GKRP

All human beings are genetically very similar, sharing approx. 99.9% of the DNA code. The remaining 0.1% explains the natural differences between people, including our predisposition to hereditary diseases. Although sequencing of our genetic material is becoming a routine diagnostic analysis, it is unfortunately far from simple to determine whether specific small differences in our DNA affect our risk of developing disease. The usefulness of DNA sequencing is therefore often limited to the few cases where it is already known if a gene variant increases the risk of disease. Researchers at the Department of Biology, University of Copenhagen, have now contributed to solving this problem for a specific gene called GCK. The study has just been published in Genome Biology. Figure: GCK gene Rasmus Hartmann-Petersen, Professor at the Department of Biology, explains: - “The GCK gene, which codes for the enzyme glucokinase, regulates the secretion of insulin in the pancreas. GCK gene variants can therefore cause a form of hereditary diabetes. Although the connection between GCKand diabetes has been known for several years, we have, until now, only known the effect of a few percent of the possible variants of this gene”. Together with colleagues at the PRISM centre, UCPH, who are currently studying the effects of genetic variations, the researchers measured the effect of all of the possible variants of GCK. PhD student Sarah Gersing, who is the first author of the article, explains: - “We used yeast cells to measure the activity of over 9000 different GCK variants. In this way, we were able to generate a list of the effects — both of already known variants, but also of variants that patients might carry, but that have not yet been discovered. This provides us with a reference for future GCK diagnostics”.  Prof. Kresten Lindorff-Larsen, who heads the PRISM centre, continues: - “Our results are quite unique; not only have we measured the effect of several thousand variants, but for many of the variants, we can now explain what they do to the glucokinase protein. In our centre, we have gathered researchers working across a range of research fields, bridging from data analysis and biophysics to cell biology and medicine, and it is now clear how this broad approach pays off in explaining how diseases arise”. Gene variants of GCK can, among other things, cause a form of hereditary diabetes called "GCK maturity onset diabetes of the young" (GCK-MODY). Professor of genetics, dr. med. Torben Hansen, who is also a member of the PRISM centre, says: - "Although GCK-MODY patients exhibit elevated blood glucose levels, this is often not associated with complications. Hence, unlike other forms of diabetes, most GCK-MODY patients might therefore not need to be treated with medication. However, due to missing or inaccurate genetic data, more than half of the GCK-MODY patients are classified with having either type 1 or type 2 diabetes – and are therefore unnecessarily medicated. We estimate that approx. 1% of those who have recently been diagnosed with type 2 diabetes in Denmark have a variant in the GCK gene, meaning that they don’t need treatment, or need to be treated differently. Our new map of GCK variants can hopefully help give these patients a more correct diagnosis.” The next step for PRISM is to transfer these methods to other genes and diseases. - "We are already well underway with genes involved in e.g., neurodegenerative diseases, and we are trying to develop precise methods that can provide us with insights on disease mechanisms", says Rasmus Hartmann-Petersen.  Kresten Lindorff-Larsen continues: - "Our data gives us the opportunity to test and develop computational models for variant effects, which will then be transferable to other genes and diseases." - “Now, we have measured the effects of almost all variants of GCK, giving us knowledge on which variants that function, and which that do not. The next step is to understand why, and how the same underlying molecular mechanisms can give rise to a wide range of different diseases", concludes Sarah Gersing.

