Preclinical Evaluation of ASK1 Inhibitor SRT-055 as a Potential Development Candidate for ALS
Abstract
Amyotrophic lateral sclerosis (ALS) is a devastating neurological disease that affects primarily the ability to move the limbs, later followed by problems with speaking and swallowing. Failure of the muscles needed for breathing leads eventually to death. The disease begins typically in the sixth or seventh decade. Most patients die within 3 to 4 years after the first symptoms are recognized. Genetic and environmental risk factors together with aging trigger the disease onset: The genetic causes of approximately 20% of ALS cases are known, which has enabled the development of reliable mouse models of the disease. In addition, cells obtained from ALS patients can be reprogramed to become stem cells. These induced pluripotent stem cells, or iPSC, can be differentiated in cell culture dish to become motor neurons, the critical nerves that control muscles and are lost as the disease progresses. These iPSC-derived motor neurons provide another important model to study the disease and assess the prospects of potential ALS treatments. Both disease-causing mutations as well as normal aging lead to severe oxidative stress in these motor neurons, irreparably damaging proteins, cellular organelles such as the mitochondria and the DNA in the cell nucleus over time. This explains why the mutations do not immediately cause problems in young people. Only the combined hit from the mutations together with the normal aging process leads to the demise of these cells. ASK1 drives the death of motor neurons, and its inhibition is a promising therapeutic approach: This cell death is a tightly regulated process in which a protein known as apoptosis signal-regulating kinase 1 (ASK1) plays a central role. We have developed a small molecule drug, SRT-055, which inhibits the signaling function of ASK1. We have tested SRT-055 in simpler cellular models where the oxidative stress was induced with hydrogen peroxide. Encouragingly, the SRT-055 treated cells were well protected from the hydrogen peroxide induced cell death. Now, as part of the proposed study, we aim to test this protective effect of SRT-055 directly in ALS patient iPSC derived motor neurons. In this case the mutation causing the disease is triggering the oxidative stress. To enable testing of SRT-055 in a mouse model of ALS as a key next step in the study proposal, we will first evaluate different solubility and formulation conditions of SRT-055 to enable optimal absorption after oral administration. Administering SRT-055 to mice, we will measure how much is absorbed from the bowel, how long it stays in the organism, and, importantly, whether it gets into the brain and spinal cord, where the motor neurons are found. These key pharmacokinetic studies will enable the identification of an appropriate dosing schedule for the next experiment, testing the efficacy in a mouse model of ALS. These mice express the mutant version of a protein which causes ALS in humans. The mice start to show weakness in their limbs at an age of 12 weeks and decline for the next 6 weeks eventually leading to death. During this period SRT-055 will be given daily and, as a key indicator of efficacy, we will monitor whether SRT-055 treatment can slow down the decline in muscle strength and extend survival of the mice. Next steps toward a therapy for ALS after this project is completed: If, in the project described here, SRT-055 turns out to be efficacious by slowing muscle weakness progression and extending animal survival, the compound will be validated and moved forward to an even more rigorous and comprehensive test program where broader and more in-depth pharmacokinetic characteristics and toxicity effects will be studied. This preclinical development phase is anticipated to take about 1 year, after which SRT-055 or a similar compound could enter clinical studies in ALS patients with the aim of slowing or even completely halting the human disease progression.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310182
Entities
People
- Johannes Grosse
Organizations
- United States Army