2021 ARCHIVE TOPICS
Neuroprotective Effects of Carnitine
Carnitine has been studied as a therapy or protective agent for many neurological diseases and neurotoxicity, such as developmental toxicity caused by prolonged anesthetic exposure in preclinical models. Carnitine is a chemical that is essential for the proper function of the human body and comes from our diet, but is also made in the kidney, liver, and brain. It helps move fatty acids across the mitochondrial membrane to be metabolized. Preclinical and clinical data suggest carnitine or acetyl carnitine may improve a patient's quality of life beyond its approved use to treat primary and secondary carnitine deficiency. NCTR scientists conducted a review summarizing the beneficial effects of carnitine or acetyl carnitine on the central nervous system, highlighting protective effects against neurotoxicity-induced damage caused by various chemicals. In the review they also encourage a thorough evaluation of treatment with carnitine as a therapy for patients suffering from neurotoxicant exposure. Read the review in Chemical Research in Toxicology.
Adapting Next-Generation Genetic Toxicology Endpoints to In Vitro Human Organotypic Tissue Models
Organotypic in vitro-tissue models are expected to create unique opportunities to improve predictive toxicology, reduce animal testing, and advance regulatory science. When incorporated into regulatory practice, these models could be used to conduct toxicity assessments using systems that improve the evaluation of human risk in a cost- and time-effective manner, and without the need for conducting in vivo animal experiments.
Among different human organotypic-tissue models, the human air-liquid-interface airway-tissue model resembles the human large-airway epithelium, both structurally and functionally, and has been used as an in-vitro alternative for evaluating the toxicity of inhaled substances (Cao et al., 2020). The measurement of genotoxicity in different tissues of the body, including the airway, is important for evaluating the carcinogenic potential of inhaled substances and the regulatory safety assessment of drugs and chemicals. Genotoxicity assessment, however, is challenging for many in vitro organotypic-tissue models because they are predominately composed of highly differentiated, non-dividing cells that don’t lend themselves to traditional analytical approaches.
NCTR scientists, in collaboration with FDA’s Center for Drug Evaluation and Research and Twinstrand Biosciences, adapted genetic toxicology endpoints to airway cultures. This was done by assessing DNA damage with the high-throughput CometChip assay and quantifying mutagenesis by Duplex Sequencing. The CometChip arranges single cells on a uniform grid where they are used to conduct the alkaline Comet assay. The Comet assay identifies cells with damage to their DNA, which contains information necessary for cell function. The predictable cell arrangement provided by the CometChip permits automated scoring of the assay, greatly increasing the number of cells scored and the speed and robustness of the assay. Duplex Sequencing is an error-corrected next-generation sequencing (ecNGS) method capable of detecting a single alteration in DNA sequence (mutation) per ten million nucleotides—the basic structural unit of nucleic acids such as DNA. This ecNGS method:
- Differentially tags the two strands of duplex DNA.
- Sequences the two strands of DNA individually.
- Compares the sequences in the two strands with themselves and a reference ‘wild-type’ sequence to look for true mutations. These true mutations are not NGS artifacts and thus will have the same sequence change in both DNA strands.
Treating the airway cultures with a prototypical mutagen resulted in time- and concentration-dependent increases in DNA damage and a concentration-dependent increase in mutant frequency. Measurement of physiological endpoints in the airway cultures—including cytotoxicity, tissue responses, and cell morphology—indicated that general toxicity and genotoxicity endpoints could be integrated into a single study. An article reporting these findings can be found in Environmental Molecular Mutagenesis. This study will serve as a starting point for using next-generation approaches for genetic toxicity assessments in human organotypic tissue models and microphysiological systems.
NCTR Represents FDA at Arkansas Bioinformatics Consortium (AR-BIC) Special Session on COVID-19
AR-BIC, an Arkansas collaborative community in bioinformatics research established in 2014, held a virtual special session on "Data Science Solutions for COVID-19" on February 25, 2021. The conference focused on emerging technologies developed in the state of Arkansas to address the COVID-19 pandemic. Approximately 180 participants from academia, industry, and government attended with many of the state’s research organizations represented including NCTR, the University of Arkansas system, Arkansas State University, and Arkansas Research Alliance (ARA). In addition to undergraduate student presentations, the program was organized into three scientific sessions listed below.