-- Company to share clinical and preclinical data on ACC2, LXR, mitochondrial protonophore, and ACMSD programs -- PALO ALTO, Calif.--(BUSINESS WIRE)-- OrsoBio, Inc., a clinical-stage biopharmaceutical company developing treatments for severe metabolic disorders, today announced the presentation of five abstracts from the company’s programs at AASLD’s The Liver Meeting® from November 4-8. OrsoBio recently announced that it has acquired novel compounds and intellectual property for four programs addressing fundamental aspects of energy metabolism, including inhibitors of acetyl-CoA carboxylase-2 (ACC2), liver X receptor (LXR), and aminocarboxymuconate semialdehyde decarboxylase (ACMSD), as well as a portfolio of mitochondrial protonophores. These compounds have potential for the treatment of a range of metabolic diseases, including type 2 diabetes, severe dyslipidemias, lipodystrophies, and nonalcoholic steatohepatitis (NASH). “There remains tremendous unmet medical need for patients with severe metabolic disorders,” said Mani Subramanian, MD, PhD, Chief Executive Officer of OrsoBio. “We believe that our portfolio of first-in-class compounds targeting central pathways in energy metabolism holds great promise to address both common and rare metabolic diseases. The breadth of our preclinical and clinical research being presented at The Liver Meeting® highlights the potential of these programs, as well as the strength of the OrsoBio research and development team and our scientific collaborations.” “Advances in organoid medicine, including our recent publication describing en masse population-based analysis of human liver organoids (HLOs) for understanding disease genetics and drug response in NASH, highlights the feasibility of a precision therapeutic approach for severe metabolic liver disease,” said Takanori Takebe, MD, PhD, Director of Commercial Innovation at Center for Stem Cell and Organoid Medicine (CuSTOM), Endowed Chair and Associate Professor of Pediatrics at Cincinnati Children’s Hospital Medical Center, and co-author on two of OrsoBio’s presentations (Abstracts #2441, #4210). “I am truly excited about translating the data on OrsoBio’s compounds in HLOs derived from genetic subsets of patients to clinical studies in patients with severe metabolic disorders.” The following abstracts will be presented as poster presentations at The Liver Meeting®, in Washington, D.C., November 4-8, 2022. Abstract #2441: Enhancement of de novo NAD+ biosynthesis by novel ACMSD inhibitors improves mitochondrial function in iPSC-derived human liver organoid models of steatohepatitis Poster Session, Saturday, November 05, 2022 (1:00-2:00 pm) This study evaluated the effect of treatment with ACMSD-inhibiting therapy TLC-065 on mouse hepatocytes and induced pluripotent stem cell (iPSC)-derived HLOs to understand whether the compound could help boost de novo NAD+ synthesis from tryptophan. The study showed multiple benefits of ACMSD-inhibition in rodents, including improved mitochondrial health, enhanced fatty acid oxidation, and decreased de novo lipogenesis, lipotoxicity, and oxidative stress. In iPSC-derived HLOs in which ACMSD expression is upregulated, ACMSD-inhibition elicited similar metabolic benefits as observed in rodent models. Abstract #2532: TLC-2716, a potent, liver-targeted, inverse agonist of the liver X receptor (LXR), demonstrates profound reductions in hepatic and plasma lipids in dysmetabolic rodent models Poster Session, Saturday, November 05, 2022 (1:00-2:00 pm) This study evaluated the effects of TLC-2716 on lipid metabolism in multiple preclinical models. In dysmetabolic rodents, TLC-2716 led to profound improvements in plasma and liver triglycerides, plasma cholesterol, and glucose tolerance. Additionally, in humanized chimeric liver (PXB®) mice, TLC-2716 suppressed the hepatic expression of genes involved in triglyceride and cholesterol metabolism. Due to high hepatic extraction, no impact on expression of genes involved in reverse cholesterol transport (ABCA1, ABCG1) in the circulation were observed with TLC-2716 treatment. Abstract #2551: TLC-6740, a potent liver-targeted mitochondrial protonophore, has multiple metabolic benefits in preclinical models Poster Session, Saturday, November 05, 2022 (1:00-2:00 pm) This study evaluated TLC-6740 in vitro, in nonhuman primates, and in multiple dysmetabolic rodent models. In vitro, mild hepatic mitochondrial uncoupling with TLC-6740 was associated with metabolic benefits in multiple cell types, including AMPK activation, increased TCA cycle flux, and inhibition of de novo lipogenesis. In rodent models of NASH and insulin resistance, TLC-6740 led to weight loss, reduced