Targeting Kv2 Channels to Prevent Neuronal Apoptosis in ALS
Abstract
Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease of motor neurons resulting in progressive paralysis and loss of motor function, with death typically occurring relatively shortly after diagnosis. Two treatments are currently approved by the FDA for ALS, riluzole (Rilutek, Teglutik), which only increases life expectancy by a few months at best, and more recently edaravone (Radicava), which needs to be given by repeated intravenous administration and only appears to slow the decline in physical function. Its mechanism of action is not known. Conventional pharmaceutical approaches for novel drug development for ALS have been very disappointing with large numbers of failed phase 2 clinical trials on treatments that appeared promising in preclinical mouse models. A different strategy is required to identify new candidates for ALS therapy, and this is exactly what our proposal aims to do. Instead of mouse preclinical models of ALS, we will use human motor neurons derived from stem cells made from ALS patients as a basis for a screen for novel ALS modifying compounds. We previously identified using patient-derived neurons, a hyperexcitability phenotype, and a patent based on this work was issued in December 2016 (USPTO Patent number 9517223: Methods to treat neurodegenerative diseases. Inventors Clifford J. Woolf, Brian Wainger, Evangelos Kiskinis, Kevin Eggan). This finding led to an phase 2 multicenter study on retigabine, a potassium channel opener (ClinicalTrials.gov Identifier: NCT02450552), which has reported a successful outcome https://alsnewstoday.com/2018/12/13/potiga-lowers- motor-neuron-excitability-als-patients-phase-2-trial/ where the effect of the drug in patient-derived motor neurons was phenocopied by the effect of the compound in patients, providing strong support for the use of human motor neurons as a means to find and test novel ALS targets and therapies. Our proposal is based on our new discovery that the only major change in ion channel expression in ALS motor neurons is that of a potassium channel Kv8.1, which is downregulated. Our data points to ER stress being a major driver of this downregulation, which given that ER stress is a common feature of most forms of ALS, implies that this may be a common pathophysiological mechanism. Kv8.1 is a silent potassium channel and does not allow for any ion flux. However, when it forms a heteromer with another potassium channel Kv2.1, it inhibits Kv2.1. The loss of Kv8.1 will result therefore in a tonic disinhibition of Kv2.1. The reason this is important is that Kv2.1 activity not only modulates membrane excitability but also initiates apoptosis. Our discovery of the downregulation of Kv8.1 led us to test the hypothesis that overactivity in Kv2.1 in ALS motor neurons promotes cell death and that Kv2.1 inhibitors are neuroprotective. Both turned out to be correct. Our plan now is to explore if this mechanism is operational for all, most, or only a few ALS patients, be they familial or sporadic, or if it is restricted to particular mutations. We anticipate the former but plan to test this. This will help define which sets of patients could benefit most from Kv2.1 inhibitors. In parallel with this, we will screen for novel Kv2.1 inhibitors with high neuroprotection efficacy and minimal effect on membrane excitability. The two existing Kv2.1 inhibitors are not suitable for human studies. Our goal is to identify scaffolds where a MedChem program can optimize the efficacy profile and improve drug-like properties such that an orally bioavailable compound with a reasonably long t1/2, good penetration across the Blood Brain Barrier, has high neuroprotective activity by blocking the pro-apoptotic action of Kv2.1 with low effects on potassium permeation through the channel to reduce risk of hyperexcitability. The goal then is to validate Kv2.1 as a target for a broad range of ALS subtypes and develop inhibitors that can form the bas
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 10, 2021
- Source ID
- W81XWH2010077
Entities
People
- Clifford J. Woolf
Organizations
- United States Army