Biomarker Development for the Evaluation of Mas Agonist RASRx1902 in Amyotrophic Lateral Sclerosis
Abstract
Amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig s disease, is a disease that affects nerve cells (neurons) in the brain and the spinal cord. Amyotrophic is Greek and literally translates to No muscle nourishment no (A); myo (myo); nourishment (trophic). This disease makes the nerve cells stop working and die. The nerves lose the ability to trigger specific muscles, which causes the muscles to become weak and leads to paralysis. French neurologist Jean-Martin Charcot discovered the disease in 1869. Around 12,000-15,000 people in the United States have ALS, with 5,000 new patients diagnosed each year. ALS is slightly more common in men than women. ALS is age-related; most people find out they have it when they are between 55 and 75 years of age and live 2 to 5 years after symptoms develop. There are two forms of ALS, sporadic and familial. Sporadic, which is the most common form of the disease in the U.S., accounts for 90% to 95% of all cases. It may affect anyone, anywhere. About 5% to 10% of ALS cases occur within families. This is called familial ALS and it means that two or more people in a family have ALS. Familial ALS is found equally among men and women. People with familial ALS typically live only one to two years after symptoms appear and there is a 50% chance each offspring will inherit the gene mutation and may develop the disease. The causes of most forms of ALS are not well understood, but what is known is that inflammation is a key driver that causes the death of neurons and progresses the symptoms of the disease. Current treatments have limited benefit. This study will target the protective side of one of the body s inflammatory responses renin angiotensin system (RAS) to increase regeneration of nerve cells and reduce inflammation, which causes nerve cell death and accelerates ALS symptoms. The therapeutic proposed in this study, RASRx1902, has been tested in several disease models, including Duchenne muscular dystrophy (DMD), systemic lupus erythematosus, and vascular dementia. RASRx1902 has been shown to reduce inflammation and oxidative stress (OS), improve cognitive function, and to have regenerative properties both in the bone marrow and in the circulation. Recently, RASRx1902 has been shown to delay the onset of neurological symptoms and increase survival in a mouse model of ALS. This was in part due to protection of motor neurons and reduction of immune cells into the spine. This grant has multiple goals: (1) to manufacture enough material to support the research that is required to move the drug into human clinical trials; (2) to determine markers in the blood that correlate with the protective effects of RASRx1902 in the mouse model used to show benefit. We will then determine if there is a population of ALS patients that have elevated markers that can be affected by RASRx1902. This work may help determine what markers may be of value to study in the future and support a clinical trial in humans. Through the extensive preclinical work that has been conducted on the use of RASRx1902 as a therapeutic for DMD, this molecule has been shown to be safe and efficacious with no toxic side-effects. Moreover, its development as an oral formulation makes for an easier transition to the clinic. RASRx1902 is currently being advanced towards an Investigational New Drug application (IND) as a treatment for patients suffering from DMD. RASRx1902 will be advancing towards a Phase I safety study in healthy volunteers. Preclinical efficacy data acquired by the studies outlined in the proposal would allow for the immediate advancement into a Phase II clinical study in patients suffering from ALS without any further investment.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210074
Entities
People
- Kathleen Rodgers
Organizations
- United States Army
- University of Arizona