liver and plasma triglycerides, and improved insulin sensitivity, without evidence of excessive systemic mitochondrial uncoupling, which can be attributed to its selective liver loading (~40x liver:plasma ratio in nonhuman primates). Abstract #3677: Evaluation of the safety and pharmacokinetic effects of the oral, acetyl-CoA carboxylase-2 (ACC2) inhibitor TLC-3595 in healthy volunteers Poster Session, Sunday, November 6, 2022 (1:00-2:00 pm) This Phase 1, first-in-human study evaluated the safety, pharmacokinetics, and pharmacodynamics of TLC-3595 in healthy volunteers. In this single and multiple ascending dose trial, TLC-3595 treatment for up to 14 days was well-tolerated and all adverse events were non-serious and mild. TLC-3595 treatment led to improvements in LDL and total cholesterol, confirming the compound’s pharmacodynamic effects, and its pharmacokinetic properties support once daily oral administration. Abstract #4210: Enhanced lipogenesis associated with a high-risk GCKR variant (rs1260326) is effectively suppressed by TLC-2716, a novel, liver-targeted LXR inverse agonist in steatotic human liver organoids Poster Session, Monday, November 7, 2022 (1:00-2:00 pm) This study utilized induced pluripotent stem cell (iPSC)-derived HLOs to evaluate the relevance of the LXR pathway in NASH, and to assess the effects of TLC-2716 on NASH-related phenotypes in HLOs from subjects with and without the glucokinase regulatory protein (GCKR) missense variant rs1260326:C>T (TT). This variant leads to increased DNL and has been associated with NASH in genome-wide association studies. The study showed upregulation of LXR expression in steatotic HLOs, and that TLC-2716 reduced the expression of lipogenic genes and lipid accumulation in HLOs from patients with and without the GCKR variant rs1260326. The data support the evaluation of TLC-2716 in NASH patients with this GCKR variant in a precision medicine approach. Further information about The Liver Meeting® 2022, hosted by AASLD, can be found at . About OrsoBio, Inc. OrsoBio, Inc. is a privately held, clinical-stage biopharmaceutical company dedicated to developing therapies to treat severe metabolic disorders, including type 2 diabetes, severe dyslipidemias, lipodystrophies, and nonalcoholic steatohepatitis. The company was co-founded by Mani Subramanian, MD, PhD, former Therapeutic Area Head for Liver Diseases at Gilead Sciences, and Samsara BioCapital. OrsoBio currently has four programs in clinical and preclinical development with first-in-class compounds that address central pathways in energy metabolism. For more information, please visit . About Samsara BioCapital Samsara BioCapital is a new breed of biotech investment fund focused on translating cutting-edge biology into new therapies to treat patients with unmet medical needs. Founded in 2016 by Srinivas Akkaraju, MD, PhD, our team of scientists, investors and entrepreneurs takes a long-term view to value creation across all stages of public and private life science companies. We believe in a collaborative, hands-on approach, working closely with entrepreneurs to harness exciting scientific advances and build leading companies. Samsara actively manages assets on behalf of endowments, foundations, and family offices. For more information, please visit .

-- Company will present preclinical data at The Liver Meeting® as it continues Phase 1 clinical trial for TLC-2716 -- PALO ALTO, Calif.--(BUSINESS WIRE)-- OrsoBio, Inc., a clinical-stage biopharmaceutical company developing treatments for severe metabolic disorders, today announced its acquisition of assets relating to the Liver X Receptor (LXR) inverse agonist program from Phenex Pharmaceuticals AG, including lead candidate TLC-2716 and associated intellectual property. The company will present preclinical data describing the efficacy of TLC-2716 in dysmetabolic rodents and human liver organoids (HLOs) at AASLD’s The Liver Meeting®, as it continues a Phase 1, first-in-human study for which data are expected in early 2023. “TLC-2716 has demonstrated highly potent and consistent effects to improve circulating plasma triglycerides and cholesterol and to reduce hepatic steatosis in preclinical models,” said Rob Myers, MD, Chief Medical Officer of OrsoBio. “Our Phase 1 study is progressing well, and we look forward to the continued development of TLC-2716 for the treatment of severe dyslipidemias in 2023.” TLC-2716 is a liver-targeted, inverse agonist (inhibitor) of LXR that regulates plasma triglycerides and cholesterol via multiple mechanisms, including inhibition of de novo lipogenesis (DNL), increased clearance of triglyceride- and cholesterol-rich lipoproteins, and reduced