Uncovering psoriasis’ root cause

Psoriasis is not deadly, but for about 3% of the world’s population, it means a lifetime of itching, scarring and, for some, negative psychological and social effects.

Yet the root cause remains a mystery. Current treatments are effective for many patients but are costly and can increase the risks of serious illnesses such as cancer.

But Jordan Yaron has identified what may be the root cause of the disease.

Supported by a $2 million grant from the National Institutes of Health, or NIH, his works aims to better understand psoriasis and develop targeted therapeutic strategies with less risk than current treatment options.

An assistant professor of chemical engineering in the School for Engineering of Matter, Transport and Energy, part of the Ira A. Fulton Schools of Engineering at Arizona State University, and a faculty member in the Biodesign Institute Center for Biomaterials Innovation and Translation, Yaron is thrilled about the potential impact of his work.

“I’m very grateful for this award, because with five years of funding, we’ll have enough runway to properly and thoroughly test my hypothesis,” he says. “If it turns out to be true, it’s a complete paradigm shift in understanding and treating psoriasis.”

How a broken protein breaks the skin

Yaron says that psoriasis vulgaris, which is the most common form of the disease, is thought to be an autoimmune condition. He argues that the prevailing belief is that when someone with psoriasis experiences a skin injury, the immune system is triggered to attack inflamed cells, leading to thick, scaly plaques. As a result, current therapies target the inflammation, which works — but with a caveat.

“Systemic antibody therapies can reduce symptoms by around 60%, but many patients eventually become resistant, forcing them onto one biologic drug after another,” Yaron says. “Some studies show long-term use can lead to a 200% increased likelihood of not just skin cancer but also lung, bladder and throat cancers.”

Over the next five years, Yaron plans to shine a light on what he believes to be the very first domino that sets off the disease. He says psoriasis vulgaris symptoms happen in a circular fashion.

When a person gets a slight irritation, such as from an accidental cut while cooking or even wearing tight clothing, the body activates a healing process. A major part of that process is the SERPINB3 protein — a discovery that Yaron and his colleague Kaushal Rege, a Fulton Schools professor of chemical engineering and director of the Center for Biomaterials Innovation and Translation, first made during their work on skin wound healing. In healthy people, the protein increases in the skin during healing, then reduces significantly once done. But, in people with psoriasis, Yaron says he found something new.

“When a person has psoriasis, SERPINB3 is always cranked up very high,” Yaron says. “The protein doesn’t turn off, even after the initial injury heals.”

As the healing process proceeds, SERPINB3, through a series of mishandling events, warps into an unfamiliar shape, which the immune system mistakes for a threat. Attacking the misfolded protein leads to autoimmunity and inflammation, which leads to the creation of more SERPINB3 in the skin — and the loop continues.

Cracking the code

Yaron’s understanding of psoriasis didn’t happen overnight.

After many years of working closely with physicians during his postdoctoral training, he recognized that traditional treatment routines often lead to adverse effects more severe than the disease itself. He couldn’t help but wonder if there was a better, lower-risk alternative.

“The fact that treatments were causing other complications really frustrated me,” Yaron says. “The antibody therapies just handicap patients’ immune systems and prevent them from protecting other critical parts of the body. I think we shouldn’t trade one problem for another.”

Yaron took an unconventional route to piece together what he feels may be the root cause of psoriasis. He says that he mined through publicly available data on psoriasis, wound healing and adjacent fields — then did something most researchers don’t usually do.

“I asked, ‘What has everyone studying psoriasis been talking about for the last 30 years, and what are they all missing?’” Yaron says. “I looked at the huge amount of available data on psoriasis and, instead of just focusing on the known story, I focused on patterns that were previously ignored. In dataset after dataset, I saw a high correlation between psoriasis and SERPINB3 gene expression, and with what we are uncovering about how this protein works in the skin, the story fits perfectly.”

Science driven by care

From ointments to drug delivery systems, Yaron’s core mission is to unlock less risky and more effective treatment techniques and tools for psoriasis patients. He says a major part of his research is developing molecular machinery that could selectively target and destroy misbehaving proteins before the immune system notices and attacks them.

By reducing SERPINB3 to normal levels, he aims to stop the body from triggering the immune overreaction that leads to painful, scaly skin in psoriasis patients.

“My goal is to leave the immune system alone so that it can protect the rest of the body,” he says.

Yaron adds that he’s grateful that the NIH can fund ambitious research projects like his.

“This grant mechanism is purely designed for high-risk, high-reward projects,” he says. “I’m really appreciative of being given the vote of confidence that this idea is worth pursuing.”

While the work required to make meaningful progress in this research may seem daunting, Yaron says that ASU is the most conducive place to get it done. Having completed his undergraduate and doctoral studies as well as postdoctoral research at ASU, he says he’s ready to leverage available resources to help solve a major issue that he cares deeply about.

“I’ve been a Sun Devil many times now, and as a scientist, I was raised at ASU,” he says. “Where else in the country do you have biophysics labs right next to environmental biotech labs and bioengineering labs? My work hinges on strengths found in many of these fields, and ASU is the best place I could imagine doing it from. From core facilities to expert collaborators, anything I need is very close by. And it’s not just that it’s there, but the resources are a very good version of what I need.”

Supported by co-investigators Rege and Clinical Associate Professor “Kevin” Jung Keun Lee from Midwestern University, Yaron says he’s confident that after five years, the way we treat psoriasis could become significantly less likely to lead to cancers and infections.