Cure for Idiopathic Pulmonary Fibrosis Target of UA Research Team with $4.35M DoD Grant

“A little factoid I like to share that always seems surprising is 45 percent of people who die annually die of scar-tissue-related diseases,” Dr. Hecker said. “We are focused on IPF because it is the most fatal form of scar tissue, but scar tissue affects most organ systems…. And a scar tissue drug like this could have far reaching implications for a number of disease types.”

Louise Hecker, PhDPictured above, a chest radiograph of a patient with idiopathic pulmonary fibrosis (left) along with a high resolution computed tomography scan (right) of the chest of an IPF patient that, in dark areas, shows peripheral basal pattern of coarse reticulation with honeycombing. [Credit: Wikipedia]

For Louise Hecker, PhD, an assistant professor in the pulmonary division of the University of Arizona College of Medicine – Tucson’s Department of Medicine, research investigator with the Southern Arizona VA Health Care System and member of the UA BIO5 Institute, every breath of life is precious.

A year after coming to Tucson in 2014 from the University of Alabama at Birmingham (UAB), Dr. Hecker went back to give a eulogy at a funeral for a close friend, Gary Godwin, a 22-year U.S. Army veteran who had suffered from idiopathic pulmonary fibrosis (IPF),  the subject of her research. IPF is a “disease of aging” that causes a rapid decline in respiratory function due to progressive scarring of lung tissue.

In September, Dr. Hecker won a $4.35 million, three-year U.S. Department of Defense (DoD) grant for a study, “Preclinical Development of Small-Molecule Inhibitors Targeting Nox4 for Pulmonary Fibrosis,” to continue her work on development and evaluation of drug candidates for their effectiveness in regulating IPF—and possibly reversing it.

She also has won almost $1.5 million in additional funding this year from the National Institute of Aging, a unit of the National Institutes of Health, (NIA/NIH Award No. R21AG054766) and from the U.S. Department of Veterans Affairs (VA Merit Award No. BX003919) for other research she’s conducting related to pulmonary fibrosis.

Dr. Louise Hecker and her DoD study research team in BIO5 Institute labFrom left, principal investigator Dr. Louise Hecker with co-investigators Drs. Heidi Mansour, Vijay Gokhale and Brett Colson and other members of her research team, Dr. Sunmi Palumbo, Yoon-Joo Shin, Dr. Maria Fernanda Acosta, Reena Chawla, Mohamed Mohamed, Dr. Priya Muralidharan, Megan Carver, Jazmin Castaneda and Adam Knox.

The DoD award is part of a larger effort in recent years by the military through its Congressionally Directed Medical Research Programs to address respiratory illnesses that disproportionately affect veterans, including pulmonary fibrosis, tuberous sclerosis and lung cancer.

According to the Pulmonary Fibrosis Foundation, IPF affects one of every 200 U.S. adults—largely men—over age 65, with 50,000 new cases diagnosed and up to 40,000 people dying from it each year. In February 2015, the foundation named the UA College of Medicine – Tucson and Banner – University Medical Center Tucson to its National PFF Care Center Network.

“A little factoid which always seems to surprise people is that 45 percent of deaths in the U.S. each year are attributed to scar-tissue-related diseases,” Dr. Hecker said. “The reason you may not be aware of this alarming statistic is because the ‘cause of death’ is organ failure, although the organ failure is often the result of progressive scar tissue. End-stage heart failure, for instance, typically results from progressive scar tissue in the heart. I study the most relentless form of tissue scarring which happens in the lungs.”

Currently, there are two drugs approved by the U.S. Food and Drug Administration for IPF, she added, but they are not a “cure” and they do not improve the quality of life for IPF patients.

Regenerative Roots

Magnified view of salamander's tail glandsA New York native, Dr. Hecker earned a bachelor’s degree in biology from Hartwick College and a master’s degree in ecology, evolution and behavior from Binghamton University, where among things she studied were tissue and limb regenerative properties of amphibians. She went on to complete another master’s degree in cell and developmental biology and a doctorate in applied physics at the University of Michigan, where her work focused on developing bioartificial tissues.

