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MGH

Published On May 2, 2019

BASIC RESEARCH

Under Your Skin

Chronic itch is agony, but new treatments that target the neural pathways responsible could finally offer some relief. 

As an associate biologist in a dermatology department, Ethan Lerner spends his days in his research lab and rarely sees a patient. Still, people seek him out. They are the people who itch, and for whom no amount of scratching gives relief. While such symptoms aren’t fatal, these patients sometimes say they wish they were dead.

Lerner tries to help, but his contributions mostly involve the fundamentals of itching, such as the discovery of itch-related cellular receptors. His work and other work like it are leading to new types of drugs targeting the neural pathways of pruritus—the sensation that provokes the desire to scratch. “This is going to be solved,” says Lerner, who directs Massachusetts General Hospital’s Itch Research Program and leads an itch laboratory at MGH’s Cutaneous Biology Research Center. “I don’t mean every kind of itch is going to be solved, any more than every kind of pain is solved by using a pain drug. But it’s going to be so much better.”

Until recently, itch was considered a minor symptom. It has a lot in common with pain and can occur as a symptom of skin diseases, as well as of kidney failure, liver disease, some types of cancer and other severe medical conditions. Historically, itch has been viewed as a reaction to an irritant or intruder in the skin, and it was thought to be triggered by the release of histamine and similar chemicals to help the immune system ward off invading pathogens. Itch often serves as an important way to alert people that there may be a larger problem. In some cases, however, itch can cross over from nuisance to medical crisis.

When patients itch, dermatologists typically recommend antihistamines, drugs designed to inhibit the actions of histamines. Those are sometimes effective, but the majority of itches are not dependent on histamines. Minor itches go away on their own, while chronic itches last for six weeks or more and can result in uncontrollable, disabling scratching. The chronic variety often stems from inflammatory skin conditions, such as eczema or psoriasis, as well as certain systemic diseases and neurological disorders—though in many cases the causes are unknown.

In 2008 Lerner and his colleagues identified a trigger that activates the itch pathway without involving histamines. It was a cysteine protease, an enzyme that breaks down proteins by cutting them into smaller fragments. Some cysteine proteases exist naturally in the body, and external sources of the enzymes include certain fruits, plants and mites.

“Since this discovery, this field of research has grown exponentially,” says Gil Yosipovitch, director of the Miami Itch Center at the University of Miami Miller School of Medicine and a co-founder of the International Forum for the Study of Itch. “It turns out that most itch is not driven by histamines but by non-histaminergic pathways, one of which Lerner was able to identify.”

Lerner’s interest in itch began with a boyhood case of eczema, which flared up every winter. The response of his parents, both dermatologists, was to give him a topical cortisone cream, which helped relieve his symptoms but didn’t answer the question that would become the focal point of his career: Why do we itch in the first place?

He began by studying cowhage, or Mucuna pruriens, a plant with bean pods covered in fuzzy hairs that trigger itching. University of Pennsylvania dermatologist Walter Shelley first studied cowhage and its itching properties in the 1950s and suggested that the active component was a protease he named “mucunain.”

Lerner and his colleagues further determined that mucunain was a cysteine protease, and they were able to isolate it and identify its mechanism of action. They discovered that when mucunian is absorbed into human skin, it “turns on” two types of molecules, or protease-activated receptors: PAR2 and PAR4, both of which have been linked to inflammation and pain pathways. The cysteine protease cleaves off a piece of these receptors, causing them to transform and to activate cells that send an itchy signal from the skin to the brain.

Lerner and his team then tried to discover similar cysteine proteases that occurred naturally in people. Using sequencing data from the human genome, they identified cathepsin S, an enzyme also linked to skin inflammation. This new enzyme turned on PAR2 as well as another receptor, MRGPRX2, which hadn’t previously been implicated in itch. Blocking these receptors, Lerner concluded, could lead to new therapies.

Lerner’s work spurred a search for other itch mechanisms that don’t involve histamines, and researchers have now found more than a dozen. Each one has the potential to be a drug target. Lerner is a scientific advisor for a San Diego-based startup, Escient Pharmaceuticals, which is now developing drugs to inhibit MRGPRX2 receptors and similar receptors known as Mas-related G protein-coupled receptors (Mrgprs).

As the complexities of chronic itch unspool, researchers such as Lerner and Yosipovitch are convinced that it should be treated as a disorder of its own rather than just as a symptom. At the front lines are the actual people who suffer from it. Lerner relies on this clinical perspective from his colleague Sarina Elmariah, a neuroscientist and dermatologist who directs the MGH Itch Clinic, where she specializes in managing patients with severe and chronic pruritus.

Elmariah and Lerner often discuss the desperation and agony with which her patients struggle because of their relentless itching. They are frequently ashamed to go out in public and are beset with insomnia. “I never give up and I never stop looking for effective treatments,” she says. “My hope is that no one will have to suffer anymore.”