A mother’s fight against CF

Valerie's Boys. The diagnosis of cystic fibrosis (CF) in her son John (left) led political science professor Valerie Hudson to develop a CF treatment that might alleviate the symtoms in other children—her other son Tommy (right).

In 1997, Valerie Hudson, a political science professor at Brigham Young University, discovered that her nine-month-old son John had cystic fibrosis (CF), a genetic disease that causes abnormally thick, sticky mucus in the lungs and pancreas. The outlook for the approximately 30,000 people in the United States with CF is grim: Organ dysfunction, particularly of the lungs, kills half before they reach 31 years of age.

After Hudson and her husband suffered the initial shock of discovering that they unknowingly carried the defective gene, they immersed themselves in CF literature. John presented with inadequate weight gain and severe vitamin K deficiency. Other CF symptoms include persistent coughing, wheezing, or pneumonia, and bulky stools. But when they learned about John’s treatment options, they really began to worry. The main treatments are vigorous tapping with cupped hands on the back and chest to dislodge the thick mucus, and antibiotics for chronic lung and digestive tract infections.

“We found out that CF treatment is pretty well stalled,” says Hudson. “Promising therapies are still at least five years out. When we’re talking about a child who is liable to die in their 20s, that’s a fifth to a fourth of their [potential] lifetime. That’s just not good enough.” Teaching herself human physiology, molecular biology, and genetics, the political science professor dove into potential treatments. It was a scene reminiscent of the movie Lorenzo’s Oil, where the determined parents of a boy with the rare disease adrenoleukodystrophy battled time and the medical establishment to find an unconventional treatment.

“We found that pharmaceutical companies are very focused on getting something new, patentable, and profitable, especially with an orphan drug,” she says, in reference to drugs for the treatment of diseases that affect relatively few people. “So we started looking at things that already exist, are available, not patentable, simple, and straightforward. The answer was nobody was doing that.”

Figure 1. The silver bullet? Hudson believes that the simple tripeptide glutathione is the ley to the treatment of cystic fibrosis.

Hudson’s hypothesis
Four years later, her after-hours work has paid off. Her hypothesis paper on a common and inexpensive tripeptide called glutathione was published last June, and preliminary studies are under way (Figure 1). Hudson also has personal reasons for hope. John, now five, and a second son Tommy, age two, have been on chemically reduced glutathione (GSH) with promising results.

The CF gene was first identified in 1989 with great fanfare, and although it has helped scientists to understand the pathology of the disease, gene therapy progress has been slow. Daniel Schidlow, pediatric pulmonologist and pediatrics chair at Hahnemann University School of Medicine (Philadelphia) admits that “though we’ve learned a lot with gene therapy, we’re not where we should be.” When the CF protein was isolated in 1990, the picture became clear.

In CF, slight errors in genetic sequence result in deformed proteins that cannot transport anions such as chloride in or out of cells. The excess chloride tells the body that there is an injury, the immune system kicks in, and a buildup of mucus results. Unfortunately, the CF protein is a large, unwieldy one that is difficult to manufacture. It is also stable only in oily environments that resemble its cell membrane home. The result to date: Both manufacturing the CF protein into a drug and using gene therapy to transport a healthy CF gene into patients ended with dismal results.

During her literature search, Hudson came up with a new understanding of how cystic fibrosis attacks the lungs and digestive system. Her work pointed to a novel and low-priced therapy. Sorting through a stack of research four feet tall—her paper cites 360 references—and across disciplines that included free radical pathology, cellular pore mechanics, and organ systems, Hudson found the GSH possibility.

Hudson proposes that GSH plays a critical role in CF pathology. Like chloride, GSH is trapped inside lung cells. And while everyone agrees that CF patients have lower GSH levels (5–20% of the levels of healthy people), many in the CF community believe that it is a secondary, not a primary, cause. The common theory is that GSH levels are depleted by CF’s chronic infections, which also occur in other pulmonary diseases and AIDS.

Expanding on the GSH research of others, Hudson proposes that the CF patients have lower GSH levels as a primary effect of gene mutation, and that the resulting GSH deficiency triggers many CF symptoms. Too little GSH wreaks havoc because it plays three important roles. It provides powerful antioxidant protection and reduces the thickness of mucus, but Hudson explains that GSH’s role as a regulator of the inflammation and immune response starts a cascade of events. “What kills you with CF is your body is constantly and exuberantly inflamed from the immune response,” she says. “And because it’s so inflamed, it’s incompetent. Restoring GSH will, we believe, help alleviate the progression of CF pathology.”

