CTNNB1

Defects in the blood vessel network of the central nervous system have been linked to early symptoms of neurodegenerative diseases such as Alzheimer's disease and amyotrophic lateral sclerosis (ALS). It is this complex vascular network that provides the necessary nutrients -- especially glucose and oxygen -- to activate all neuronal functions. A new study reveals that the TDP-43 protein is essential for forming a stable and mature blood vessel network in the central nervous system. Defects in the blood vessel network of the central nervous system have been linked to early symptoms of neurodegenerative diseases such as Alzheimer's disease and amyotrophic lateral sclerosis (ALS). It is this complex vascular network that provides the necessary nutrients -- especially glucose and oxygen -- to activate all neuronal functions. Now, a study led by the University of Barcelona and the Bellvitge Biomedical Research Institute (IBIDELL) reveals that the TDP-43 protein is essential for forming a stable and mature blood vessel network in the central nervous system. According to the study, featured on the cover of the journal JCI Insight, the TDP-43 protein is also critical in maintaining the integrity of the blood-brain barrier, which prevents toxins and pathogens from reaching the central nervous system. The project is led by Professor Eloi Montañez, from the Faculty of Medicine and Health Sciences of the University of Barcelona and IDIBELL, and involves teams from the Faculty of Biology and the Institute of Biomedicine of the UB (IBUB), the Josep Carreras Leukaemia Research Institute, and the National Centre for Genomic Analysis (CNAG-CRG). What is the role of the TDP-43 protein in the vascular system? The TDP-43 protein is a key factor in nervous system function and neuronal plasticity. It is a DNA- and RNA-binding protein that regulates gene expression, and its dysfunction has been associated with various neurodegenerative disorders. Although much progress has been made recently in understanding the functions of TDP-43 in neurons, its exact role in the endothelial cells that make up the circulatory system, the formation of new blood vessels (angiogenesis) and vascular function was not yet known. "The study reveals for the first time that TDP-43 is essential for the formation and stability of blood vessels in the central nervous system, and for the integrity of the blood-brain barrier," says Professor Montañez, from the UB's Department of Physiological Sciences. The vascularization of the central nervous system and the formation of the blood-brain barrier are regulated by different signalling pathways. For example, the integrin signalling pathway that regulates the interaction of cells with the extracellular matrix and the signalling carried out by the transcription factor β-catenin. "In the study, we found that TDP-43 deficiency alters the extracellular matrix that surrounds blood vessels and reduces β-catenin signalling in endothelial cells," says the researcher. "Thus, mice without endothelial TDP-43 protein show multiple haemorrhages and vascular degeneration in the brain and spinal cord." Vascular defects and inflammatory response in neurosciences The authors also identify TDP-43 in endothelial cells as a potential contributing factor to the vascular defects that trigger the inflammatory response observed in patients diagnosed with TDP-43-associated diseases. "Some alterations in the blood vessels of the central nervous system -- defects in the integrity of the blood-brain barrier or degeneration of endothelial cells -- are associated with inflammatory and immune responses that can cause neuronal loss. This process of neuronal degeneration underlies the origin or progression of various neurological disorders -- stroke, diabetic retinopathy -- and some neurodegenerative diseases such as Alzheimer's disease, ALS or LATE (Limbic-predominant age-related TDP- 43 encephalopathy). The study will help to better understand the molecular mechanisms linking vascular defects and neuroinflammation. "Our goal now is to analyse whether defects in TDP-43 protein function in the endothelium of mature vessels could be involved in ALS or other TDP-43-associated pathologies due to increased vascular permeability or inflammatory processes," Montañez concludes.

