Remote ischemic preconditioning treatment in amyotrophic lateral sclerosis
RATIONALE: There are no effective disease modifying therapies for amyotrophic lateral sclerosis (ALS). Complete understanding of the physiopathology of ALS is lacking, and single-target therapies have failed clinical translation. The overarching goal of this grant application is to test the hypothesis that remote ischemic preconditioning (REIP), a non-invasive, endogenous, pleiotropic neuroprotective intervention, can modify the toxic/cellular microenvironment in the central nervous system (CNS) in ALS. We have preliminary data showing that REIP stimulates neurotrophins in the CNS, but it has never been tested in animal models of ALS.
HYPOTHESIS: We will test the hypothesis that REIP will improve motor function and slow down neurodegeneration in an animal model of ALS through epigenetic regulation (SIRT1) and secretion of trophic factors (HGF, BDNF). To test this hypothesis, we propose the following aims: Aim 1: To investigate the effects of chronic-repeated REIP in the mutant ALS-linked SOD1 G37R (line 42) model. We will induce daily REIP in pre-symptomatic ALS-linked mutant SOD1 mice. Variables measured will include motor performance and lifespan, and also evaluate motor neuron degeneration and brain and spinal cord inflammation; Aim 2: To unravel the potential mechanisms underlying the effects of REIP. We will determine the expression of neurotrophic factors (BDNF, HGF) and SIRT1 deacetylase in the tissue microenvironment and changes associated with REIP from experiments in Aim 1 using proteomics and metabolomics. We will explore alternative mechanisms, specifically focusing on the pleiotropic and wide-ranging neuroprotective effects of REIP, instead of a single molecular pathway.
SIGNIFICANCE: ALS is a devastating neurodegenerative disease for which there is no cure or effective DMTs, and despite advances in our understanding of the pathophysiology of ALS, bench to bedside translation has experienced significant failures. We propose to investigate the effects of REIP on the abundance of trophic factors in the anterior horn in mouse models of ALS, and if these may slow down neurodegeneration. REIP is safe and inexpensive, and thousands of patients with vascular/surgical disorders have undergone REIP in clinical trials. It is thus ripe for fast clinical translation in ALS.
Carlos Camara Lemarroy , University of Calgary
Partners and Donors