- Molecular Modeling
- Artificial Intelligence (AI) and Deep Learning
- Screening and Testing Methods
As stated on the ARA website, COVID-19 has drawn together the brightest minds to defeat the ongoing pandemic—and Arkansas is no exception. The AR-BIC community, established to facilitate communication and collaboration to leverage Arkansas expertise and resources in data sciences and bioinformatics, has been adding to the global body of knowledge about COVID-19 through cutting-edge scientific research.
Two of the three scientific sessions, “Molecular Modeling” and “Screening and Testing Methods,” were chaired by NCTR scientists from its Divisions of Systems Biology and Microbiology. The four NCTR presentations included:
- Artificial Intelligence (AI)-Powered Drug Repositioning for Treating COVID-19—discussed how AI-powered analysis can be used to prioritize the treatment regimen of COVID-19 patients with different severities.
- Elucidating Interactions Between SARS-CoV-2 Trimeric Spike Protein and ACE2 Using Homology Modeling and Molecular Dynamics Simulations—explored the role of molecular docking strategies in understating the molecular interactions in spike proteins in SARS-CoV-2.
- SpecID – Portable Rapid Detection of Viruses Directly in Saliva—introduced a new mass-spectrometer-based technique to detect viruses directly from saliva samples in less than eight seconds.
- Ongoing Studies to Address Coronavirus Knowledge Gaps—described how wastewater in Arkansas is being tested to screen for COVID-19 and the role (in cellular pathways) of proteins of SARS-CoV-2 during the process of infecting the host.
Nanotechnology at NCTR — 2020
Standards provide common ground for product developers and FDA, and these standards facilitate the development of products containing nanomaterials. At the 2016 Global Summit on Regulatory Science (GSRS16), FDA and international regulatory agencies identified the need for nanotechnology standards as a priority. NCTR researchers from FDA’s NCTR/ORA Nanotechnology Core Facility (Nanocore) continue to develop these prioritized standards via the ASTM E56 Subcommittee on Nanotechnology and ISO Technical Committee 229, through stakeholder collaboration and support from the NIEHS/National Toxicology Program. Examples of standards under development include characterization methods to ascertain product quality, consistency, and in vitro safety. Two work items developed by the NCTR Nanocore staff became standards in February 2019 and January 2020 (Standard Practice for Performing Cryo-Transmission Electron Microscopy of Liposomes and Standard Test Method for Quantitative Measurement of the Chemoattractant Capacity of a Nanoparticulate Material in vitro, respectively) and are available through ASTM International. Seven additional work items developed by the NCTR Nanocore scientists are going through the consensus-standard process at ASTM International E56 for quality assurance and testing for biocompatibility.
Nanotechnology Task Force Report
Nanomaterials can have different chemical, physical, or biological properties than their conventionally-scaled counterpart materials used in many products regulated by FDA. To date, over 600 drug products that contain nanomaterials have been submitted to FDA, with over 70 products approved for clinical use. The Nanocore has advanced and comprehensive characterization facilities which allow NCTR to conduct regulatory science research and develop standards that are relevant to FDA-regulated products that contain nanotechnology/nanomaterials. The Nanotechnology Task Force (NTF), chaired by Anil Patri, Ph.D., NCTR Nanocore Director, published a comprehensive progress report, Nanotechnology—Over a Decade of Progress and Innovation, in July 2020. The report highlights the current state of science in nanotechnology and the progress at FDA in:
- interagency engagement
- international engagement
FDA Grand Rounds
The FDA Grand Rounds seminar, “Nanotechnology, Over a Decade of Progress and Innovation at FDA,” was presented by Anil Patri, Ph.D., on August 13, 2020. This seminar highlighted the 2020 Nanotechnology Task Force Report on the progress FDA has made in nanotechnology since 2007. Also discussed were the basics of nanotechnology, FDA facilities overview, regulatory science research at FDA, guidance documents, standards, domestic and international collaborations, and emerging challenges in regulatory science.
FDA’s Nano Day Virtual Research Symposium: “A Decade of Progress and Innovation in Nanotechnology at U.S. FDA,” was organized by NCTR and hosted by the FDA Nanotechnology Task Force on October 9, 2020. This 3.5-hour virtual event drew over 300 participants from around the globe and highlighted the 2020 Nanotechnology Task Force Report and regulatory science research conducted at FDA. Additionally, a virtual tour of FDA’s nanotechnology facilities was provided. Over 20 speakers gave presentations that highlighted the collaborative efforts within FDA, other government agencies, and academia, and demonstrated the expertise and strength within the Agency to promote and protect public health. A list of the 20+ speakers is available in the agenda, and presentations can be viewed in the recorded symposium. Read more about nanotechnology at FDA, nanotechnology at NCTR, or contact Anil Patri, for additional information.