intestinal lipid absorption. The unique pharmacology of TLC-2716, namely hepatic and intestinal restriction, mitigates potential impact on peripheral reverse cholesterol transport, and supports its development for the treatment of patients with severe hypertriglyceridemia, familial hypercholesterolemia, and nonalcoholic steatohepatitis (NASH). “The LXR pathway is central to lipid and cholesterol homeostasis. We developed TLC-2716 to be liver and intestinally restricted in order to restore lipid homeostasis in patients with dysregulation of the LXR pathway,” said Claus Kremoser, PhD, Co-Founder and Chief Executive Officer of Phenex Pharmaceuticals. “I am truly excited that OrsoBio is progressing TLC-2716 into the clinic to unlock the potential of this first-in-class compound for patients with severe dyslipidemias.” Abstracts being presented at AASLD’s The Liver Meeting®, November 4-8, 2022, in Washington, D.C., highlight preclinical studies that demonstrate the potential of TLC-2716 to improve liver triglycerides, circulating lipids, and glucose homeostasis in dysmetabolic rodents, and to reduce the expression of genes involved in lipogenesis and steatosis in HLOs. Abstract #2532: TLC-2716, a potent, liver-targeted, inverse agonist of the liver X receptor (LXR), demonstrates profound reductions in hepatic and plasma lipids in dysmetabolic rodent models This study evaluated the effects of TLC-2716 on lipid metabolism in multiple preclinical models. In dysmetabolic rodents, TLC-2716 led to profound improvements in plasma and liver triglycerides, plasma cholesterol, and glucose tolerance. Additionally, in humanized chimeric liver (PXB®) mice, TLC-2716 suppressed the hepatic expression of genes involved in triglyceride and cholesterol metabolism. Due to high hepatic extraction, no impact on expression of genes involved in reverse cholesterol transport (ABCA1, ABCG1) in the circulation were observed with TLC-2716 treatment. Abstract #4210: Enhanced lipogenesis associated with a high-risk GCKR variant (rs1260326) is effectively suppressed by TLC-2716, a novel, liver-targeted LXR inverse agonist in steatotic human liver organoids This study utilized induced pluripotent stem cell (iPSC)-derived HLOs to evaluate the relevance of the LXR pathway in NASH, and to assess the effects of TLC-2716 on NASH-related phenotypes in HLOs from subjects with and without the glucokinase regulatory protein (GCKR) missense variant rs1260326:C>T (TT). This variant leads to increased DNL and has been associated with NASH in genome-wide association studies. The study showed upregulation of LXR expression in steatotic HLOs, and that TLC-2716 reduced the expression of lipogenic genes and lipid accumulation in HLOs from patients with and without the GCKR variant rs1260326. The data support the evaluation of TLC-2716 in NASH patients with this GCKR variant in a precision medicine approach. About TLC-2716 TLC-2716 is a potent, small-molecule, liver-targeted, inverse agonist of the Liver X Receptor (LXR). Based on modulation of key mechanisms involved in lipid homeostasis, including de novo lipogenesis, clearance of lipoproteins, and intestinal lipid absorption, TLC-2716 has potential as a treatment for severe hypertriglyceridemia, familial hypercholesterolemia, and NASH. TLC-2716 is currently being evaluated in a Phase 1, first-in-human study in New Zealand (ClinicalTrials.gov NCT05483998). About OrsoBio, Inc. OrsoBio, Inc. is a privately held, clinical-stage biopharmaceutical company dedicated to developing therapies to treat severe metabolic disorders, including type 2 diabetes, severe dyslipidemias, lipodystrophies, and nonalcoholic steatohepatitis. The company was co-founded by Mani Subramanian, MD, PhD, former Therapeutic Area Head for Liver Diseases at Gilead Sciences, and Samsara BioCapital. OrsoBio currently has four programs in clinical and preclinical development with first-in-class compounds that address central pathways in energy metabolism. For more information, please visit . About Samsara BioCapital Samsara BioCapital is a new breed of biotech investment fund focused on translating cutting-edge biology into new therapies to treat patients with unmet medical needs. Founded in 2016 by Srinivas Akkaraju, MD, PhD, our team of scientists, investors and entrepreneurs takes a long-term view to value creation across all stages of public and private life science companies. We believe in a collaborative, hands-on approach, working closely with entrepreneurs to harness exciting scientific advances and build leading companies. Samsara actively manages assets on behalf of endowments, foundations, and family offices. For more information, please visit .