This Small Business Innovation Research (SBIR) Phase I project will address the demand for new and evolving approaches to alleviate shrinking drug pipelines and costly failed human safety trials and recalls by implementation of new technologies to transform complex human stem cell-derived neural cultures into informative temporal high content screening (HCS) assays. A robust means to interrogate complex cell cultures is important since it is believed that many diseases, drug side effects, and environmental phenotypes are the result of multi-cellular interactions that have been disrupted, leading to physical changes at the complex cell/tissue level. Extended studies toward improving differentiation to specific neural phenotypes and translation of developed techniques will include cell types beyond neural cells. The proprietary expertise in developing scalable manufacturing systems is key to the success of a robust cellular HCS for neural and other cells. Published studies using the company's proprietary neural cells in HCS assays demonstrates utility of the human cell platform, and reported transformative results indicative of human pluripotent-sourced cells that are of significant importance.
The broader impact/commercial potential of this project are that it will provide alternatives to animal model testing through development of novel human stem cell-based assay systems that provide potentially more predictive and translational outcomes for drug discovery. Previously, gene targeted rodent models transformed our understanding of how genes control or affect mammalian development and disease. The robust HCS amenable adherent proprietary neural cells combined with new technologies will enable transformational human cell-based assays that edit, knockout, or knock-in any genome sequence before or during the HCS. As industry and academic researchers move forward in their quest to enhance their understanding of human development and diseases, discover novel therapeutic compounds and develop improved tests for toxicity, so will demand for relevant sources of research materials. Successfully facilitating complex high content system assays at reduced cost while improving throughput also will limit assay variability. This will be met with keen commercial interest from Pharma, chemical companies, CROs and academic and government researchers. Anticipation is that the proposed new genetically modified cellular products will shorten development lead times in early phase compound assessment programs compared to animal studies and provide more robust and informative compound information than current in vitro assays.
The fields of neurotoxicity and drug discovery are making significant contributions toward improving the speed in which toxins, chemicals and candidate drugs can be analyzed. Today the EPA estimates that there are approximately 80,000 man-made chemicals in our environment that we know little to nothing about in terms of their potential effects on human health, and especially on brain development and function. Currently the only assay for developmental neurotoxicity can cost $1.5 million for each compound and take up to 2 years to complete. There is a need for a simple but informative way to prioritize which chemicals require animal studies, and this will likely be best served by an in vitro study using human neurons representing the continuum of human neural development. Through NSF SBIR Phase I funding, ArunA has developed a human neural stem cell product line that has been genetically modified to express a Green Fluorescent Protein (GFP). This new human pluripotent stem cell derived neural product line provides a scalable solution to current labor intensive, single-end-point neurotoxicity assays and may significantly decrease development and informative timelines. Along with these genetically modified neural progenitors and differentiated neurons, the company is developing a set of protocols for a range of standard toxicity assays that will be made available to end-users. Among the assay protocols the company is developing are those that allow testing of multiple chemicals simultaneously to screen for those that have an effect, either on the overall health of nerve cells or on their ability to form circuits and communicate with each other as they are expected to do in a healthy human brain. Based on these early large scale studies researchers could more rapidly select chemicals that call for further in-depth studies. Moreover, researchers with access to common fluorescence based imaging instrumentation should be able to utilize these cells for a variety of other studies. This advancement could reduce the number of animal studies, reduce study time and cost, and by using human cells, will provide results more relevant to the human brain. Thus in the end ArunA’s human pluripotent stem cell derived neural reporter cells developed through this grant may be more informative in neurotoxicity assays and translate more directly to human health and environment than currently used animal and cancer cell lines. Apart from directly impacting drug development, drug safety and environmental toxicity studies, these cells will be made available to academic laboratories that can use them as an exciting teaching resource given the simplicity of use.
