Coda Biotherapeutics wants to control pain by genetically engineering neurons to turn off at will

Coda Biotherapeutics wants to control pain by genetically engineering neurons to turn off at will

Joseph C. Glorioso III has spent decades working in two of medicine’s most difficult fields: gene therapy and pain management. It hasn’t been an easy ride.

The University of Pittsburgh scientist witnessed the gene therapy field almost fall apart in 1999 after the therapies proved to be unexpectedly toxic and sometimes deadly. The other arm of his research—non-addictive pain medications—is no cakewalk either. The hunt for those therapies has grown increasingly urgent in the midst of a national opioid crisis.

Gene therapy scientists eventually worked out the kinks, and the first commercial gene therapy was approved in the U.S. last year. Now the field is undergoing a resurgence, with investors eagerly backing a plethora of gene therapy companies with new ideas.

In 2014, Glorioso cofounded one of those companies, South San Francisco-based Coda Biotherapeutics, which unites his life’s work in both gene therapy and pain management. Last week, the start-up made its first public appearance and announced raising $19 million in series A financing to achieve its goals.

Opioids are addictive, and current non-addictive pain medications work on neurons throughout the body, causing a systemic side effects and drowsiness, Glorioso says. “We want to treat pain where the pain is arising,” he adds.

To do it, Coda is developing gene therapies that will install newly engineered ion channels in people’s sensory neurons to turn the neurons—and thus the pain—off on an as-needed basis. The switch is a small-molecule drug designed specifically for the job.

The strategy is part of an emerging technique called chemogenetics. Coda is the first biotech company attempting to develop chemogenetic therapies for humans. If the idea works, it could be monumental for both the gene therapy and pain fields. The treatment could grant people more control over their pain without addiction or body-wide side effects.

And since most gene therapies in development are for rare genetic conditions that affect small numbers of people, Coda’s therapy would be an economic game changer. The company’s lead program is for chronic neuropathic pain, which afflicts some 19 million people in the U.S. alone.

It’s still early days for the firm and the field. CEO Michael Narachi says Coda will spend another year building up its chemogenetics platform. It will be yet another 18 months before any experimental therapy is ready to test in humans, he adds.

The basis of Coda’s science began in 2010, when Glorioso’s lab devised a method for controlling pain in rats using a herpes simplex virus to deliver a glycine receptor gene into sensory neurons. When glycine binds these receptors, a pore opens, causing a rapid influx of negatively charged chloride ions. That temporarily halts the neuron’s electrical activity, preventing it from transmitting signals to the spinal cord—and thus preventing the perception of pain (Mol. Ther. 2010, DOI: 10.1038/mt.2010.246).

Giving the rats glycine blocked the pain. But glycine is found widely in the body, and for this concept to work in humans, Glorioso needed to create a system that wouldn’t interfere with other bodily functions.

When he learned that ivermectin—a drug normally used to treat parasitic infections—binds mutant versions of glycine receptors, he had an idea: engineer glycine receptors to interact solely with a synthetic drug, one that doesn’t bind to any of the normally occurring ion channels in the body. A one-time gene therapy gets the engineered receptor into neurons, and repeated doses of small-molecule drugs control the receptors.

Coda is currently developing a collection of ion channel variants that can be tested with a library of synthetic binders to find the optimal pair. The firm is expediting discovery of the binders by looking at compounds previously designed to target ion channels, especially ones that failed in clinical trials for other diseases but were shown to be safe in humans.

“That gives a good starting point,” says Elizabeth Alcamo, Coda’s vice president of corporate strategy and business operations. “But our goal is to use a proprietary molecule.”

Getting the gene therapy into the right neurons will be a challenge. The therapy could be injected into clusters of sensory neurons, called dorsal root ganglia, that line the spinal cord. That should ensure that the pain is only numbed in regions of the body innervated by that ganglion. “There are a lot of steps to engineer, which is intriguing and fun, and also makes it hard,” Narachi says. “But if we are successful, it will be unique.”

The chemogenetics approach could also be applied to neurological conditions beyond pain. Coda’s website lists 21 such conditions, including ALS, anxiety, eating disorders, epilepsy, memory loss, and sleep apnea.

Any disease characterized by hyperactive neurons could potentially be curbed by a chemogenetic approach that inactivates neurons, Glorioso explains. Future approaches could use other neuronal receptors that activate neurons. For now, though, the firm will focus on pain.

“Over the years we’ve been through a whole gamut of different strategies for treating pain,” Glorioso says. “I think this new approach is a real winner.”


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