Cell Reports publishes data supporting the importance of ion channel, Kv7.2/7.3 as a target in ALS

CAMBRIDGE, Mass.–(BUSINESS WIRE)–QurAlis Corporation, a biotech company developing breakthrough precision medicines for ALS and other genetically validated neurodegenerative diseases, today announced the publication of an article in Cell Reports titled Human Amyotrophic Lateral Sclerosis Excitability Phenotype Screen: Target Discovery and Validation by QurAlis founders Kasper Roet, Ph.D., Clifford Woolf, M.D., Ph.D., and Kevin Eggan, Ph.D., who pioneered a high-content, live-cell imaging screen using ALS patient-derived motor neurons in combination with a compound library generated by Pfizer to identify drug targets to treat hyperexcitability induced neurodegeneration in ALS patients.

The publication describes a live-cell screening strategy targeting abnormal electrophysiological properties to reveal targets that modulate the intrinsic hyperexcitability of ALS motor neurons. This unbiased screen using human ALS motor neurons identified Kv7.2/7.3 as a strongly overrepresented drug target. Dysfunction of Kv7.2/7.3 in ALS motor neurons had been previously identified by Drs. Kevin Eggan, Clifford Woolf, Brian Wainger, and Evangelos Kiskinis, which led to the development of a precision medicine program at QurAlis to develop a selective Kv7.2/7.3 ion channel opener to treat ALS patients. The validity of Kv7.2/7.3 as a drug target for ALS patients was recently also strongly supported by results of a clinical study published in JAMA Neuro showing that Kv7 modulation can decrease spinal and cortical motor neuron excitability, both of which have been linked to patient survival. Through bioinformatic deconvolution, the screen, which was a concerted effort of scientists from the Boston Children’s Hospital, including shared first author Dr. Xuan Huang, The Harvard Stem Cell Institute, and the Pfizer Centers for Therapeutic Innovation also found AMPA receptors and D2 dopamine receptors as novel excitability modulating targets that contribute to ALS motor neuron excitability.

“These research results strengthen our hypothesis that the QurAlis selective Kv7.2/7.3 opener, QRL-101 (QRA-244), has the potential to be an effective therapy for patients suffering from hyperexcitability induced motor neuron degeneration,” said Kasper Roet, Ph.D., CEO and Founder of QurAlis. “Previous research has identified Kv7.2/7.3 as an ALS drug target and the unbiased nature of this screen further emphasizes the importance of Kv7.2/7.3 in ALS motor neuron dysfunction.”

“It is widely believed that by reducing motor neuron hyperexcitability in ALS patients, we may be able to slow the progression of the disease,” said Leonard van den Berg, M.D., Ph.D., Chairman of the European Network to Cure ALS. “This study shows that excitability phenotypic screening using patient derived motor neurons is a novel and powerful method for the identification of drug targets that act on abnormal excitability and offers the potential to produce more effective therapies with fewer side effects.”

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Please refer to the Cell Reports publication for additional results from this study.

About Kv7.2/7.3 Ion Channel Openers

Kv7.2/7.3 is a hetero-tetrameric voltage-gated potassium channel in cell membranes which is encoded by KCNQ2 and KCNQ3. Kv7.2/7.3 is the dominant component of the neuronal M-current in human motor neurons, which stabilizes the membrane potential and controls neuronal excitability.¹

Therapies that reduce abnormal electrical activity in the brain by activating or opening the Kv7.2/7.3 ion-channel show the potential to decrease spinal and cortical motor neuron excitability in patients with ALS and the potential to positively effect CMAP (compound muscle action potential) amplitude², suggesting that this may be an effective therapeutic approach for patients suffering from hyperexcitability induced motor neuron degeneration.

About QRL-101 (QRA-244)

QRL-101 (QRA-244) is QurAlis’ lead drug candidate intended to treat motor neuron hyperexcitability-induced disease progression in ALS patients, which is estimated to be up to 50% of all ALS cases. A Kv7 opener, QRL-101 has been shown in preclinical studies to have strong potential to control motor neuron hyperexcitability induced excitotoxicity with significantly fewer side effects than other drug candidates. QurAlis plans to initiate first-in-human studies of QRL-101 at the end of 2021, or the beginning of 2022.

About QurAlis Corporation

QurAlis is applying precision medicine to advance a novel therapeutic pipeline for the treatment of amyotrophic lateral sclerosis (ALS) and other genetically validated neurodegenerative diseases. The QurAlis platform enables the design and development of drugs that act directly on disease-causing genetic alterations. We are advancing three antisense and small molecule programs addressing sub-forms of ALS that account for the majority of ALS patients. QurAlis is at the leading edge of neurodegenerative research and development. For more information, please visit http://www.quralis.com or follow us on Twitter @QurAlisCo.

Sources:

¹ Ihara Y, Tomonoh Y, Deshimaru M, Zhang B, Uchida T, et al. (2016) Retigabine, a K_v7.2/K_v7.3-Channel Opener, Attenuates Drug-Induced Seizures in Knock-In Mice Harboring Kcnq2 Mutations. PLOS ONE 11(2): e0150095. https://doi.org/10.1371/journal.pone.0150095

² Wainger BJ, Macklin EA, Vucic S, et al. Effect of Ezogabine on Cortical and Spinal Motor Neuron Excitability in Amyotrophic Lateral Sclerosis: A Randomized Clinical Trial. JAMA Neurol. 2021;78(2):186-196. doi:10.1001/jamaneurol.2020.4300

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