January 22, 2021
Summary of 10th Annual Global Summit on Regulatory Science (GSRS20)
The 10th Global Summit on Regulatory Science (GSRS20) was held virtually September 28-30, 2020, co-hosted by NCTR and the National Center for Advancing Translational Sciences. The theme for the 10th anniversary Global Summit was “Emerging Technologies and Their Application to Regulatory Science—A Global Perspective.” It included over 60 presentations and 2 workshops, speakers from 14 different countries, and scientific leadership from FDA, National Institutes of Health, European Food Safety Agency, Joint Research Centre, Canadian Food Inspection Agency, National Institutes for Food and Drug Control, and National Institute of Health Sciences—to name just a few organizations. You can click on the links throughout the GSRS20 program to view the recorded scientific presentations and workshops on the following topics:
- Plenary Presentations from World Health Leaders
- Artificial Intelligence for Drug Development and Risk Assessment
- OMICS, Biomarkers, and Precision Medicine
- Microphysiological Systems and Stem Cells
- Artificial Intelligence/Machine Learning
The annual Global Summit is sponsored by the Global Coalition for Regulatory Science Research which is comprised of regulatory-science leaders from around the world. NCTR’s Director serves as the co-chair of the Coalition’s executive committee and works with the Coalition to promote global interaction. The GSRS20 drew over 1,100 registrants from approximately 50 countries representing regulatory and research institutes along with academic and industry participants.
Despite the worldwide challenges from the COVID-19 pandemic, the virtual GSRS20 was a huge success with in-depth scientific presentations on emerging technologies for regulatory application. A limited number of academic and industry presenters were invited to showcase cutting-edge research, successes, ongoing clinical trials, and challenges. A recording of the Q & A session where research presenters answered participants’ questions in real-time via chat is available for viewing.
Read more about GSRS here: www.fda.gov/globalsummit.
January 11, 2021
FDA Alternative Methodologies Report — NCTR Achievements
FDA has released the Advancing Alternative Methodologies report that focuses on Agency activities to improve predictivity of human and animal response to FDA-regulated products. As noted in the report, the FDA has developed the Advancing Alternative Methods webpage, which hosts related publications, presentations, and a webinar series that enables developers to showcase their pioneering technologies to FDA scientists. The FDA will continue to update our progress on alternatives in real time for stakeholders on our website.
NCTR achievements toward advancing alternative methods included in the report:
- Evaluation of Patient-Specific Induced Pluripotent Stem-Cell Derived Cardiomyocytes (iPSCCMs) to Improve Oncology Drug-Induced Cardiotoxicity Detection and Prediction
- Human ALI Airway Epithelial Tissue Model
- Development of In Vitro Testicular Models for Evaluating the Potential Reproductive Toxicity of Regulated Products
- Global Summit on Regulatory Science
The following quote is attributed to FDA Chief Scientist RADM Denise Hinton.
“The Advancing Alternative Methodologies report highlights the activities that FDA scientists are undertaking to foster the development of new regulatory approaches-—whether in our laboratories or through innovative collaborations with partners—that can help improve predictivity and potentially replace, reduce and/or refine animal testing.
While the FDA is committed to doing all that it can to reduce the reliance on animal-based studies, there are still many areas where animal research is necessary. Without the use of animals, it would be impossible to gain some of the important knowledge needed to prevent human and animal suffering for many life-threatening diseases. Animal research has played an important role in advancements such as preventing polio, eradicating smallpox and identifying new cancer treatments. We understand and share concerns that animals be involved in research only when there is no other way to fulfil an important public health objective.
Evaluating groundbreaking alternative methods will add to the body of knowledge that the agency can draw upon in conducting its regulatory mission and may even help bring new FDA-regulated products to consumers faster.”
NCTR Research Highlights Archives
- 2019-NCTR Research Highlights
- 2018-NCTR Research Highlights
- 2017-NCTR Research Highlights
- View Research Highlights prior to 2017