Therapeutic validation of gene-based strategies aimed at restoring neuronal KCC2 in ALS
Project Overview
An imbalance between excitation and inhibition is one of the earliest detectable features of amyotrophic lateral sclerosis (ALS). In fact, changes in the inhibitory synaptic system appears to be central to this imbalance and the modulation of this system using potassium-chloride co-transporter 2 (KCC2)-enhancing compounds have proven to be an exceedingly effective therapeutic strategy for ALS. However, pharmaceutical-based therapies are not without their drawbacks. In fact, many neurodegenerative diseases, including ALS, could benefit from already validated pharmaceutical treatments. Unfortunately, long-term side effects of chronic drug administration and the inability to get said drugs across the blood-brain-barrier while maintaining concentrations low enough to be in a toxicity-free zone have proven difficult. Given the versatility and minimal long-term side effects associated with gene-based therapies (compared to long-term drug-administration), it is no surprise that clinical trials are underway for the treatment of several diseases with such therapeutics. Thus, I hypothesize that restoring KCC2 membrane expression via the application of gene-based therapies will be an effective therapeutic strategy in preclinical models of ALS. Using a well-characterized KCC2-overexpression virus which will systemically delivery exogenous KCC2 into the CNS and a CRISPR-based intervention that will upregulate native KCC2 membrane expression, I will determine if I can prevent or delay the onset of the disease, improve motor function, and prolong survival. Finally, I will use a similar mode of viral enhancement of KCC2 in combination with MRI-guided-focused ultrasound to locally increase KCC2 at the membrane in specific motor regions to minimize the effects of a global CNS increases in KCC2. Findings from this study will provide early preclinical evidence for gene-based strategies that can be translated into clinical therapeutics for ALS.
Principal Investigator
Sahara Khademullah , Université Laval
Partners and Donors
ALS Society of Canada