AC expression and production in mucus, decreases mucus viscosity, eliminates accumulation in the airways, and reduces infection and inflammation as demonstrated in three proof of-concept disease animal models. Chronic overexpression of MUC5B is suggested to be the single greatest risk factor for the development of IPF. SPL5B is an ASO that lowers MUC5B expression and production avoiding accumulation of MUC5B mucin and plugs in the distil regions of the lungs. By lowering MUC5B levels and plugs formation, SpliSense aims to slow or delay IPF progression and improve patient's clinical condition and quality of life. About SpliSense SpliSense is a biotechnology company focused on the development of RNA-based treatments for pulmonary diseases. The Company's pioneering platform harnesses ASOs for treatment of unmet cystic fibrosis mutations and large pulmonary diseases including muco-obstructive diseases and IPF. Through its novel ASO pulmonary approach, SpliSense aims to address specific genetic mutations or deficiencies, by restoring or reducing protein function, thus targeting the root cause of the disease. The Company's investors include Cystic Fibrosis Foundation, OrbiMed, Israel Biotech Fund, Integra Holdings and Biotel Limited. For additional information, please visit our website at: Company contact: Tsipi Haitovsky Global Media Liaison +972-52-5989-892 [email protected] SOURCE SpliSense

In a new study, researchers used CRISPR technology to test the impact of every human gene on SARS-CoV-2 infections in human lung cells. Their findings revealed new pathways that the virus relies on to infect cells, as well as the antiviral pathways that protect against viral infection. Notably, they showed that mucins -- the main component of mucus found in the lungs -- seem to help block the SARS-CoV-2 virus from entering cells. Researchers have taken an important step toward understanding the microscopic battle that plays out between our lung cells and the SARS-CoV-2 virus that causes COVID-19. A UC Berkeley-led study has identified specific proteins within our bodies that can promote or protect us from SARS-CoV-2 infections, potentially opening the door to new antiviral therapies. In the study, published this week in Nature Genetics, researchers used CRISPR technology to test the impact of every human gene on SARS-CoV-2 infections in human lung cells. Their findings revealed new pathways that the virus relies on to infect cells, as well as the antiviral pathways that help protect against viral infection. Notably, they showed that mucins -- the main component of mucus found in the lungs -- seem to help block the SARS-CoV-2 virus from entering our cells. "Our data suggest that mucins play a key role in restricting SARS-CoV-2 infection by acting as a barrier to viruses that are attempting to access our lung epithelial cells," said Scott Biering, the study's co-lead author and a postdoctoral researcher in Eva Harris's lab at UC Berkeley's School of Public Health. "Further, our data suggest that mucin expression levels in an individual's lungs may impact COVID-19 disease progression." Patrick Hsu -- cofounder of the Arc Institute and Berkeley assistant professor of bioengineering, Deb Faculty Fellow and Innovative Genomics Institute Investigator -- is the principal investigator of the study, which brought together researchers from 10 institutions. Harris, professor of public health at UC Berkeley, and Silvana Konermann, assistant professor at Stanford University School of Medicine, were co-senior authors of the study. Other collaborators contributed from Stanford University, the University of North Carolina at Chapel Hill, Yale School of Medicine and Cornell University, and spanned disciplines ranging from immunology, bioengineering, epidemiology, molecular biology and genetics. Together, the researchers were trying to determine how the SARS-CoV-2 virus enters human cells and replicates so efficiently during illness. They also wanted to identify specific defense mechanisms in human cells that might be able to fight infection, which could inspire new therapeutic strategies. Researchers discovered that MUC1 and MUC4, types of mucins found in lung cell membranes, defend lung cells from infection. This finding is important because previous studies had suggested that an accumulation of mucus could be the reason why some people became seriously ill with COVID-19 -- since the mucus can make it difficult for people to breathe -- and proposed using drugs to deplete mucus. This Berkeley-led study suggests that such a strategy could interfere with mucins that provide a valuable defense mechanism against SARS-CoV-2 infection. Still, mucins are complex, and more research is needed to fully understand them. The researchers discovered that other mucins -- MUC5AC and MUC5B -- which are secreted into the mucus lining of the lungs, either do nothing to stop SARS-CoV-2 infection or can even promote viral infection. According to Biering, both the type and amount of mucus that each person produces may result in different outcomes for SARS-CoV-2 infection -- and lead to different treatment strategies. "Somebody who produces a lot of the right type of mucus could be very protected. But somebody who produces a lot of the wrong type of mucus might have more risk of infection," said Biering. "And somebody who produces very little of the right type also could be at more risk." This is also the first study in which researchers looked at how the SARS-CoV-2 virus interacts with human lung cells, marking a critical advancement in COVID-19 research. "It is well known that virus infection can be promoted or inhibited by our own proteins," said Biering. "But this is the first time that a systematic investigation of these host cell proteins has been conducted in human lung epithelial cells for SARS-CoV-2 infection." Past studies of SARS-CoV-2 infection have used cell types that do not naturally contain the receptors or other pathways that the virus uses to infect our lungs. For this study, researchers wanted to use a more relevant cell type, human epithelial cells called Calu-3, found on the inner surface of the lung. Though this cell line is extremely challenging to work with, researchers managed to gain a more accurate understanding of the biology involved in human SARS-CoV-2 infections. "[Using Calu-3 cells] was a huge advancement, given that these are very representative of the first cells the virus contacts and infects in humans, and it revealed new pathways not seen in other cell lines," said co-lead author Sylvia Sarnik, an assistant specialist in Hsu's lab at the time of the study. "Overall, this study is a step forward in understanding viral infection pathways and paves the way for research toward better treatments in the future." The researchers conducted genome-wide CRISPR gain-of-function and loss-of-function screening to eliminate or overexpress every gene in the human genome. Then they measured the impact of these gene expression changes on SARS-CoV-2 infection in human lung epithelial cells. Importantly, many of the genes highlighted by this screen have yet to be investigated experimentally, providing a starting point for future work. "You can run these massively parallel 'Hunger Games'-style experiments on human cells to see which genes you can change to tune the ability of our lung cells to survive or grow when the virus infects them," said Hsu. "Our screen successfully identified hundreds of genes that were important for replication of SARS-CoV-2 and hundreds of genes that could restrict SARS-CoV-2," said Biering. "In this study, we chose to focus on understanding the role of these mucin proteins." The researchers identified mucin glycoproteins as key restriction factors for infection in cells, both in mouse models and potentially in humans. Researchers also studied how mucins would interact with other respiratory viruses, including influenza A virus, human parainfluenza virus, common cold coronaviruses and respiratory syncytial virus. As with SARS-CoV-2, the results were unpredictable. "What we showed was mucins are broadly antiviral, but the story is actually much more complicated than that," said Hsu. "In fact, in some viruses, we found that mucin overexpression actually seemed to increase infectivity." Future work will be critical to better understand how viruses interact with mucins, but, for now, these findings provide an important starting point. "This study helped us learn more about the virus and opened new avenues for research to further investigate druggable targets," said Sarnik. Fast Grants, the National Institutes of Health and the Centers for Disease Control and Prevention helped support this research.