Development of an Ultrasensitive Biomarker Panel for Alzheimer’s Disease
There are two major challenges standing in the way of better treatment for the Alzheimer’s Disease (AD). The first is that our current understanding of disease progression comes primarily from post-mortem brain tissue analysis. This results in a static view of human neurodegeneration, as opposed to a dynamic one. Second, while many pharmaceutical companies have developed drugs to treat the disease, most trials end without demonstrating significant clinical utility. Recently, scientists have fixated on the idea that these failures were occurring, in part, because the drugs were administered after symptoms had manifested, which means substantial neurodegeneration had already taken place. As a result, pharmaceutical companies are now designing clinical trials with pre-symptomatic, quinquagenarian patients in the hopes that the drugs will meaningfully alter the course of the disease. A considerable impediment, however, is that there are no available tests that predict who will develop the disease before symptoms appear. In addition, there are no tests that can measure the efficacy of new drug candidates.
Some markers in cerebrospinal fluid such as ABeta 42, Tau, and phosphorylated forms of Tau have been shown to be upregulated in Alzheimer’s patients. Even if such measurements were to be further validated and demonstrated to be predictive before the onset of the disease, healthy individuals will likely not be screened using a lumbar puncture, as this procedure is costly, invasive, and exposes patients to the risk of Central Nervous System infection. Instead, it is imperative to develop a simple blood test that predicts which individuals will develop AD such that the right medication can be delivered to the right person at the right time.
With the Simoa technology pioneered by our lab, we plan to take a three-pronged approach with the goal of developing a robust biomarker panel that can be used to measure early-onset AD, disease progression and therapeutic efficacy. We will 1. Identify and develop ultrasensitive protein, PTM, and microRNA assays; 2. Characterize both intra-and inter-subject variability by performing baseline measurements; 3. Develop a novel neuronally-derived exosome isolation technology to concentrate the biomarkers to improve the analytical sensitivity. This comprehensive program should contribute to new detection and monitoring capabilities for AD and enable clinical translation to help stem disease progression.