Canadian Institutes of Health Research

Arch is repurposing cilastatin, a dipeptidase-1 inhibitor, as a new treatment for acute kidney injury (AKI) Cilastatin is particularly well suited to prevent AKI caused by drug toxins due to its unique off-target effects that block toxin uptake into the kidney tissue Arch continues to perform a Phase II trial for LSALT peptide targeting cardiac surgery-associated-AKI Drug toxins and CS-AKI account for up to 50% of all AKI occurring in hospitals, for which there is no treatment available Aug. 02, 2024 -- Arch Biopartners Inc., (“Arch” or the “Company”) (TSX Venture: ARCH and OTCQB: ACHFF), announced today that cilastatin, the Company’s second drug candidate for preventing acute kidney injury (AKI), will participate in the upcoming investigator led trial entitled “Prevention Of NephroToxin Induced Acute kidney injury with Cilastatin” (PONTIAC). PONTIAC is a 900 patient Phase II trial that will evaluate the efficacy of the dipeptidase-1 inhibitor cilastatin for preventing AKI caused by drugs such as antibiotics, chemotherapeutic agents and radiographic contrast. The PONTIAC clinical team of investigators, based out of the Universities of Calgary and Alberta, was awarded $1,500,000 by the Canadian Institutes of Health Research (CIHR) to fund the trial. The clinical team also received $400,000 as part of the Accelerating Clinical Trials (ACT) call for proposals to “Evaluate Canadian Biotechnologies with Randomized Controlled Trials” (October 2023). Funds from both grants will be used by the clinical team to conduct the PONTIAC trial. The PONTIAC clinical team sponsoring the trial is based in Calgary and is currently preparing to submit a Clinical Trial Application (CTA) to Health Canada to proceed with the trial by the fourth quarter of 2024. Arch is acting as a study partner for grant funding opportunities, providing cilastatin drug product and providing scientific and regulatory advice. Cilastatin is an enzymatic dipeptidase-1 (DPEP1) inhibitor approved by the FDA in 1985 for use as fixed combination with imipenem to treat different types of bacterial infections. Arch has method-of-use patents for repurposing cilastatin as a treatment for acute kidney injury (AKI) in several jurisdictions, including North America and Europe. There is no commercial history of cilastatin as a stand-alone drug product. The drug has a slightly different mechanism of action compared with Arch’s novel drug candidate, LSALT peptide (Metablok) a non-enzymatic DPEP1 inhibitor. Whereas LSALT peptide specifically blocks DPEP1-mediated inflammation in the kidney, lungs and liver, cilastatin has off target-effects that prevent toxin uptake in the kidneys. As such, cilastatin is particularly effective for toxin-related AKI. The PONTIAC trial builds on research published by lead Arch scientists and their colleagues in JCI (The Journal of Clinical Investigation) in 2018, when cilastatin was shown in pre-clinical models to effectively inhibit leukocyte recruitment and drug toxin uptake in the kidney, thereby preventing AKI caused by radiographic contrast. Today’s announcement provides Arch’s drug development program with a second target indication to prevent acute injury to the kidneys. The Company is currently dosing patients with its lead drug candidate, LSALT peptide, in an ongoing, international Phase II study targeting cardiac surgery-associated AKI (CS-AKI). Quote from Mr. Richard Muruve, CEO Arch Biopartners: “We are excited to be the industry partner of the PONTIAC trial while we continue to sponsor the Phase II trial for LSALT peptide targeting CS-AKI. The PONTIAC and CS-AKI trials combined are targeting about half of all AKI cases occurring in hospitals today. We are very driven to complete these trials and improve global kidney care with the first ever therapeutics to prevent acute kidney injury.” AKI reflects a broad spectrum of clinical presentations ranging from mild injury to severe injury that may result in permanent and complete loss of renal function. Clinically, the causes of AKI include sepsis, ischemia-reperfusion injury, and various endogenous as well as exogenous (drug) toxins. There is no specific therapeutic treatment available in the market today that prevents AKI. In the worst cases, the kidneys fail, requiring dialysis or kidney transplantation for patient survival. Drug toxins cause approximately 30% of AKI cases in hospitalized patients and include a wide range of pharmaceutical drugs such as antibiotics (vancomycin, aminoglycosides), chemotherapeutic agents and radiographic contrast. Additionally, AKI related to cardiac surgery (CS-AKI) accounts for up to 20% of in-hospital AKI cases. Cilastatin was originally developed in the early 1980s by Merck Sharp & Dohme Research Laboratories to limit DPEP1’s role in the breakdown of imipenem, a β-lactam antibiotic used for the treatment of systemic infections. Cilastatin was approved for use as fixed combination with imipenem to treat different types of bacterial infections. This fixed combination, approved by the FDA in 1985, is currently marketed under different names, including Primaxin® (USA, UK, Australia, Italy), Tienam® (Spain, Belgium) or Zienam® (Germany). Patents for imipenem and cilastatin have expired and the combination drug is currently in a generic phase. There is no commercial history of cilastatin as a stand-alone drug product. Arch Biopartners Inc. is a late-stage clinical trial company focused on preventing acute kidney injury. The Company is developing a platform of new drugs to prevent inflammation injury in the kidneys, lungs and liver via the dipeptidase-1 (DPEP1) pathway and are relevant for many common injuries and diseases where organ inflammation is an unmet problem. The content above comes from the network. if any infringement, please contact us to modify.

