Dr Stephen Barat, Senior Vice President and Therapeutics Division Head at HTG Molecular Diagnostics tells DDW how transcriptomics is driving drug discovery and precision medicines.
DDW: Could you explain the process of transcriptomics?
SB: Transcriptomics is the study of genomic RNA transcripts in a biological system. RNA transcript expression levels can provide insight into underlying biology – eg. which genes are upregulated, and which ones are downregulated – which is very useful when studying different disease states. Comparison of changes in the transcriptome allows the identification of genes that are differentially expressed in response to different treatments which can then be used to help further understand cellular perturbation. In terms of technical process, traditional RNA sequencing was a very laborious process that could take several weeks and was prone to errors. Now with the recent advances in ultra-efficient RNA sequencing the same process can be accomplished within only a few days and with much more reliable and higher-quality data.
DDW: What are some of the challenges in early-stage drug discovery and development?
SB: The pursuit of safe and effective therapies is filled with challenges as evidenced by only about 10% or less of drug candidates successfully making it from discovery, through development and registration, and ultimately to patients. Time and again we see the high attrition rate being attributed to mainly inadequate efficacy or unacceptable safety (or both). The aspiration is to as quickly and early as possible, identify candidate molecules that will have the greatest chances for development success. The approach we are pioneering – what we call transcriptome-informed drug discovery and design – represents an approach that we are using to better inform the candidate selection and design process which we believe will meaningfully contribute to this challenge of candidate attrition, thereby rendering greater chances for success in development.
DDW: How can transcriptomics be used to improve drug development timelines and chances of success?
SB: Our transcriptome-informed drug discovery and design approach is a compliment to traditional drug discovery. Very early on in the discovery process following chemical library design and refinement, we apply specific cell-based test systems to understand, from the whole transcriptome level (including epitranscriptomic changes), what specific changes in gene expression occur as related to target engagement and off-target effects, and thereby deductively choose candidates with more desirable features, and iteratively modify those structures to render candidate molecules based on these very unique insights that ordinarily would not be acknowledged. Taking this approach early on in discovery, which is dependent upon our captive RNA profiling capabilities and use of AI via a bespoke machine learning platform, allows us to “enter” the more traditional discovery studies with compounds that have already been refined. Doing so increases our hit rate along with a reduction in discovery costs and time, thereby getting to a recommendation of a new molecular entity for entry to development much sooner and arguably with greater chances for success.
DDW: Does transcriptomics have particular benefits in certain therapy areas such as precision medicine?
SB: Absolutely. Transcriptomics are a necessary compliment to the development of precision medicine therapy approaches in many different disease areas. HTG’s RNA profiling technology has been featured in hundreds of peer-reviewed publications in this area. Diseases ranging from cancer to viral immune response, from cardiovascular to reproductive health, and from metabolic to nervous systems all have the potential to benefit from in-depth transcriptomics.
DDW: Can RNA profiling be used past the point of early development to monitor how drugs perform within clinical trials?
SB: Certainly. RNA profiling can be used in a variety of ways to meaningfully inform the development of a given molecule, such as application in biomarker development, disease signatures, and of course as a companion diagnostic for patient selection.
DDW Volume 24 – Issue 1, Winter 2022/2023
Biography
Dr Stephen Barat has served as Senior Vice President and Therapeutics Division Head for HTG Molecular Diagnostics (HTG), Inc. since October 2021. During his extensive and successful career, he has contributed to developing and registering 15 new drug products, been an active member of industry working groups and earned international recognition for continuing education faculty on drug development topics.
