Contributed Commentary by Jonah Riddell, Ph.D., Exosome Diagnostics
December 9, 2022 | Liquid biopsies based on circulating tumor DNA or tumor cells have been a remarkable success in improving our prognostic and diagnostic capabilities in oncology. Additionally, cell-free DNA liquid biopsies have been just as important for improving prenatal screening. Now, exosome-based liquid biopsies offer the opportunity to bring the benefits of non-biopsy approaches to a broader range of medical areas.
The most pressing need today comes from neurodegenerative disorders, for which traditional tissue biopsies are either impossible or highly undesirable. Today, Alzheimer’s disease is diagnosed with cognitive function tests that are sometimes paired with imaging-based tests. However, a biomarker-based approach has the potential to be more accurate and would ensure that patients get the most appropriate treatment.
There are two reasons that the field of neurology—with its associated diseases and disorders—has been left behind in this golden age of biomarker development. One is the limited ability to access tissue samples from living patients. Various types of dementia, for instance, can only be accurately diagnosed from post-mortem analysis. The other problem is the blood-brain barrier, which restricts the widespread circulation of neurons and other brain cells to other body parts where they could be more easily accessed.
But the health burden of neurodegenerative diseases is tremendous. One analysis of the global incidence of these diseases found that they affect nearly one in six people (Lancet Neurology, DOI: 10.1016/S1474-4422(18)30499-X). Overall, the number of deaths and disabilities from Alzheimer’s disease, Huntington’s disease, Parkinson’s disease, and many other neurological disorders is increasing worldwide. Unfortunately, the trend holds for brain cancers as well. While five-year survival rates for different cancers have improved thanks to new kinds of treatment, the rates for neuro-related cancers have seen little change (Journal of the National Cancer Institute, DOI: 10.1093/jnci/djx030).
Exosome-based testing has been successfully demonstrated to provide independent biomarker assessment for clinical diagnostic use in other disease areas. Now, scientists are validating the technique for Alzheimer’s, glioblastoma, and other neurodegenerative conditions that can be challenging to diagnose by conventional means. Exosome analysis also offers significant promise for developing companion diagnostic tests that could match patients with neurological disorders to the specific treatments most likely to be effective for them. This analysis could spur innovation in targeted therapies for several truly debilitating diseases.
Exosomes are small, information-packed particles that allow for communication between cells. Released through membrane budding and packed in a protective lipid bilayer, they can contain DNA, RNA, and proteins that shed light on their cell of origin and its state of health or disease. Because they are a fraction of the size of cells, exosomes can cross the blood-brain barrier, bringing their valuable cargo to cerebrospinal fluid and plasma. That allows scientists to tap into accessible biological samples and retrieve key genomic, transcriptomic, and proteomic biomarker data directly from the brain. In addition, the information generated through exosome analysis provides important clues about dynamic changes and cellular activity, allowing for longitudinal monitoring with minimally invasive procedures.
For basic and clinical research, exosomes offer several advantages. Cells produce them frequently, making them an abundant target in biological fluids. Because of their protective coating, they are more stable than cell-free DNA. They can also facilitate the detection of RNA elements that are usually sensitive to degradation, such as gene rearrangements or splice variants. In addition, they can be studied in cell culture, unlike other liquid biopsy targets. Cells in culture continue to produce exosomes, providing a renewable supply for research labs and the opportunity to test drug responses in vitro. For optimal utility in biomarker discovery and development, enrichment and depletion assays can be deployed to target exosomes from specific cell types to ensure that even rare cell types—such as the phosphorylated tau associated with Alzheimer’s disease—can be monitored successfully.
Scientists in academia and pharmaceutical companies are already conducting studies demonstrating the utility of exosome-based testing for several neurological conditions, including brain cancer. One team, for example, showed that RNA sequencing of exosomes could distinguish responders from non-responders for a tyrosine kinase inhibitor used for glioblastoma, indicating the strong potential for developing exosome-based biomarkers into companion diagnostic tools (JCO Precision Oncology, DOI: 10.1200/PO.19.00295). The approach would be particularly appealing for clinical trials since the availability of a non-invasive test would make it easier to collect richer data from each patient more often.
For pharmaceutical and biotech companies, it is possible to streamline the process of discovering, developing, and validating exosome-based biomarkers for companion diagnostic use by partnering with a diagnostic developer experienced in exosome analysis. This partnership enables access to niche expertise about isolating exosomes, enriching for specific cell types, and developing the companion diagnostic parallel to the candidate drug. In addition, the partnership model can accelerate the development of targeted therapies for the underserved field of neurodegenerative diseases.