When it comes to managing blood sugar levels, most people think about counting carbs. But new research shows that, for some, it may be just as important to consider the proteins and fats in their diet. The study is the first large-scale comparison of how different people produce insulin in response to each of the three macronutrients: carbohydrates (glucose), proteins (amino acids) and fats (fatty acids). The findings reveal that production of the blood sugar-regulating hormone is much more dynamic and individualized than previously thought, while showing for the first time a subset of the population who are hyper-responsive to fatty foods. When it comes to managing blood sugar levels, most people think about counting carbs. But new research from the University of British Columbia shows that, for some, it may be just as important to consider the proteins and fats in their diet. The study, published today in Cell Metabolism, is the first large-scale comparison of how different people produce insulin in response to each of the three macronutrients: carbohydrates (glucose), proteins (amino acids) and fats (fatty acids). The findings reveal that production of the blood sugar-regulating hormone insulin is much more dynamic and individualized than previously thought, while showing for the first time a subset of the population who are hyper-responsive to fatty foods. "Glucose is the well-known driver of insulin, but we were surprised to see such high variability, with some individuals showing a strong response to proteins, and others to fats, which had never been characterized before," said senior author Dr. James Johnson, a professor of cellular and physiological sciences at UBC. "Insulin plays a major role in human health, in everything from diabetes, where it is too low, to obesity, weight gain and even some forms of cancer, where it is too high. These findings lay the groundwork for personalized nutrition that could transform how we treat and manage a range of conditions." For the study, the researchers conducted tests on pancreatic islets from 140 deceased male and female donors across a wide age range. The islets were exposed to each of the three macronutrients, while the researchers measured the insulin response alongside 8,000 other proteins. Although most donors' islet cells had the strongest insulin response to carbohydrates, approximately nine per cent responded strongly to proteins, while another eight per cent of the donor cells were more responsive to fats than any other nutrient -- even glucose. "This research challenges the long-held belief that fats have negligible effects on insulin release in everyone," says first author Dr. Jelena Kolic, a research associate in the Johnson lab at UBC. "With a better understanding of a person's individual drivers of insulin production, we could potentially provide tailored dietary guidance that would help people better manage their blood sugar and insulin levels." The research team also examined a subset of islet cells from donors who had Type 2 diabetes. As expected, these donor cells had a low insulin response to glucose. However, the researchers were surprised to see that their insulin response to proteins remained largely intact. "This really bolsters the case that protein-rich diets could have therapeutic benefits for patients with Type 2 diabetes and highlights the need for further research into protein-stimulated insulin secretion," said Dr. Kolic. The team conducted a comprehensive protein and gene expression analysis on the pancreatic islet cells, providing insights into the molecular and cellular characteristics that shape insulin production. In the future, the researchers say it could be possible use genetic testing to determine which macronutrients are likely to trigger a person's insulin response. As a next step, the researchers hope to expand their work into clinical studies that would test insulin responsiveness to the trio of macronutrients in a real-world setting, and to begin developing personalized nutrition approaches based on the findings. This research was supported by the Canadian Institutes for Health Research and JDRF Canada. The researchers would like to thank the organ donors and their families for their gift that enabled this research, made through the Human Organ Procurement and Exchange program and Trillium Gift of Life Network.

