Targeting Synapse Loss in ALS/FTD Using Spine-Regenerating Compounds
Abstract
The goal of this proposal is to test the efficacy of a novel therapeutic small molecule compound in three different models of amyotrophic lateral sclerosis/frontotemporal dementia (ALS/FTD). One of the disease mechanisms in ALS/FTD that is thought to occur early in disease development, independent of disease etiology, is the reduced ability of neurons to efficiently communicate with each other or, in the case of a motor neuron, to signal to connecting muscle tissues. These neuronal communications are happening at a very special cellular structure present on neuronal processes, called spines. These spines allow one neuron to link onto a neighboring neuron by forming a so-called synapse, where information will be exchanged. Many neurodegenerative diseases, including Alzheimer s disease, but also ALS/FTD, are characterized by the loss of these spines and synapses, which is thought to eventually lead to the degeneration of the neuron. The collaborating biotech company, Spinogenix Inc., has developed, synthesized, and optimized novel small molecule compounds that have been shown in other models of neurodegeneration to regenerate those lost spines and synapses. Here, we will test one of the Spinogenix lead compounds for its spine-regenerating activities in three different human ALS/FTD patient-derived induced pluripotent stem cell (iPSC) models (iPSC cortical neurons, iPSC motor neurons, iPSC cortical organoids), as well as a transgenic mouse model of ALS/FTD. The mouse studies will be accompanied by a biomarker evaluation of a synapse-specific PET imaging tracer, which, if successful, can easily be translated to patient trials. In parallel efforts, the proposed compound is undergoing preclinical toxicology evaluations. Therefore, if the proposed studies show significant improvement and efficacy, this compound can be moved forward into clinical trials for ALS/FTD patients very swiftly. To our knowledge, this is the only current therapeutic under evaluation to regenerate synapses lost in ALS/FTD. Therefore, our lead compound could be used as a monotherapy and, in principle, as a co-therapy with any among the large and diverse set of emerging therapeutics aimed at inhibiting neurodegeneration in ALS/FTD patients.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110145
Entities
People
- Rita Sattler
Organizations
- United States Army