Advanced Patient-Derived Microglia Assay for Preclinical and Clinical Trial Drug Validation
Abstract
Abnormal inflammation in the brain and spinal cord is now recognized to have an important contributory role in many degenerative brain diseases, including amyotrophic lateral sclerosis (ALS). The primary immune cell in the brain and spinal cord is the microglia. This cell type normally monitors the brain and spinal cord and rapidly responds to any damage or infection, initiating a range of protective and repair actions. Unfortunately, in disorders such as ALS, the microglia have impaired function and actually contribute more damage to the tissue around them, resulting in the death of critical neurons responsible for motor functions. It is now recognized that microglia are a major drug target for potential treatments in ALS. Several leading pharmaceutical companies are gearing up to generate a range of potential drug candidates to target this unique cell type. However, at present, there is a critical lack of any suitable cell (lab-based) model to test drugs for their ability to improve microglia function in patients. It is also essential to match the right drugs to the right person, as there is a broad range of disease factors associated with ALS and every patient has a slightly different disease experience. Being able to select the right patients for clinical trials of new drugs provides a major advance in potential drug outcomes and helps reduce the burden on people with ALS who may otherwise enter clinical trials for drugs that are not suited to their form of the disease. Having a model system to monitor drug action during trials is also essential to help improve outcomes for both the drug and patient. The current models include either mouse-derived microglia, or human microglia generated from stem cells. The former is obviously not suited for monitoring drug action in patients. The latter (stem-cell microglia) are useful for initial drug development, but as these cells are expensive and time consuming to establish, they are unsuited to monitoring drug-patient interactions during drug trials. In addition, none of these current models consistently express major classical markers of ALS disease, and, therefore, it can be difficult to know what to measure in the cells to show that a drug is working. In this proposal, we are investigating the potential of a new model system to culture microglia from people with ALS, and demonstrate that this model is ideal for patient pre-selection for clinical trials, and for ongoing monitoring of drug action during trials. The model involves the relatively straightforward preparation of microglia directly from cells in the blood called monocytes. Therefore, we only require a standard blood sample from each patient and can prepare the microglia rapidly and cost-effectively from large numbers of patients to provide statistically meaningful data, as well as investigate patient-specific responses to each drug. In addition, the model shows consistent expression of two key changes that occur in many people with ALS. These include the abnormal accumulation of a protein called TDP-43, and impairment in a key microglia function, called phagocytosis (the uptake and removal of potentially damaging cell debris). The presence of these changes in monocyte-derived microglia provides us with the unique opportunity to determine if drugs are able to induce normal outcomes in these cells, and therefore, more likely improve function in people with ALS. This would be the first available drug action biomarker for microglia in ALS and, potentially, could be used as a surrogate marker for improved function in patients. Importantly, this model involves the use of microglia generated from people with sporadic ALS, which accounts for over 90% of all cases. We consistently see the disease-related changes in these cells and therefore can monitor drug action for the majority of patients. The outcome of this proposal has the potential to revolutionize the ability to provide advanced screening of pot
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210714
Entities
People
- Anthony White
Organizations
- QIMR Berghofer Medical Research Institute
- United States Army