Researchers have harnessed a bacterial immune defense system, known as CRISPR, to efficiently and precisely control the process of RNA splicing. The technology opens the door to new applications, including systematically interrogating the functions of parts of genes and correcting splicing deficiencies that underlie numerous diseases and disorders. Researchers at the University of Toronto have harnessed a bacterial immune defense system, known as CRISPR, to efficiently and precisely control the process of RNA splicing. The technology opens the door to new applications, including systematically interrogating the functions of parts of genes and correcting splicing deficiencies that underlie numerous diseases and disorders. "Almost all human genes produce RNA transcripts that undergo the process of splicing, whereby coding segments, called exons, are joined together and non-coding segments, called introns, are removed and typically degraded," said Jack Daiyang Li, first author on the study and PhD student of molecular genetics, working in the labs of Benjamin Blencowe and Mikko Taipale at U of T's Donnelly Centre for Cellular and Biomolecular Research. Exons can be alternatively spliced, such that the regulation and function of the approximately 20,000 human genes that encode proteins are greatly diversified, allowing the development and functional specialization of different types of cells. However, it is unclear what most exons or introns do, and the mis-regulation of normal alternative splicing patterns is a frequent cause or contributing factor to various diseases, such as cancers and brain disorders. However, existing methods that allow for the precise and efficient manipulation of splicing have been lacking. In the new research study, a catalytically-deactivated version of an RNA targeting CRISPR protein, referred to as dCasRx, was joined to more than 300 splicing factors to discover a fusion protein, dCasRx-RBM25. This protein is capable of activating or repressing alternative exons in an efficient and targeted manner. "Our new effector protein activated alternative splicing of around 90 percent of tested target exons," said Li. "Importantly, it is capable of simultaneously activating and repressing different exons to examine their combined functions." This multi-level manipulation will facilitate the experimental testing of functional interactions between alternatively spliced variants from genes to determine their combined roles in critical developmental and disease processes. "Our new tool makes possible a broad range of applications, from studying gene function and regulation, to potentially correcting splicing defects in human disorders and diseases," said Blencowe, principal investigator on the study, Canada Research Chair in RNA Biology and Genomics, Banbury Chair in Medical Research and professor of molecular genetics at the Donnelly Centre and the Temerty Faculty of Medicine. "We have developed a versatile engineered splicing factor that outperforms other available tools in the targeted control of alternative exons," said Taipale, also principal investigator on the study, Canada Research Chair in Functional Proteomics and Proteostasis, Anne and Max Tanenbaum Chair in Molecular Medicine and associate professor of molecular genetics at the Donnelly Centre and Temerty Medicine. "It is also important to note that target exons are perturbed with remarkably high specificity by this splicing factor, which alleviates concerns about possible off-target effects." The researchers now have a tool in hand to systematically screen alternative exons to determine their roles in cell survival, cell type specification and gene expression. When it comes to the clinic, the splicing tool has potential to be used to treat numerous human disorders and diseases, such as autism and cancers, in which splicing is often disrupted. This research was supported by the Canadian Institutes of Health Research and the Simons Foundation.