(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. 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."
Kasper Roet, PhD, CEO and Founder of QurAlis
"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."
Huang, X., et al. (2021) Human amyotrophic lateral sclerosis excitability phenotype screen: Target discovery and validation. Cell Reports. doi.org/10.1016/j.celrep.2021.109224.
Posted in: Biochemistry
Tags: Amyotrophic Lateral Sclerosis, Antisense, Brain, Cell, Cell Imaging, Children, Clinical Trial, Compound, CT, Dopamine, Drugs, Genetic, Hospital, Imaging, Ion, Ion Channel, Medicine, Membrane, Membrane Potential, Molecule, Motor Neurons, Muscle, Neurodegeneration, Neurodegenerative Diseases, Neuron, Neurons, pH, Phenotype, Potassium, Potassium Channel, Preclinical, Research, Sclerosis
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