Improving ER Proteostasis as a Therapeutic Strategy to Treat ALS
Abstract
Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease that affects neurons in the brain and spinal cord. Symptoms are not always the same for all individuals; however, all people with ALS will develop progressive muscle weakness and paralysis that in advanced stages will lead to breathing and swallowing problems and death. ALS has no cure that stop or delays disease progression or the intensity of symptoms; therefore, major efforts are needed to define innovative approaches that can result in therapeutic opportunities. Our grant proposal is focused on testing a new concept where targeting and improving motoneuron s protein homeostasis can be used as a possible therapeutic option to treat ALS (familial and sporadic). ALS patients develop several cellular and molecular changes where the most common is the accumulation of misfolded/aggregated proteins and the alteration of protein homeostasis. Protein homeostasis is monitored and maintained at the cellular level by a complex signaling pathway named Unfolded Protein Response (UPR) that senses the status of protein folding at the endoplasmic reticulum (ER), the main protein factory in the cell. The UPR transmits stress information to the nucleus regulating several adaptive gene expression programs that aims to reduce protein overload and enhance protein folding capacity. Our lab is a pioneer in the field and we have obtained encouraging data indicating that the artificial enforcement of the UPR using gene therapy by delivering an active central controller of the UPR to the nervous system of ALS mice provides significant neuroprotection. ATF6 is a sensor and transcription factor that has not been explored as a target to treat ALS. We have been pioneers in developing gene therapy approaches to alleviate ER stress using AAVs to enforce UPR programs in the context of Parkinson disease, Huntington disease, spinal cord injury, peripheral axonal degeneration, Alzheimer disease, and even aging, generating several patents and licensed technologies to further move our ideas into the clinic. Therefore, we intend to determine the possible therapeutic use of enhancing ATF6 pathway by gene therapy or pharmacological activation in ALS progression through the establishment of a strong international collaboration network. Since protein disturbance is a common feature in ALS, we predict that this DOD proposal may result in the possibility of developing a Pan-strategy to treat ALS of different etiologies. The success of recent clinical trials for spinal muscular atrophy (SMA) using gene therapy AVXS demostrated that single administration of adeno-associated viral vectors (AAV) in humans is safe and effective in treating and curing a complex and lethal motoneuron disease. This clearly opens the possibility of using AAVs as carriers in the context of ALS illness. Gene therapy using recombinant viruses is becoming an attractive strategy to deliver active UPR components to specific tissues because it may avoid the pleiotropic effects of systemic and chronic administration of ER stress-targeting compounds. We believe that enhancing UPR programs by the delivery of ATF6 in the brain of ALS mouse models will (i) attenuate ER stress levels, (ii) promote axonal repair, (iii) reduce the levels of protein aggregates and (iv) improve synaptic function and (v) ultimately prolong survival. Additionally, we will administrate Compound 147, a small molecule that activates ATF6 into ALS mice. Our working plan will allow us to define the significance of ATF6 as a feasible target to treat ALS. The successful completion of this grant proposal represents the first step to develop a new clinical application for ALS patients. If successful, we intend to move forward into additional preclinical studies to test safety and efficacy in different ALS mouse models and iPSC-derived motoneurons from ALS patients. Our close association with gene therapy companies such as Genzyme Co
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310990
Entities
People
- Claudio Hetz
Organizations
- Buck Institute for Research on Aging
- United States Army