CAMBRIDGE, Mass.--( BUSINESS WIRE )--FogPharma®, a clinical-stage biopharmaceutical company dedicated to delivering a new class of therapies that go beyond the limits of currently available medicines using its Helicon™ peptide platform, today announced the successful closing of a $145 million Series E financing round. The financing was led by Nextech Invest with participation from other new investors including RA Capital Management, Rock Springs Capital, General Catalyst, Marshall Wace, Samsara Biocapital, Foresite Capital, Symbiosis, Catalio Capital Management, Sixty Degree Capital and former chairman and CEO of Johnson & Johnson, Alex Gorsky. There was strong support by existing investors, including ARCH Venture Partners, Fidelity Management & Research Company, GV, Cormorant Asset Management, funds and accounts advised by T. Rowe Price Associates, Inc., Farallon Capital Management, venBio Partners, Invus and Milky Way Investments. Alexis Borisy, an accomplished investor and entrepreneur, also joined the company's board of directors in the position designated to Nextech. The financing will fund the ongoing clinical development of FOG-001, the company’s first-in-class intracellular TCF-blocking β-catenin inhibitor currently being evaluated in a Phase 1/2 study in solid tumors. The round will also accelerate the development of its robust portfolio of unique discovery programs, deepen its data science capabilities and strengthen its core Helicon therapeutics platform. FOG-001 is a Helicon designed to block the key oncogenic step in the Wnt/β-catenin signaling pathway, one of the most frequently activated pathways in a variety of cancers. Mutations in the pathway are particularly prevalent in colorectal cancer, the second leading cause of all global cancer deaths, with an estimated two million new cases per year, according to the World Health Organization . Despite significant biological validation of the β-catenin:TCF interaction as a cancer driver, no existing treatment has been able to disrupt it due to its inaccessibility to antibody and traditional small molecule medicines. “Millions of colorectal cancer patients have been told by their oncologists that no more can be done for them. We believe FOG-001 may represent the long-awaited major technological breakthrough needed to address one of the most common yet unaddressed oncogenic signaling pathways,” said Mathai Mammen, M.D., Ph.D., FogPharma’s chairman, president and chief executive officer. “This financing will allow us to execute on our expanded clinical development and commercialization strategy to deliver FOG-001 to patients, while simultaneously strengthening our discovery efforts against other compelling intracellular targets that drive a range of diseases.” FOG-001 is the first of several wholly-owned programs generated by FogPharma’s Helicon platform being advanced to address biologically validated disease-driving intracellular targets by modulating protein-protein and protein-DNA interactions inside the cell. FogPharma’s Helicon platform combines ultra-diverse and tunable stabilized helical peptides with custom-built computational physics and artificial intelligence (AI) techniques to enable the discovery and development of novel programs across a vast array of intracellular targets that have never before been drugged. “We are excited by the tremendous potential of FOG-001 to meaningfully change the therapeutic landscape through a novel approach, and are equally impressed by FogPharma’s robust pipeline of programs for significant drivers of cancer,” said Nextech Managing Partner Thilo Schroeder, Ph.D. “The company’s rapid progress across its growing pipeline demonstrates FogPharma’s team is enabled to deliver on the vast potential of its Helicon therapeutics platform.” The financing follows a period of rapid growth for the company as its leadership team has expanded with industry veterans with track records in clinical, commercial and data science execution. This includes the company’s Chairman, President and Chief Executive Officer Mathai Mammen, M.D., Ph.D.; healthcare data science pioneer and Chief Data Officer Brandon Allgood, Ph.D.; Chief Technical Operations Officer Rohin Mhatre, Ph.D.; and Chief Business Officer Gregory Miller, MPH, MBA. About FogPharma® FogPharma is a biopharmaceutical company pioneering the discovery and development of Helicon™ therapeutics, which are peptides capable of efficient cell entry and modulation of both protein-protein and protein-DNA interactions. Through Helicon therapeutics, FogPharma is poised to revolutionize the medical possibilities for patients by precisely drugging intracellular targets long understood to be significant drivers of disease but never before drugged due to the limitations of existing drug modalities to act within the cell. FOG-001, the company’s first-in-class TCF-blocking β-catenin inhibitor, is being evaluated in a Phase 1/2 study for patients with advanced solid tumors, including colorectal cancer. FogPharma is fully leveraging the unprecedented potential Helicons present by deploying proprietary, custom-built machine learning and computational methods as part of its discovery and development process. FogPharma has raised more than $500 million to date from leading life sciences investors. FogPharma is headquartered in Cambridge, Mass. For more information, please visit: www.fogpharma.com .

Dive Brief:Cancer drug developer FogPharma has raised $145 million in fresh funding, the company revealed Friday, announcing a Series E round that will give a financial boost to the nearly decade-old biotechnology company.The funding will support development of FOG-001, FogPharmas most advanced drug candidate, which is designed to target a protein known as beta-catenin as a way to inhibit tumor growth. The drug is currently in a Phase 1/2 study.FogPharmas financing was led by Nextech Invest and involved other big-name investors like RA Capital Management, Arch Venture Partners and GV. Veteran biotech investor Alexis Borisy has also joined FogPharma's board of directors.Dive Insight:In prior years, promising young biotechs would often make a run at Wall Street after raising their first two or three venture rounds.As initial public offering activity has slowed, however, some companies are staying private for longer, even if they eventually do make it to public markets. CG Oncology, the years breakout IPO so far, closed a $105 million Series F just five months before it went public, for instance.Some of the venture investors that participated in FogPharmas Series E round are notable for often partaking in so-called crossover rounds, such as RA Capital, Fidelity and Cormorant Asset Management, which back both public and private companies. The company also received funding from Alex Gorsky, the former chairman and CEO of Johnson & Johnson.This financing will allow us to execute on our expanded clinical development and commercialization strategy to deliver FOG-001 to patients, while simultaneously strengthening our discovery efforts against other compelling intracellular targets that drive a range of diseases, Mathai Mammen, FogPharmas CEO, said in a statement.FogPharma last year tapped Mammen, who previously ran R&D at J&J, to replace co-founder Greg Verdine as its CEO.When we started the company, we said were going to drug beta-catenin, Verdine told BioPharma Dive in 2023. Beta-catenin is, hiding in plain sight, a monster oncogene.It's part of a cell signaling pathway thats often activated in a number of cancers, particularly colorectal cancer. Though the protein has been a known target for oncology researchers for years, its been exceedingly difficult to drug. FogPharma claims its Helicon polypeptide drugs could overcome those challenges.Other programs in its pipeline target oncogenes that are implicated in prostate, ovarian and pancreatic cancers.Correction: An earlier version of this story mistakenly identified the series of FogPharmas funding round. '