Clark Bishop, a pulmonologist and regional medical director at Utah Valley Regional Medical Center (Provo), agrees. “It’s true that we had bits and pieces of information about GSH, but no one had tied it together in a nice package and put a bow on it, as Valerie did,” he says. While acknowledging that gene therapy is the best avenue for completely curing CF, Bishop says that Hudson’s hypothesis deserves to be tested. “The basic science is sound, and the mechanism is well worked out.”

Henry Forman, co-director of the Center for Free Radical Biology at the University of Alabama at Birmingham, published Hudson’s paper in the June issue of Free Radical Biology and Medicine. When Hudson told Forman of her political science background, he replied, “I don’t care what your Ph.D. is in; if it’s a good idea, let’s look at it.” He sent it out for the anonymous review process.

“The reviewers, with whom I agreed, viewed Hudson’s paper as thorough and presenting an interesting and testable hypothesis,” says Forman, who had previously published studies on the role of GSH in CF. He personally believes that the inhaled GSH that Hudson proposes is less effective than increasing glutathione secretion from epithelial cells by using a synthetic peptide. Hudson welcomes that theory but says, “From a parent’s point of view, how long will it take before that becomes standard treatment for my children?”

Spurred on by Hudson’s hypothesis, Matthias Griese, a CF researcher at the University of Munich, has a study involving inhaled GSH under way involving 18 adult CF patients. Two patients have finished the roll-through study, and side effects have been minimal. “Because of the mechanical damage and destruction of the airways that occurs, we think we’ll see even better results before patients are in their 20s,” says Hudson.

Community response
Before the paper was published, medical director Bishop received a cold shoulder when he approached several CF researchers about conducting a trial. The indifference he encountered prompted him to consider conducting the clinical trial himself if the $50,000 funding could be secured.

Hudson’s response to the CF community’s indifference was more pointed: “It’s unglamorous. It’s old. It’s unpatentable. Nobody is going to get intellectual property rights off of it, so nobody’s going to make a fortune,” she says.

But it appears that the publication of Hudson’s paper has provided a boost. Aside from numerous requests for reprints, Bishop reports that two other CF researchers have since expressed interest. Bishop’s study will include 20 children this summer, 10 on placebo and 10 who will inhale buffered GSH three times a day. The daily cost of the buffered GSH per child? Two dollars.

To date, Bishop and Hudson have raised $35,000 and received a recent commitment from the Cystic Fibrosis Foundation to look at a grant. According to Hudson, the foundation’s support was slow in coming, but a flood of inquiries from CF patients and parents helped turn the tide.

Hudson is willing to discuss her sons’ GSH treatments when asked. John, whose CF before GSH she describes as severe, started GSH at age two. “Because his salivary glands were obstructed, he had no saliva and he could only eat wet foods. After we started GSH, he actually began to drool,” she says. His frequent loose bowel movements have stopped, and his growth jumped from 35% below average for his age to 10% above average after three months of treatment. “But what delighted us the most is he routinely cultured staph and influenza B in his sputum. Now he cultures nothing, and that is without antibiotic treatment. That’s unheard of,” she says.

Tommy, who started GSH when he was three weeks old, is doing well, according to Hudson. When asked about the experiences of Hudson’s sons, Bishop says that CF is notorious for its huge variability. “I’m pleased that they’re doing well, but it doesn’t impress me. All it means is we have to do a controlled study. And to Valerie’s credit, she isn’t saying we have to get everyone on GSH. She says, ‘We need proof, we need to have the study.’”

As for Hudson, she doesn’t mind if a pharmaceutical company develops a time-release GSH-based drug and makes money off it. That’s not her dream. “We’re not looking to profit,” she says. “We don’t want one thin dime. We want other CF patients to feel as good about their children’s future as we do about ours.”

Further reading
The Cystic Fibrosis Foundation hosts a website at www.cff.org. The Utah Valley Institute of Cystic Fibrosis website can be found at www.members.tripod.com/uvicf.

Linda Richards is a health writer living in Flagstaff, AZ. Send your comments or questions regarding this article to mdd@acs.org or the Editorial Office by fax at 202-776-8166 or by post at 1155 16th Street, NW; Washington, DC 20036.