Developing Cell-Based and Mechanism-Focused Preclinical Platforms with Diseased Upper Motor Neurons
Abstract
Current approaches to drug discovery for Amyotrophic Lateral Sclerosis (ALS) treat ALS as a homogeneous disease. On the contrary, ALS is a very heterogenous disease. Although patients exhibit similar clinical presentations, the underlying causes of the disease differ vastly from patient to patient. This one drug - one disease approach to ALS treatment has resulted in many drug failures in clinical trials, because the expectation was that one drug was going to cure all ALS patients. Even though many patients showed improvement in all clinical trials, their overall numbers were not high enough to be considered statistically significant and many of the non-toxic compounds with proven efficacy were denied FDA approval. This is the source of a major frustration in the field and an immense roadblock to our success of building effective and long-term treatment strategies for ALS. There is an urgent need for a new approach that can identify therapies targeted toward specific subtypes of ALS, e.g., precision medicine, similar to approaches now in use for treatment of cancer patients. In this proposal, we describe a new approach that will allow more effective and precise development of new treatments that are based on specific subtypes of ALS. We can distinguish between different underlying mechanisms of disease and use brain cells (neurons) that mirror those mechanisms to identify potentially active chemical compounds that can halt the progression of the disease mechanism. These neurons are upper motor neurons (UMNs), which are required to initiate movement and degenerate in ALS patients. We propose to take advantage of UMNs that we have isolated and engineered to light up fluorescent green so that we can rapidly screen for their responses to potential therapeutic chemical compounds in a semi-high throughput fashion. This approach will allow us to reveal whether compounds of interest also improve the health of diseased UMNs and, if so, which underlying cause is more responsive to treatment. This information will help reveal which patient will benefit from which treatment, so that better clinical trials can be developed and much better success rates can be achieved. This proposal is unique and important because it incorporates for the first time a once forgotten neuronal component into ALS drug discovery. This approach increases the opportunities to identify compounds that will have greater efficacy in ALS clinical trials. We propose to develop a semi-high throughput drug discovery platform so that many others in the field will be able to leverage this approach to expedite drug discovery efforts and success rates of ALS clinical trials. The likelihood of success of this approach is strengthened by our access to Northwestern University s high throughput drug discovery core facility, the team s deep knowledge and experience in studying the cell and molecular biology of UMNs, and extensive expertise in cell-based and mechanism-focused drug discovery efforts. These studies will contribute to improving the success rates of clinical trials in two ways: first, we will be able to identify compounds that improve the health and stability of UMNs, and second, we will learn which compounds improve the health of all diseased motor neurons and those that preferentially act upon a specific subset of diseased neuron. The impact of this new paradigm for ALS drug discovery and disease stratification is likely to be profound and will lead to more precise and sensitive approaches to identifying potential therapeutic candidates and more effective and reliable clinical trials that are tailored around the needs of the patient. It is time to appreciate that each patient is different and we cannot assume that one drug is going to cure all patients. We need to develop better preclinical approaches to reveal which patient will benefit the most from a specific therapeutic approach. This proposal sets the stage for these preclinic
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210271
Entities
People
- Hande Ozdinler
Organizations
- Northwestern University
- United States Army