Polygenic Risk Score Test for Drug-Induced Liver Injury Moves Toward Commercialization with IPO Filing
Takeda
Biopharmaceutical Manufacturer
Cincinnati Children's Hospital Medical Center
Cincinnati Children's Hospital Medical Center (CCHMC) is a 700-bed[1] pediatric hospital located in Cincinnati, Ohio. In the U.S. News & World Report’s 2018–19 Best Children’s Hospitals rankings, it ranked second among all hospitals on the Honor Roll. It is home to the busiest pediatric emergency department in the United States, performs the second-highest volume of surgical procedures among children’s hospitals nationwide, and serves as the only Level I pediatric trauma center in southwestern Ohio. Cincinnati Children’s receives the third-highest amount of funding from the National Institutes of Health (NIH) among pediatric institutions in the United States. Its pediatric residency training program is one of the largest in the country, training approximately 200 graduating physicians annually. Cincinnati Children’s operates a large neonatology division that oversees neonatal nurseries at local hospitals as well as its own 59-bed Level IV neonatal intensive care unit (NICU).
Tokyo Medical and Dental University
Tokyo Medical and Dental University (Japanese: 東京医科歯科大学, Tōkyō Ika Shika Daigaku; Chinese: 东京医科齿科大学) is a Japanese national university established in 1928, with its university-level education commencing in 1946. The university is commonly abbreviated as “Ika Shika Dai” or “Tokyo I-Shi Dai.” Its Faculty of Dentistry is the oldest public dental education institution in Japan and was one of the original six dental universities. In April 2004, it was incorporated as a National University Corporation. Currently, Tokyo Medical and Dental University comprises two undergraduate faculties, two graduate schools, two libraries, and two affiliated hospitals, along with numerous research institutes. The university operates across three campuses: the Yushima Campus (building area: 265,623 square meters), the Surugadai Campus (building area: 18,028 square meters), and the Kounodai Campus (building area: 13,900 square meters). Located in Bunkyo Ward, the cultural and educational center of Tokyo, the Yushima Campus serves as the main campus. It houses the Faculty of Medicine, the Faculty of Dentistry, the Graduate School of Medical and Dental Sciences, the Graduate School of Health Care Sciences, the affiliated hospital, and the Central Library. It is also home to the central administrative offices and various research centers. Separated from the Yushima Campus only by a canal, the Surugadai Campus is located in Chiyoda Ward, Tokyo. It hosts the International Exchange Center, the Institute of Biomaterials and Bioengineering, the Research Institute for Diseases of Old Age, and the Data Science Center. The Kounodai Campus, situated in Ichikawa City, Chiba Prefecture, accommodates the College of Liberal Arts, the International House, and international student dormitories. Guided by its educational philosophy, the university is dedicated to cultivating healthcare professionals who possess comprehensive refinement, rich humanistic sensibilities, outstanding creativity, and a broad global perspective.
This work was conducted by scientists from Cincinnati Children’s Hospital, Tokyo Medical and Dental University, Takeda Pharmaceutical Company Limited in Japan, and several other research centers in Japan, Europe, and the United States. These findings represent a significant step forward in addressing challenges that have plagued drug developers for years.
“Currently, we lack reliable methods to predict whether a drug that is generally effective in the majority of the population will cause liver injury,” said Dr. Jorge Bezerra, Director of the Division of Gastroenterology, Hepatology, and Nutrition at Cincinnati Children’s Hospital Medical Center. “This has led to the failure of many promising drugs in clinical trials and, in rare instances, has resulted in serious harm from approved medications. If we could identify which individuals are at highest risk, we could prescribe a broader range of drugs with greater confidence.”
“Our genetic risk score may directly benefit individuals, much like consumer-facing diagnostic applications such as 23andMe. People can undergo genetic testing to determine their risk of developing drug-induced liver injury (DILI),” said Dr. Takanori Takebe, the corresponding author.
The team developed risk scores by reanalyzing hundreds of genome-wide association studies (GWAS), which identified an extensive list of genetic variants that may indicate the likelihood of adverse liver reactions to various compounds. By integrating the data and applying several mathematical weighting methods, the team derived a formula that appeared effective. The risk score incorporates more than 20,000 genetic variants.
The team validated the predictive power of the score in cell cultures, organoid tissues, and using archived patient genomic data. The score proved effective in tests involving more than a dozen drugs: cyclosporine, bosentan, troglitazone, diclofenac, flutamide, ketoconazole, carbamazepine, amoxicillin-clavulanate, methylenedioxymethamphetamine, tacrine, acetaminophen, and tolcapone.
This test is applicable to different types of drugs, as the score focuses on a range of common mechanisms by which the liver metabolizes drugs, including oxidative stress pathways in hepatocytes and endoplasmic reticulum (ER) stress responses.
For clinicians, this will enable rapid genetic testing to identify patients at higher risk of liver injury before prescribing medications. The results may prompt physicians to adjust the dosage, order more frequent follow-up tests to detect early signs of liver damage, or switch to an alternative medication entirely.
For drug research, this test can help exclude individuals at high risk of liver injury from clinical trials, thereby enabling a more accurate assessment of the drug’s benefits. (Bioon.com)
Source:Gene test can predict risk of medications causing liver injury
Original Source:Polygenic architecture informs potential vulnerability to drug-induced liver injury, Nature Medicine (2020). DOI: 10.1038/s41591-020-1023-0 , www.nature.com/articles/s41591-020-1023-0