FZD1

Morphogens are the secreted molecules that pattern embryonic tissues. These molecules are important not only for the embryo during development, but also for the adult during tissue repair. However, the way these morphogens are distributed to ensure patterning occurs is still not fully understood. Using a combination of experiments and mathematical modeling, researchers learned more about the role morphogens play in tissue patterning. Their results are relevant to medical applications, such as drug design. Morphogens are molecules that travel from biological cell to cell to pattern tissues in the embryo. These molecules are important not only for the embryo during development, but also for the adult during tissue repair. However, the way these morphogens are distributed to ensure patterning occurs is still not fully understood. Using a combination of experiments and mathematical modeling, a research team from the University of Tokyo and their international collaborators has learned more about the role morphogens play in tissue patterning. The results are relevant to medical applications, such as drug design. The team's findings are published in the journal eLife. The Wnt morphogen has emerged as a key regulator of heart development in vertebrates. These Wnt proteins are molecules that play an important role in cell development. However, it is still generally unclear to scientists exactly how Wnt regulates heart development. There are differences among the vertebrate classes, as well as redundancy in some species. However, scientists can study how Wnt regulates heart development in the Xenopus, an aquatic frog that is native to sub-Saharan Africa. The Xenopus, with its lungs and three-chamber heart, is cost-effective and useful to scientists in their study of human diseases. In Xenopus heart development, scientists have already established that the Wnt6 morphogen is sent out by the epidermis, those outer layers of cells that make up the skin, to pattern the cardiogenic mesoderm, which is the group of cells in the embryo that will form the heart. From this patterning, a relatively thin pericardium (the membrane around the heart) and a broad myocardium (the heart's muscular tissue) develop. Scientists are still working to better understand how the Wnt6 morphogen distribution is regulated to ensure reproducible positioning of the pericardium and myocardium in the cardiogenic mesoderm. "It is still unclear how reproducible patterning can be achieved with diffusing molecules, especially when that patterning concerns differentiation of thin tissues." said Takayoshi Yamamoto, an assistant professor at the University of Tokyo and the first author and corresponding on the paper. Scientists do know that in early embryo development, the range of Wnt8 morphogen signaling is precisely regulated heparan sulfate and secreted Wnt binding proteins, including Frzb (which is also known as sFRP3). Heparan sulfate is a carbohydrate that is important is embryo development. Wnt signaling is one of the main processes by which tissue takes shape during the development of the embryo. The research team wondered whether mechanisms similar to those that operate in early embryos also regulate distribution of Wnt6 morphogen in the cardiogenic mesoderm. The Wnt receptor, Frizzled7, is essential for heart development. The expression of Frizzled7 is increased by Wnt signaling in the development of the nervous system in the Xenopus and in the development of human embryonic carcinoma cells, but there are no such reports in heart development. So the research team focused their study to analyze the way Wnt signaling occurs in the development of the heart, focusing on the extracellular components -- the Frizzled7 cell-surface receptor, sFRP1 (an inhibitor of Wnt6 that can also travel from cell to cell) and heparan sulfate. "With a combination of experiments and mathematical modeling, this receptor-feedback appears essential to shape a steep gradient of Wnt signaling. In addition, computer simulation revealed that this feedback imparts robustness against variations of Wnt ligand production and allows the system to reach a steady state quickly," said Yamamoto. Wnt6 and sFRP1 molecules not only regulate normal heart development in the embryo, but also regulate repair and regeneration after heart muscle injury, such as in the case of a myocardial infarction, or heart attack. "Our findings will be relevant to medical applications, for example, for drug design, since cell-surface molecules such as Frizzled or a specific modification of heparan sulfate or even the secreted molecule sFRP1, generally provide better drug targets than molecules inside cells. To reveal the precise regulation of morphogens and to consider medical applications, regulatory mechanisms of these components must be investigated further," said Yamamoto. The research was conducted in collaboration with researchers at the University of Aberdeen in the U.K.

