Optimization and Evaluation of Small Molecules That Increase CNS Progranulin for Use as ALS Therapeutics
Abstract
Background: Amyotrophic Lateral Sclerosis (ALS) is a deadly disease in which the neurons controlling the muscles die, leading to weakness and eventually paralysis and death, usually from respiratory failure within 3-5 years of diagnosis. The majority of ALS patients will also experience mental and behavioral abnormalities. Sharp Edge Labs, Inc. has developed small molecule lead compounds that could become treatments for ALS by preventing the neuron cell death that leads to paralysis and respiratory failure. These compounds target cells within the central nervous system called microglia. Microglia become activated in ALS and produce signals that cause neurons to die. Our compounds can prevent microglia from becoming activated, thus protecting neurons. The new approach targets a secreted protein (progranulin) that is expressed in various cell types in the central nervous system (CNS) including neurons, microglia, endothelial cells, and astrocytes. Progranulin has growth factor properties, with roles in cellular proliferation, survival, wound healing, and inflammation. Importantly, progranulin has been shown to promote survival of neurons and delay their death. Sharp Edge Labs has taken this approach and developed an orally available small molecule that elevates progranulin levels in the rat brain. Elevated progranulin levels should reduce nerve cell damage and inflammation. The ultimate plan is to test a drug candidate in ALS patients, but this will require animal studies first. Having already identified compounds that elevate progranulin levels in neuronal cell lines, and in rats, we will use the ALS animal model and test the ability of these compounds to prevent the neural death and paralysis that occurs in this model. This will be a critical step in choosing a compound to take forward into human clinical trials for ALS. Preliminary Studies: We have identified molecules that selectively increased the progranulin levels by preventing progranulin from being degraded in the brain. We then administered these compounds to rats and have identified brain-penetrant compounds that result in increased progranulin concentration in CNS. Increased progranulin has been shown many times to protect neurons in disease animal models such as Parkinson s, and Alzheimer s, and we plan to extend those studies to ALS. Project Objectives: To advance the development of our molecules, this project aims to first improve the stability of these compounds in animals, increasing their half-life so that stable dosing can be achieved while retaining their activity in neuron cell lines. Secondly, we will perform experiments in mice to demonstrate elevated progranulin levels, which should lead to neuroprotection. Successful completion of this aim will lead us to test these compounds in mouse models specific to ALS where neuronal cell death leads to paralysis. We will evaluate the effects of our molecules in preventing the symptoms associated with ALS as well as performing brain imaging and subsequent analysis of the mouse neurons to determine if we have achieved neuroprotection. Impact: If successful, this research would result in novel small molecule therapies for testing in ALS clinical trials. An orally available drug that treats a fundamental aspect of neurodegeneration in ALS, neuroinflammatory glial cell activation resulting in neuronal cell death, would be a true innovation for ALS patients. Contribution to Advancing Therapeutic Development for ALS: Sharp Edge Labs proposes to identify selective and potent small molecules that possess neuronal protective properties. The targeted molecule will reduce neuroinflammation and extend the lifespan of neurons, by increasing progranulin levels in the CNS. A compound with neuroprotective properties can be an effective therapy for ALS.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210139
Entities
People
- Scott Sneddon
Organizations
- United States Army