Detecting a Change in Disease Trajectory With Synthetic Molecules
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Fibrotic diseases such as non-alcoholic steatohepatitis (NASH) – caused by inflammation of the liver by a buildup of fat – currently have no non-invasive methods to monitor treatment response. In order to address this, Glympse Bio has developed activity-based biosensors, designed to detect early signs of disease, predict stage of disease and support the development of novel therapies.
Technology Networks spoke with Dr. Caroline Loew, CEO of Glympse Bio, to learn more about the use of activity-based biosensors in fibrotic disease.
Anna MacDonald (AM): Can you tell us about the history and origins of Glympse and its technology?
Caroline Loew (CL): Glympse Bio was founded in 2015 as a spinout of Dr. Sangeeta Bhatia’s lab at MIT. Dr. Bhatia envisioned a tool that could measure disease progression real-time, in a noninvasive way. The Glympse team was able to build on Dr. Bhatia’s foundation in its effort to own the diagnostic continuum in drug development and beyond. This goal was powered by our novel technology: activity-based biosensors that are bioengineered and tunable to any protease-mediated disease.
In 2019, Glympse announced a collaboration with Gilead to utilize our technology to measure the change in disease state of patients with non-alcoholic steatohepatitis (NASH) as they participated in a Gilead clinical study.
Since then, Glympse has been advancing its biosensor technology to allow both earlier detection of disease and to support development of better therapies.
AM: What is an activity-based biosensor, and how do they work to detect a disease state?
CL: Activity-based biosensors are synthetic molecules that can directly and non-invasively query biological activity to detect a change in health and disease trajectory. These measurable changes are directly correlated to changes in protease activity. Proteases are a class of enzymes that drive critical disease pathways. Protease biology has been studied for a long time; the difficulty is that many proteases have been hard to measure, so changes in their activity are harder to detect. This is why an approach using activity-based biosensors has been particularly advantageous.
The biosensors are comprised of three main components: a polyethylene glycol (PEG) structural backbone, peptides that are designed to measure relevant protease enzymatic activity for the disease state and markers detectable by mass spectrometry to read the diagnostic signal upon collection. The biosensors are tailor-made and refined to each protease-mediated disease.
Once administered, the biosensors rapidly measure the activity of proteases that are dysregulated in the disease, which in turn correlates to the current disease state. The proteases modify the biosensors and amplify the detectable markers over the course of an hour.
The markers are detected using standard laboratory approaches, analyzed with a proprietary classifier unique to the disease state, and reported as clinically actionable results. The results from each patient are amassed into a data engine that enhances the precision of the classifiers and powers future discovery.
AM: Glympse is currently exploring the use of the biosensors in fibrotic diseases such as non-alcoholic steatohepatitis. Why were this group of diseases chosen as the first target?
CL: NASH impacts 16 million people in the U.S. and 100 million worldwide. Currently there is no easy-to-use, non-invasive method to either detect disease or measure treatment response across all stages of NASH. The current standard of care is a needle liver biopsy, which is limited both because of its invasiveness and the limited accuracy of its results. Glympse’s biosensors, by contrast, safely, noninvasively and accurately predict specific stages of NASH, and have shown potential to reliably measure response to therapy long before histopathology changes become visible.
Glympse recently announced and presented clinical and preclinical data sets at the American Association for the Study of Liver Disease (AASLD) conference in 2020. The first-in-human clinical data showed that the biosensors are safe and well-tolerated.
AM: Can you tell us about some of the advantages of this approach to disease detection and monitoring for NASH patients compared to traditional methods such as surgical biopsies?
CL: Needle biopsy is limited in two major ways: invasiveness and for some diseases, accuracy. First, because the technique requires a piece of diseased tissue be removed for examination, needle biopsies are invasive for patients. Increased risk and discomfort often lead to patients being unwilling to repeat the procedure, and even if they do agree, the test cannot be repeated frequently. Additionally, to get the result the tissue sample must then be examined by a histopathologist, which is time consuming. Because of both inherent inaccuracy in sampling in some organs and diseases - the liver and non-alcoholic steatohepatitis or NASH being one (each needle biopsy sample is about 1/50,000th of the liver) - and the difficult in reading the tissue slides, the results of the test are much less accurate than is desirable for any diagnostic for this disease.
Glympse’s technology addresses these issues in several ways. The technology helps avoid any patient non-compliance by providing a safe, repeatable, noninvasive measure of disease activity. Our Phase 1 clinical trial data showed that the biosensors are safe and well-tolerated. The peptides that are excreted from the biosensors are detected and measured using standard laboratory approaches, analyzed with a proprietary classifier unique to the disease state, and reported as clinically actionable results.
Glympse’s technology can also be far more accurate and reproducible because it directly measures the activity of proteases that are dysregulated in the disease and directly queries biological activity to detect a change in health. Additionally, with predictive algorithms and machine learning, Glympse’s technology has a unique approach to capture the biology inside the body and not only track changes in diseased tissue but create a map for disease progression. An additional benefit of this approach is that the technology can track response to a treatment by measuring the change in disease trajectory.
AM: The biosensors are tunable and can be designed for other protease-mediated diseases. What other indications are being explored or have the potential to be explored in the future?
CL: Many conditions, including fibrotic diseases, cancer, and infectious diseases, are highly protease-mediated and difficult to readily diagnose. In addition, while there are some options for tracking response to therapy depending on the disease, these diagnostics often have limitations. In cancer for example, liquid biopsy measures are limited by the reliance on shed tumor markers, the degradation of signal from those markers, and the amount of time it takes to obtain results. Imaging measures are limited by binding probes that can modify targets and prevent signal amplification. Glympse’s technology by contrast measures the response to a therapy in real-time and provides a functional readout that shows not only that a tumor is responding, but
Glympse also has preclinical validation of their technology platform across a number of disease areas. With over 20 major disease types that are protease-mediated, there are many opportunities for Glympse to provide highly accurate disease measurements for patients where the standard of diagnostic care is either absent or invasive.
AM: What does 2021 hold for Glympse?
CL: Glympse is continuing to test its biosensors in NASH, further developing its biosensors in fibrotic diseases and infectious diseases, and investigating new indications for the technology. Glympse will also continue to advance its NASH clinical program.
As Glympse’s platform and diagnostic indications advance the company will consider exploring additional strategic collaborations that expand the diagnostic and therapeutic applications of the platform in drug development, diagnosis and staging, and drug response monitoring. The technology can have a breadth of impact for potential partners, from reducing the cost and time associated with signal-seeking trials by monitoring drug/target engagement and activity, to helping to identify a target patient and ensuring they are responding to treatment, all with a noninvasive approach that provides real-time, clinically actionable results.
As Glympse looks forward in 2021, the company is confident about the path forward for its biosensor technology, and its potential to meaningfully advance healthcare for patients.
Caroline Loew was speaking to Anna MacDonald, Science Writer for Technology Networks.