A framed image of turquoise scales (right) hangs on Dr. Louise Hecker’s UA office wall—a magnified view of a salamander’s tail glands. During her earliest research experiences, she studied regenerative properties of amphibians that informs her work on lung reparative properties. Amphibians regrow damaged parts, while humans’ reaction to injury is to form scars. “Having training in development and regeneration helps me to better understand aging and the lack of repair that occurs as we get older,” she said.

Cover - Nature Medicine, September 2009At Michigan, she also completed a post-doctoral fellowship in lung injury-repair responses, where she was the lead author on the research team that was the first to identify a critical role for the oxidant-generating enzyme Nox4 as a key mediator in regulating scar tissue in the lung. The study further demonstrated that Nox4 overexpression is significantly elevated in IPF patient lungs, which may be the cause of excessive lung scarring in these patients (see "NADPH oxidase-4 mediates myofibroblast activation and fibrogenic responses to lung injury," Nature Medicine, September 2009).

Nox enzymes, Dr. Hecker noted, are crucial to our bodies’ natural ability to protect and heal themselves, including mechanisms of inflammation and scar tissue. Without the capability to develop scar tissue, we wouldn’t be able to repair tissue injury. Since Dr. Hecker’s original finding that Nox4 mediates scar tissue in the lungs, hundreds of studies that followed have demonstrated that it is a key regulator of scar tissue in many other organs, including the heart, skin, kidney and liver.

Cover - Science Translational Medicine, April 2014From Michigan, Dr. Hecker joined UAB’s faculty in 2009, where she became interested in understanding why normal repair processes “go awry” in aging. The problem as we age is that our bodies’ ability to efficiently repair itself declines, she said. Progressive scar tissue that can become fatal is a hallmark of aging in many organ systems. Dr. Hecker’s work showed that, in aging, Nox4 becomes dysfunctional—as if the switch to “turn off” Nox4 is broken, so it remains “turned on” leading to excessive scar tissue formation (see “Reversal of Persistent Fibrosis in Aging by Targeting NOX4-Nrf2 Redox Imbalance,” Science Translational Medicine, April 2014). While at UAB, she also won a small grant to develop a screening assay for Nox4 to allow faster evaluation of 30,000 potential drug candidates for treating IPF.

The Lure of Expertise (and a Friend)

In 2014, Dr. Hecker was recruited to the UA under the leadership of then-UA Health Sciences senior vice president Joe G.N. “Skip” Garcia, MD, a leading authority on the genetic basis of lung disease and the prevention and treatment of inflammatory lung injury. Her mentor, Dr. Garcia is a member of her DoD study’s advisory board, which also includes the UA College of Pharmacy’s Laurence Hurley, PhD; past College of Medicine – Tucson pulmonary division chief Ken Knox, MD; the UA Center for Accelerated BioMedical Innovation’s Marvin Slepian, MD, and Rakhi Gibbons, of Tech Launch Arizona—the commercialization arm of the university which helps bring UA-developed innovations to market.

Another member is the patient advocate Susan Godwin, the widow of Gary Godwin, who was diagnosed with IPF. Dr. Hecker met the Godwins when Gary was in a clinical trial for advanced lung disease at Birmingham’s UAB Hospital. In 2010, after several false starts, he got a lung transplant there.

“In a very short time, this 60-something couple had become my extremely close friends,” Dr. Hecker acknowledges. “I was devastated when he died. Yes, it’s sad—but, on the other hand, Gary did beat the odds. Less than 50 percent of lung transplant patients survive five years, and Gary made it beyond that point.”

Susan, founder of Christian Copyright Solutions in Fairhope, Ala., said she is happy to be able to contribute. “I'm thrilled to serve as a patient advocate for this exciting project,” she said.

“Susan’s role on the advisory board is to speak to the challenges an IPF patient might face with an inhaled therapy, given this is a disease where patients already have trouble breathing,” Dr. Hecker said.

Part of what attracted Dr. Hecker to the UA was the medicinal chemistry and drug development expertise here. With further financial support from the BIO5 Institute, she was able to assemble a team to continue pre-clinical development and testing of novel drug candidates developed at the UA. Patents were filed for two different classes of promising IPF drug candidates last summer.

