Targeting the ER Stress Sensor IRE1 to Treat ALS
Abstract
Amyotrophic lateral sclerosis (ALS) is a progressive and deadly adult-onset motor neuron disease characterized by muscle weakness, atrophy, paralysis, and premature death. The primary mechanism responsible for the progressive loss of motoneurons in ALS remains poorly understood. Clues have been obtained from the identification of altered genes in familial cases of ALS (fALS), which cause problems in the folding of proteins, essential components of the cells. Importantly, perturbations in protein production are also a hallmark of sporadic ALS (sALS) cases, which represent the vast majority of patients. The failure of protein quality control in a subcellular "protein factory" called the endoplasmic reticulum (ER) has been identified as a common factor driving motoneuron dysfunction in ALS. Previous studies from our laboratory and critical analysis of the scientific literature allowed us to formulate a new hypothesis of pathogenic mechanism in ALS. According to our view, problems in ER function activates in a chronic manner a master regulator of protein folding and RNA metabolism, named IRE1, that controls cell fate and triggers neurodegenerative cascades in the motoneuron. In this project, we conceived an experimental plan to investigate the contribution of IRE1 to ALS using complementary animal models of the disease. We will employ genetic ablation of IRE1 in two different transgenic models of ALS to understand its contribution to motoneuron degeneration. Then we will test the therapeutic potential of novel drug that specifically block IRE1 function. We expect that intervening with IRE1 pathway will afford strong protection to affected motoneurons in the long term, preserving motor function. So far the drug selected is the best available in the field for preclinical testing, discovered by our collaborators at the University of California, San Francisco. Importantly, our collaborators are working in parallel to generate better and better drugs by optimizing the compound tested here. According to our rationale, the inhibition of IRE1 will decrease early neurodegenerative cascades by improving protein quality control and restoring cell survival signals. In this manner, both familial and sporadic patients of ALS should benefit from an IRE1-based therapy. To better recapitulate patient treatment, we will test our pharmacological approach in two distinct transgenic models of ALS at early symptomatic stages. Because IRE1 has important functions beyond the nervous system, we will carefully compare systemic and local administration of IRE1 inhibitors for therapeutic efficiency and adverse side effects. Importantly it was recently demonstrated that the chronic administration of this drug is safe and can revert the disease course in models of diabetes and retinal failure. Since our therapeutic idea may interfere with major pathogenic mechanisms underlying the progressive demise of motor neurons, we expect it to alleviate or even halt disease symptoms. If we are successful to provide proof of concept for our strategy, we anticipate that within 5 to 8 years we will be able to move forward a clinical trial for IRE1 in ALS. This process will be accelerated by our strategic alliance with Dr. Robert Brown at the University of Massachusetts, a collaborator on this proposal, who is leading major efforts to move into the clinic several treatment strategies for ALS patients. Importantly, the field has recently witnessed major advances in drug development of IRE1 inhibitors given the increasing interest in targeting IRE1 to treat other relevant human diseases such as cancer and diabetes. Finally, we will profile gene expression of motoneurons to identify molecular and cellular mechanisms that can account for the potential beneficial effects of IRE1 inhibition in ALS transgenic models, thus possibly uncovering new disease modifiers that can be developed into complementary therapeutic approaches in the future. This project
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 31, 2017
- Source ID
- W81XWH1610112
Entities
People
- Claudio Hetz
Organizations
- United States Army