Is There a Space-Based Technology Solution to Problems with Preclinical Drug Toxicity Testing?

Abstract

Even the finest state-of-the art preclinical drug testing, usually in primary hepatocytes, remains an imperfect science. Drugs continue to be withdrawn from the market due to unforeseen toxicity, side effects, and drug interactions. The space program may be able to provide a lifeline. Best known for rockets, space shuttles, astronauts and engineering, the space program has also delivered some serious medical science. Optimized suspension culture in NASA’s specialized suspension culture devices, known as rotating wall vessels, uniquely maintains Phase I and Phase II drug metabolizing pathways in hepatocytes for weeks in cell culture. Previously prohibitively expensive, new materials and 3D printing techniques have the potential to make the NASA rotating wall vessel available inexpensively on an industrial scale. Here we address the tradeoffs inherent in the rotating wall vessel, limitations of alternative approaches for drug metabolism studies, and the market to be addressed. Better pre-clinical drug testing has the potential to significantly reduce the morbidity and mortality of one of the most common problems in modern medicine: adverse events related to pharmaceuticals.

A Critical Perspective on 3D Liver Models for Drug Metabolism and Toxicology Studies

“…It also enabled culturing aggregates of iPSC-derived HLCs or of hepatic cell lines with increased up-regulation of metabolic and hepatocyte-specific gene transcripts, and expression of tight junction proteins providing a more physiologically relevant system that has even been used for the study of hepatitis viruses infections ( Chang and Hughes-Fulford, 2009 ; Sainz et al, 2009 ; Berto et al, 2013 ; Yamashita et al, 2018 ). Nevertheless, translating this technology to absorption, distribution, metabolism, excretion, and toxicity (ADMET) studies has been challenging due to the expensive equipment and labor intensive loading, maintenance, and harvesting ( Hammond et al, 2016 ).…”

Hepatocyte CYP2B6 Can Be Expressed in Cell Culture Systems by Exerting Physiological Levels of Shear: Implications for ADME Testing

“…CYP2B6 has frequent polymorphisms that induce a dynamic range of activity, leading directly to hepatotoxicity and mortality during administration of common drugs [40–42]. New suspension culture methods that introduce physiological levels of shear can now maintain expression of CYP2B6 in vitro [5, 33]. Hepatocytes expressing known polymorphisms of CYP2B6 should be a standard part of preclinical metabolism testing.…”

“…Stress in rotating wall vessels can be delivered at physiological levels by the maintenance of laminar flow conditions [30, 31]. The rotating wall vessel can be spun at a rate to deliver ~0.4 to 0.12 dynes/cm 2 of shear stress, a value close to in vivo levels [17, 18, 30–33]. …”

Harnessing the Space Environment for the Discovery and Development of New Medicines

“…Reported attrition numbers vary according to company and reports (Hay et al 2014) though the issue is well recognized by those in the industry and more prevalent with small molecules. The development by NASA of the rotating wall vessel (RWV) which enables cultures of primary hepatocytes to grow in suspension has been invaluable, more so as phase I and phase II metabolizing enzymes can be maintained for many days and weeks (Hammond et al 2016). Although utilization of RWVs to measure parameters of drug metabolism on an industrial drug-hunting scale is prohibitive, the advent of 3D printing and very recently 3D bioprinting, which will be discussed in more detail in a later section, holds considerable promise for processes relating to drug discovery and toxicity testing (Kizawa et al 2017;Wang et al 2018), through to liver regeneration and transplantation (Wang et al 2018).…”