Multifunctional Small Molecules for ALS Therapy
Abstract
Amyotrophic lateral sclerosis (ALS), commonly called Lou Gehrig s disease, is a fatal neurological disease that involves death of the motor neurons that control movement and breathing. The disease affects approximately 5 out of 100,000 civilians. Military veterans exhibit a significantly increased risk of developing ALS, although the exact reasons for this are unclear. Only two drugs are currently approved to treat ALS. However, both only treat the symptoms and do not prevent the underlying motor neuron death that causes ALS. There is an urgent and unmet medical need to develop new drug candidates that can alter the course of ALS disease. The majority of drug discovery efforts focus on one protein target for one disease. This works well in many indications but neurodegenerative diseases such as ALS evolve from dysfunction of not just one protein but several. As such, developing a drug that targets only one protein has been shown to be ineffective. Herein, we propose to continue the development of a collection of novel patented compounds first synthesized in our laboratory. In previous work we have successfully characterized the compounds to establish their chemical identity and have shown their ability to be protective in several cell lines including in neurons derived from stem cells that were obtained from patients with a similar neurodegenerative disease to ALS. Our compounds show effect to abort neuron death and to increase the cell s ability to clear misfolded proteins that may cause ALS. We understand how these compounds work to achieve these effects and they do so by a mechanism that has previously been very difficult to engage. The current project is composed of two interlinked aims in early phase drug discovery both supported by a multidisciplinary team of experts with complementary skillsets. First, we will continue to develop our novel compounds to enhance their protective effect and to optimize their ability to pass through the human body and into the brain. Our laboratory has particular expertise in the design of drug-like chemical compounds that can penetrate into the brain. We will use a variety of techniques including computational molecular modelling, chemical synthesis, and molecular pharmacology methods to access compounds that have the properties required of drug molecules. Our aim is to identify at least two compounds that can be progressed to preclinical studies in animals at the end of this project. The second aim of this project is to develop a model system that will provide data on the effects of the compounds. We will use commercially available stem cells from three sets of patients, those with mutated SOD1 protein, those with mutated C9orf72 protein, and those with mutated TDP-43 protein. As the exact protein that mutates in ALS and causes the disease is a subject of some debate, using three distinct models from patients with these mutations increases the likelihood that these compounds can treat a range of ALS patients. We will culture the stem cells to develop into several types of cell on their way to full motor neurons. At each stage of development, we will test our best compounds to determine protective effect. If we can show that cells obtained from iPSCs at an early stage of development can be used for robust drug screening, this will provide a highly valuable and rapid way to screen our compounds. We will use ALS patient stem cell-derived motor neurons to test the protective effect of our best developed compounds. Preliminary data shows that our compounds can activate cellular mechanisms that are protective to neurons that share similar defects to ALS motor neurons, these neurons themselves being derived from iPSCs. In summary, this is an early stage drug discovery proposal to identify ALS therapeutic candidates with high potential for development. While direct patient outcomes are several years or more away, the work proposed is essential to begin the i
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210365
Entities
People
- Paul C Trippier
Organizations
- United States Army
- University of Nebraska Medical Center