ALS is characterized by the progressive death of motor neurons — the nerve cells that control muscle movements — in the brain and spinal cord. Understanding exactly what biological processes lead to this cell death, and finding new strategies to stop these processes, are ongoing areas of study.
One feature of ALS motor neurons is hyperexcitability, when neurons fire electrical signals more readily than is normal. This abnormal electrical behavior occurs in up to half of ALS patients and is linked to poor survival. It is thought to be a result of abnormally low activity of ion channels, which are proteins in the neuronal membrane that control electrical currents by regulating the movement of charged ions in and out of the cell. Specifically, this low activity is linked to a channel called Kv7.2/7.3.
The anticonvulsant medication ezogabine can activate this channel. In fact, in a recently completed clinical trial (NCT02450552), the medication was shown to reduce hyperexcitability in the motor neurons of ALS patients.
However, ezogabine — also called retigabine — can cause substantial side effects, in part because it targets other proteins, in addition to Kv7.2/7.3.
“While KV7 agonists have shown great potential as a treatment for the 20-50% of ALS patients who present with hyperexcitability in their motor system, they can often cause undesired side effects such as dizziness and fatigue,” Daniel Elbaum, PhD, chief scientific officer of QurAlis, said in a press release.
QurAlis researchers instead turned to QRA-244, a molecule that more selectively targets the Kv7.2/7.3 channel.
Elbaum reported on the development of this molecule in the presentation, titled “QRA-244 a Potent, Selective KCNQ2/3 Opener and a Potential Therapy for Motor System Hyperexcitability induced Disease Progression in ALS patients” (abstract TST-20).
“We have been working to discover, characterize, and develop a novel KCNQ2/3 activator with an improved channel specificity, which is expected to translate into a better clinical safety profile
with comparable or better efficacy,” the researchers wrote.
Experiments in patient-derived motor neurons demonstrated that QRA-244 does indeed activate its ion channel targets, but needs up to 20 times lower concentrations to reach comparable effects to ezogabine.
Side-by-side comparisons in rat models also showed that QRA-244 did not induce dizziness or fatigue to the extent that ezogabine does. Additionally, QRA-244 did not affect human bladder tissue at clinically relevant concentrations, whereas ezogabine does.
From these results, the researchers concluded that QRA-244 is, “a more potent and selective Kv7.2/7.3 activator aimed at normalizing excitability of the ALS motor system, with a significant reduction in off-target driven adverse events.”
The data, Elbaum said, “show that the improved channel specificity of our novel Kv7.2/7.3 agonist could translate into an improved clinical safety profile with significant reduction in off-target adverse events.”
The company is planning to advance QRA-244 into clinical studies at the end of next year, or in early 2022, the company said in a separate press release.
Apart from hyperexcitability, another molecular feature of ALS is reduced autophagy, which is the process cells use to degrade and recycle unneeded cellular components.
In the presentation, titled “TBK1 Autophagy Pathway Disease Mechanisms in ALS” (abstract TST-07), researchers from QurAlis and Harvard University showed that Tbk1 activity was reduced in some ALS patients, at that a reduction of Tbk1 activity in human neurons leads to impaired autophagy.
Further, the researchers identified a molecular target that normally reduces the activity of Tbk1. The researchers propose that reducing the activity of this target might be a useful treatment strategy for ALS.
“Our therapeutic strategy is to inhibit this target … thereby restoring TBK1 pathway activity, to slow or halt disease progression,” the researchers wrote.
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