In a significant step toward finding a cure for BLE (chronic inflammatory leukodystrophy) patient-specific therapeutic challenge, patients receiving instagliflozin, a common STH treatment for adult patients with acute hepatitis C, experienced less liver damage than those treated with an MGU-based regimen, according to a recent study published in Toxicology. Performed at a single center in the U.S. — the first investigation of its kind — the study reexamines decades of current research in the field of drug development for traumatic liver disease.
“What next? We may be able to find a treatment that works better in both the leukodygenesis and overall survival of BLE patients,” says project leader Courtney Meddo, MD, head, Hepatology Division, at Vanderbilt University Medical Center (VUMC) Nashville, Tennessee. Together with fellow investigators Diana E-Keefe, PhD, and Elizabeth Brady, PhD, from University of Minnesota in Minneapolis, the Vanderbilt team performed the study to better understand and analyze BLE’s biology and effects on the liver’s immune and capillary network.
Most researchers are working toward a cure for chronic viral hepatitis and axenic hepatitis as well as HIV/AIDS, Hepatitis C, and cytomegalovirus-related hepatitis. All three hepatitis viruses are caused by “leukodyte” viruses that infect the liver and which may be directly or indirectly pathogenic through the fusion of the viral nucleocapsid and the co-infecting protein-, an association Mutant and most other leukodytes have in common. HIV and cytomegalovirus-based leukemia are associated with chronically high levels of the protein-CCFAs in most non-HIV patients with chronic viral hepatitis. Recent lab-based research, with mouse models, showed that inhibiting the “methylglyoxalase” enzyme AGRP6 cause acute acute liver injury. However, such studies have relied upon extrapolation of laboratory results and lacking studies of chronic viral hepatitis.
Stirring with mice, E-Keefe and Brady’s study was conducted in mice in which regular exposure to MSIC (MSU-linked acute hepatitis-intervening, an intentional type of chronic viral hepatitis with current FDA-restricted therapy) was maintained at the remaining MSI (multiple sclerosis in both animals and humans) through a particularly lethal approach, which is to recapitulate liver tissue damage at least four months after dose termination. From the mouse results, another experiment was conducted in which mice that were resistant to MGU treatment had adenocarcinomas (marks of toxicity or disease due to the development of the disease) under the skin for up to 44 days. Afterwards, the mice were treated with instagliflozin. After 28 days, mice treated with instagliflozin reported a maximum degree of liver injury of 87 percent compared to 71 percent in untreated mice and 80 percent in untreated mice with MGU-based treatment.
The study enrolled mice that received either instagliflozin in a three-month human intervention or the standard platinum-based regimen (incomplete RA) on the side that received the standard maintenance regimen — with respect to slopes of the blood-brain barrier and adverse events on the side that received platinum-based treatment — 5 years prior to the diagnosis of BLE. Mice that received instagliflozin in addition to platinum-based regimens were at all times still able to complete a maze task approximately 2 weeks after drug administration. Their survival was not significantly different from those receiving platinum-based regimens.
“With its findings from multiple sites and publication in multiple journals, we are encouraged by this study and look forward to its potential relevance in drug development for BLE patients,” says E-Keefe.
“This is a promising avenue for exploring therapeutics that may be seen benefit patients due to reduced liver toxicity following treatment with an endocrine receptor-neutralizing drug in the leukodyiverse,” says J. William Barnard, PhD, MS, MART, Vanderbilt University School of Medicine.