Drug induced liver injury (DILI) is a concern for patients, clinicians, the FDA, and the pharmaceutical industry
as the leading cause of clinical drug attrition and post-marketing drug withdrawals. According to the FDA, DILI
has been the most frequent cause of safety-related drug withdrawals for the past 50 years. As a potential
solution to the problem, the IQ-MPS Affiliate to the International Consortium for Innovation and Quality in
Pharmaceutical Development highlighted the need to qualify human liver microphysiological systems (MPS) for
DILI context of use (CoU) with a set of pragmatic engineering and quality requirements for the MPS
implementation into standard operating procedures. During an ongoing NCATS SBIR, Lena Biosciences (LB)
developed and commercialized an SLAS-standardized, Perfused Organ Panel MPS that meets these
prerequisites. The ultimate goal of this SBIR is to qualify the MPS with a revolutionary synthetic hemoglobin,
Blood Substitute, for DILI CoU using the guidance of the FDA CDER and the IQ-MPS Affiliate.
Our recent publication (Front. Mol. Biosci. 2020) shows that the MPS restores cellular oxidative metabolism in
diverse, perfused, 3D liver models, significantly increasing cell respiration by mitochondrial electron transport
chain, CYP450 oxidation required for metabolism of drugs, and OXPHOS ATP production required for holistic
cell function, and all cell processes from active transport of molecules across the cell membrane to organelle
function. An OXPHOS-competent model of cellular redox homeostasis will provide in vivo-like cell sensitivity to
drugs and their reactive metabolites and free radicals, and drug-induced oxidative and nitrosative stress that
leads to the loss of cellular antioxidant defense for comprehensive characterization of DILI threats, positioning
the MPS to adequately meet biological qualification prerequisites for DILI CoU.
While numerous factors contributing to DILI have been reported, to date there is no consensus on the rank of
these factors for in vitro testing using primary human cells, and on the types of in vitro assays that are the most
relevant for DILI prevention. Therefore, in this SBIR we will focus on testing those compounds that the drug
industry found the most difficult to de-risk, examine the role of oxidative cell stress in the sequence of cellular
events that lead to DILI, provide mechanism-informative insight into the DILI sequelae using a battery of
assays to isolate the trigger(s) and identify causalities, and resolve temporal and log-fold change in
biomarkers, including the FDA-designated biomarkers for clinical exploration, relative to vehicle controls and in
relation with the coinciding rise of ALT and ALP, clinical DILI biomarkers, in order to isolate those with the
highest log-fold change and specificity at low or moderate ALT.
To successfully carry out the studies and ensure the project’s success, we have assembled a team of experts
in advanced, OXPHOS-competent cell cultures (LB), and predictive screening of drug-induced livery injury (Dr.
Salman Khetani, UIC).
