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NEW YORK—Redpin Therapeutics, a gene therapy company using its proprietary chemogenetics platform to advance targeted cell therapies that address currently intractable diseases of the nervous system, has announced the publication of a new paper in the journal Science, describing the company’s foundational science. The paper, published March 14th, documents the discovery and development of an ion channel-based platform that enables targeted cell activation or inhibition controlled by low doses of the anti-smoking drug varenicline (Chantix).
Scott Sternson, Ph.D., group leader at the Janelia Research Campus of the Howard Hughes Medical Institute (HHMI), led the study. Redpin Therapeutics has a worldwide exclusive license from HHMI for therapeutic use of this technology. Sternson is also a scientific co-founder of Redpin. The researchers developed a novel method for engineering ligand-gated ion channel receptors to have ultrapotent sensitivity to U.S. Food and Drug Administration (FDA)-approved agonists. These chemogenetic receptors enable the selective control of cells in vivo, which Redpin is developing for potential clinical therapies.
Current approved and investigational treatments for neurological and psychiatric diseases typically involve the use of systemic drugs to address diseases caused by local neuron dysfunction. Traditional systemic therapeutics for targeted dysfunctions have limited response rates, due to adverse off-target side effects. Chemogenetics is an approach to selectively control cell function by installing a genetically engineered receptor that renders any targeted cell population sensitive to modulation by an agonist designed to target that receptor. According to Redpin, chemogenetics represents a radical new paradigm for targeted cell therapy, integrating the principles of synthetic biology, gene therapy and traditional pharmacotherapy.
In chemogenetics, a genetically engineered receptor is targeted to be expressed only in disease-causing neurons via gene therapy. The receptor only modulates cell activity when an orally delivered small molecule drug (agonist) is administered. Depending on the type of chemogenetic receptor, the same agonist can either activate or inhibit neuronal cellular activity, and thus address the neuronal dysfunction.
Chemogenetics has been widely adopted in animal research to explore the relationship between neuronal activity and behavior. As a clinical approach, it could be an important new therapeutic modality, promoting activity only in the cells to which the engineered receptors have been targeted, with the potential to enhance potency while minimizing off-target side effects.
“The breakthrough discoveries unearthed by Scott and his colleagues have paved the way for Redpin to lead the clinical application of chemogenetics, which up until this point has not been possible,” said Elma Hawkins, M.D., Ph.D., M.B.A., president and CEO of Redpin and a co-founder of the company. “We are advancing a pipeline of first-in-class gene therapies for critical unmet needs of patients with neurological and psychiatric disorders. The opportunity to help countless patients who currently do not have an approved treatment, do not respond to existing treatments, or experience difficult-to-manage side effects from untargeted systemic drugs is significant.”
The Science paper describes the development and use of a chemogenetic platform that greatly advances the potency, selectivity, and durability of approaches for targeted modulation of cell function. Pharmacologically selective actuator modules (PSAMs) are a modular chemogenetic platform based on modified ion channel ligand-binding domains (LBDs), which are engineered to selectively interact with brain-penetrant agonists, like varenicline. PSAMs can be combined with various ion pore domains (IPDs) from different ion channels to produce chimeric ligand-gated ion channels (LGICs) with common pharmacology, but distinct functional properties.
The authors combined structure-guided ion channel engineering with synthetic chemistry and testing by in vivo imaging, electrophysiology and behavioral perturbations to develop a chemogenetic system of engineered chimeric ion channels that could be suitable for both research and clinical applications. They noted that varenicline is a particularly attractive molecule for chemogenetic applications in the central nervous system because it is well tolerated by patients at low doses, has excellent brain penetrance and has long-lived pharmacology in humans.
The researchers created chimeric LGICs with extremely high sensitivity to varenicline. Two different ion channels were reported for activation or inhibition of neurons. As the authors noted, the low concentrations of varenicline required for chemogenetic modulation are multiples less than the estimated range of steady-state brain levels of varenicline used therapeutically in humans. This suggests the possibility that varenicline can be used for chemogenetic applications at lower doses than those used for anti-nicotine therapy. In addition, the researchers also synthesized a number of novel subnanomolar potency and brain-penetrant analogues of varenicline that were also effective in modulating neuronal activity in rodents.