Mas Receptor Agonism for the Treatment of Amyotrophic Lateral Sclerosis (ALS)

Abstract

Amyotrophic lateral sclerosis (ALS) is a rare, progressive neurodegenerative disease characterized by the loss of motor neurons, leading to complete paralysis and death. As of today, approximately 32,000 people are suffering from ALS within the United States, with a worldwide prevalence reaching about 250,000 people. This number is expected to increase by 69% by 2040, highlighting how important it is to better understand this devastating disease. Challenges remain around all facets of this disease, from diagnostic challenges to the lack of viable treatment options. Currently there are only three Food and Drug Administration (FDA) approved medications for ALS, with the majority having very limited benefit for patients. Therefore, there is a critical need for not only research leading to a better understanding of ALS pathology, but also for the development of novel therapeutics that provide better efficacy than those currently on the market today. While the exact mechanism(s) underlying the loss of motor neurons remains to be elucidated, several neurotoxic pathways have been observed across both familial (fALS) and sporadic (sALS). Glutamate mediated excitotoxicity, mitochondria dysfunction, neuroinflammation, increased oxidative stress, and the formation of protein aggregates are believed to be key mediators implicated in ALS pathology. To address this need, new targets may facilitate more effective drug discovery. One target of interest is by modulating the renin-angiotensin system (RAS), mediated by the activation of the mas receptor. The RAS consists of a family of G-Protein Coupled Receptors (GPCR) that serve a dual role. The pathological arm includes angiotensin converting enzyme (ACE), angiotensin-II, and the angiotensin type 1 receptor (AT1R). When this arm is activated, it is known to increase oxidative stress and inflammation. Using a medical informatic approach, we found that blocking AT1R activation, through ACE inhibitors and angiotensin receptor blockers (ARB), was associated with a 12% risk reduction in developing ALS. The opposing arm is viewed as the protective arm, consisting of ACE-II, angiotensin (1-7), angiotensin type 2 receptor (AT2R), and the Mas receptor. The Mas receptor (MasR) is widely expressed on various tissues within the body, specifically in neurons, astrocytes, and microglia within the central nervous system (CNS). Within the CNS, MasR activation reduces many of the mechanisms leading to ALS pathology, including astrogliosis, neuroinflammation, oxidative stress, and promotes neurogenesis and proper synapse formation. In an effort to refocus the therapeutic strategy for ALS, I investigated the efficacy of our novel MasR agonist, RASRx1902, in treating ALS. Utilizing the widely used SOD1G93A mouse model, we investigated the effects of RASRx1902 treatment on slowing ALS disease progression by focusing on the hallmarks of ALS, specifically neuroinflammation, neuronal excitotoxicity, and hypermetabolism. With daily treatment of 2mg/kg RASRx1902, SOD1G93A mice experienced a 25% increase in survival when treatment began at symptomatic onset. This increase in survival was paired with significantly decreased levels of activated microglia within the spinal cord, indicating a reduction in neuroinflammation. Additionally, RASRx1902 treatment was associated with protection of motor neuron activity within the ventral horns of the lumbar spinal cord, indicating a neuroprotective effect. Lastly, RASRx1902 treatment was associated with a stabilization of many metabolites responsible for energy production, indicating a prevention from the metabolic crisis that is associated with ALS pathology. Collectively, this body of new knowledge supports the further investigation for targeting the mas receptor as a novel approach for treating this difficult disease. Mas agonism may be viable target serving as a broad therapeutic for ALS patients, regardless of disease type, due to its protective effect in common ALS mechanisms.