Narrowing in on a Solution

Now, with the DoD grant, Dr. Hecker and her team will push four aims to develop an effective therapy to halt IPF’s progression and more importantly, to reverse it. The first is to optimize medicinal chemistry on drug candidates; next is to develop and evaluate novel formulations for both oral and inhaled methods of administration; third, they will evaluate those candidates for safety and efficacy in animal models; and, finally, the lead drug candidate will be tested in larger animal models. That fourth aim is an FDA requirement prior to consideration for human clinical trials. Those tests will be performed at Albuquerque, N.M.’s Lovelace Respiratory Research Institute. Lovelace, Dr. Hecker points out, is the largest respiratory pre-clinical contract research organization in the country.

Serving as co-investigators on the DoD study are Phil Kuehl, PhD, Lovelace’s director of scientific core laboratories, and the UA’s Vijay Gokhale, PhD, Heidi Mansour, PhD, and Brett Colson, PhD.

Dr. Colson is a UA College of Medicine – Tucson assistant professor of cellular and molecular medicine, Dr. Mansour is a UA College of Pharmacy assistant professor of pharmaceutics and drug delivery with other appointments in the UA College of Medicine, BIO5 Institute, UA Cancer Center and UA Institute of the Environment, and Dr. Gokhale is the director of computational chemistry at the BIO5 Institute’s Drug Discovery and Development Center. BIO5 funding allowed Dr. Hecker to hire a Reena Chawlamedicinal chemist, Reena Chawla, who was instrumental in working on the chemistry team with Dr. Gokhale and identifying the lead drug candidates. Dr. Colson will work closely with the chemistry team to ensure that the binding of the active ingredients interacts tightly with Nox4 to achieve maximal potency. Dr. Mansour will develop optimized formulations for oral and inhaled drug administration. This may be unique to each compound, since Dr. Hecker’s identified leads suggest that one may be better as an oral drug whereas the other class of drug candidates seem better suited for inhaled delivery.

“We’re going to test if it works and if it’s safe,” Dr. Hecker said, referring to efficacy and toxicology screening. “Before you give these drug candidates to human patients in clinical trials, we have to perform rigorous, controlled testing to evaluate both. Lovelace will play an important role to evaluate our top lead candidate on FDA requirements that are necessary in order to initiate clinical trials later.”

Dr. Gokhale said, “I am confident that our team will be able to meet the goal of developing a therapy for effective treatment of this disease.”

“If successful, a potentially new ‘first-in-class’ therapeutic platform will be discovered for use in pulmonary fibrosis,” Dr. Mansour added. First-in-class designation means novel or innovative drugs that use a new and unique mechanism of action for treating a medical condition, according to the FDA.

Above and Beyond

The successful development of a first-in-class selective Nox4 inhibitor could have profound healthcare impacts, Dr. Hecker underscored.

Cover - American Journal of Physiology - Lung Cellular and Molecular, March 2017In her most recent studies, Dr. Hecker’s team has demonstrated Nox4 may play a role in other age-related lung diseases, including acute respiratory distress syndrome (ARDS) that involves widespread lung inflammation in critically ill patients. These findings appeared in the American Journal of Physiology - Lung Cellular and Molecular Physiology’s March 2017 issue. “This is exciting because it suggests the drug candidates that we are developing for IPF may also provide therapeutic benefit to other patient populations,” Dr. Hecker said. There are currently no FDA-approved drug treatments for ARDS. Nox4 targeting drugs could provide a first-in-class treatment option for ARDS patients.

“Heart failure is another major killer in the United States. We can manage the complications following a heart attack, but we have no drug that addresses the progressive scar tissue of your heart that ensues, a key component of end-stage heart failure,” she added. “Our Nox4 inhibitors could potentially address this unmet health burden.”

With her work, Dr. Hecker hopes to relieve others of the burden of struggle that her friends, the Godwins suffered through prior to Gary Godwin’s death in 2015.

This work was supported by the Office of the Assistant Secretary of Defense for Health Affairs, through the Peer Reviewed Medical Research Program under Award No. W81XWH-17-1-0443. Opinions, interpretations, conclusions and recommendations are those of the author and are not necessarily endorsed by the U.S. Department of Defense.

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Release Date: 
01/09/2018 - 2:30pm