By Robert S. Jones
A brighter future in the field of pharmaceutical sciences depends, in part, on the consistent discovery of novel targets and delivery modalities. Dr. Marilyn E. Morris’ lab contributes to this paradigm by characterizing novel drug transporters in order to better understand their role in human physiology and disease. Through the utilization of high-throughput bioanalytical approaches and the development of genetically-engineered preclinical mouse models, we aim to shed light on transporter proteins that have no defined functional role or endogenous substrates—termed “orphan” transporters.
Recently in the scientific community, technologies such as these have rapidly evolved, which have effectively expedited the process of orphan transporter characterization. For example, high-resolution LC/MS/MS technologies, such as Orbitrap, allow for the global analysis of biological samples in a high-throughput approach with accurate, precise, and absolute quantification. These multiple “–omics” strategies have yielded fruitful results thus far, and only continue to grow. With regards to the research in drug transporters, analysis of biofluids such as plasma, serum, and/or urine in this high-throughput approach allows for the simultaneous comparison of metabolic profiles between wildtype and knockout mice. Also, tissues may be analyzed in a similar manner to determine whether there are compensatory mechanisms associated with transporter knockout. These data combined may give evidence into an orphan transporter’s endogenous function in vivo and potentially reveal substrates and/or up/downstream compounds associated with that transporter’s physiological role.
In addition to the progress scientists have made in these bioanalytical approaches, there have been considerable advances in the development of genetically-modified preclinical rodent models using the recently popularized resource CRISPR/Cas9. CRISPR/Cas9 is unique in that it has high specificity and efficiency in comparison to the prototypical gene-editing technologies such as zinc finger nucleases (ZFNs) and transcription activator-like effector nucleases (TALENs). Its ability to genetically modify multiple genes simultaneously while eliminating the time it takes to undergo this process makes it an attractive tool in research. In particular for its utilization in orphan transporter research, this technology is advantageous in tandem with the bioanalytical approaches previously mentioned. The Food and Drug Administration highlights the importance of transporters in their Draft Guidance for Drug Interaction Studies, and states that investigational drugs should be evaluated as potential substrates for a wide range of drug transporters due to clinically significant interactions demonstrated by substrates of P-gp, BCRP, OATP1B1/1B3, OAT1/3, and OCT2.
Moving forward, with the continued development of technologies such as these, we will be able to better understand how novel transporters may be manipulated (as drug targets, delivery strategies, or biomarkers), to further expand their therapeutic potential which will eventually improve health care overall.