-- Novel approach to creating R-spondin-mimetics establishes proof-of-concept for targeted regenerative antibodies -- SOUTH SAN FRANCISCO, Calif., Aug. 19, 2020 (GLOBE NEWSWIRE) -- Surrozen Inc., a biotechnology company pioneering a new class of targeted regenerative antibodies, today announced a peer-reviewed publication describing its novel platform for the generation of potent and selective R-spondin mimetics. The article, “Tissue-targeted R-spondin mimetics for liver regeneration” was published online in Scientific Reports, a Nature Research journal. The article describes Surrozen’s R-spondin-mimetic program, culminating in a hepatocyte-targeted bispecific antibody that potently and selectively enhances the Wnt signaling pathway in the liver. The publication describes a novel approach to the regeneration of hepatocytes, and highlights the potential for the approach in treating a range of severe liver diseases. “This publication underscores Surrozen’s mission of developing targeted therapeutics for safe and effective tissue regeneration via the Wnt pathway. Conceived and engineered in house, Surrozen’s R-spondin mimetic platform provides an entirely new approach to targeted regeneration for various diseases. I am proud of all the scientists who contributed to this body of work,” said Wen-Chen Yeh MD, PhD, chief scientific officer of Surrozen and a co-author on the paper. “This approach, which complements our Wnt-mimetic platform, is the second proprietary platform for selectively activating the Wnt pathway that Surrozen has described in a peer-reviewed publication.” Notable results in the publication include the discovery that hepatocyte-specific Wnt agonism can be directed through replacing LGR binding with a liver specific receptor, ASGR1. Through mutating R-spondin to replace LGR binding with ASGR1 while maintaining ZNRF3/RNF43 signaling, Surrozen has shown the ability to effectively and robustly enhance Wnt stimulation within the liver, leading to the proliferation and maturation of hepatocytes. The molecule described in the paper, αASGR1-RSPO2-RA, upregulated Wnt target genes in hepatocytes and stimulated cell proliferation specifically in the liver. Other Wnt-sensitive tissues were not responsive to administration of the R-spondin mutant. Significantly, αASGR1-RSPO2-RA showed the ability to improve liver function in diseased mice within three days. “These results suggest that a targeted R-spondin-mimetic can stimulate functional regeneration in a cell-specific manner,” said Yang Li, PhD, vice president of Biology at Surrozen and a co-author on the paper. “The novel Wnt pathway engineering method described in the article can be tailored to diseased tissues with high levels of endogenous Wnt ligand and specific cell surface receptors, highlighting the potential of the technology to impact multiple disease areas. This publication describes the constructs and experiments that have led to SZN-043, our preclinical candidate for severe liver diseases.” About Wnt SignalingWnt signaling plays key roles in the control of development, homeostasis, and regeneration of many essential organs and tissues, including liver, intestine, lung, kidney, central nervous system, cochlea, bone, and others. Modulation of Wnt signaling pathways has potential for treatment of degenerative diseases and tissue injuries. There are 19 Wnt ligands (Wnts) in mammals, and they signal through Frizzled receptors 1-10 and co-receptors LRP5 or 6, two families of receptors. Endogenous Wnts bind to multiple Frizzled receptors and are heavily modified post-translationally, making them difficult to manufacture consistently. R-spondin stabilizes Frizzled receptors, enhancing the body’s response to endogenous Wnts. About Surrozen’s Proprietary Antibody Platforms and Harnessing Wnt Signaling Since its founding in 2016, Surrozen has developed two proprietary platforms to selectively modulate the Wnt pathway for the potential treatment of injury and disease. Surrozen Wnt-mimetics, also referred to as SWAP (Surrozen Wnt signal activating proteins), are bi-specific full-length human (IgG) antibodies that directly activate the canonical Wnt signaling pathway in target tissue. Surrozen R-spondin-mimetics, also referred to as SWEETS (Surrozen Wnt signal enhancers engineered for tissue specificity), are antibody-based molecules that enhance Wnt signaling by stabilizing Frizzled receptors on targeted cells. About SZN-043 Preclinical Candidate for Severe Liver DiseasesSZN-043 is the first development candidate designed using Surrozen’s SWEETS platform. In preclinical animal models of liver injury and fibrosis, SZN-043 has been shown to selectively activate Wnt signaling in the liver, stimulate hepatocyte proliferation, improve synthetic function, and reduce fibrosis. The Company’s goal is to clinically evaluate the candidate in settings of drastic hepatocyte loss, such as severe acute alcoholic hepatitis (AAH), where SZN-043 may have a rapid impact on hepatocyte regeneration, as well as settings of advanced chronic disease conditions of cirrhosis. Liver cirrhosis is characterized by a decline in liver synthetic function and an increase in liver fibrosis, culminating in various complications such as portal hypertension, ascites, varices, and hepatic encephalopathy. About Surrozen Surrozen is a biotechnology company pioneering a new class of targeted regenerative antibodies to repair a broad range of tissues and organs damaged by serious disease. Surrozen is designing tissue-specific antibodies that engage the body’s own biological repair mechanisms resulting in a broad pipeline of disease-specific therapies to help patients across multiple disease areas, including severe liver diseases, inflammatory bowel disease, retinopathies, hearing loss, lung and airway diseases, and certain neurological disorders. For more information, please visit surrozen.com.