Hope for Patients with Rare Genetic Liver Disease

Jen Childress clearly remembers the day she first heard about a disease called Alpha-1 Antitrypsin (AAT) Deficiency. “Our daughter Grace was born about six weeks premature, and she was in the Neonatal Intensive Care Unit in Wisconsin for 23 days,” says Childress. “She was under weight and not doing well and I noticed that the whites of her eyes had turned mint green.”

Doctors called in specialists, and the family was told that something might be wrong with Grace’s liver or gall bladder. She was soon diagnosed with a severe form of AAT deficiency.

AAT is a specific protein manufactured primarily by the liver. Its main purpose is to protect the lungs from inflammation caused by various infections or irritants, such as smoke or poor air quality. In individuals with an AAT deficiency, however, a gene mutation in their genetic code causes the body to create malformed copies of the AAT protein. The abnormal shape prevents the liver from moving the protein into the bloodstream and to the lungs. Not only are the lungs left unprotected, but the abnormal AAT builds up in the liver, eventually causing scarring.

An estimated 100,000 people in the United States are affected by this disease, but most are not diagnosed or are misdiagnosed as something else. As the disease progresses, it can potentially lead to liver failure, inflammation in the blood vessels and chronic lung disease.

There is no cure for AAT deficiency; however, there is a treatment available called augmentation therapy that raises the level of AAT protein in the lungs, which can slow lung damage, but does not help the liver. There is no treatment for the liver damage other than a liver transplant if the damage becomes life-threatening.

For Grace, it took about six months before she felt better. “Her eyes cleared up and we fortified her diet with extra calories and vitamins,” says Childress. “But we were told to get regular liver function tests as she grew older.”

With a 1 in 4 chance that another child would inherit the disease, Childress gave birth to another daughter, Meghan, two years later. She was born even more premature than Grace and weighed just 1 pound, 9 ounces. At first, she was too small to have blood drawn for genetic testing. But when she finally opened her eyes at three weeks old, Jen Childress again saw the mint green eyes. “I shed a few tears because we had two children with a fairly rare disease,” she says. “But I knew how to handle it and I decided I needed to know more about the disease and what treatments were available.”

Within the past two years, laboratory research and early clinical trials have identified a promising drug that can treat AAT deficiency.

Jeffrey Teckman, MD, in the Division of Pediatric Gastroenterology and Hepatology at SSM Health Cardinal Glennon Children’s Hospital has studied AAT deficiency in the lab for almost 30 years. He and other collaborators at Saint Louis University, in California and Europe, and at Arrowhead Pharmaceuticals and Takeda Pharmaceutical Company, had been searching for a way to turn off production of the abnormally shaped AAT proteins. They found the answer in a specific strand of RNA. RNA, or ribonucleic acid, is the “messenger” in genetic processes that controls, in part, how proteins develop and function. By interfering with that RNA strand, the researchers figured out how to block an abnormal type of AAT from forming.

A new drug, fazirsiran, was developed out of that RNA research. An early clinical trial found that seven of the first 15 patients who were given the drug saw scarring in their liver diminish. Results were published in the New England Journal of Medicine in 2020.

“It was a small trial, but It was the first time that a drug for AAT deficiency had been shown to improve liver health and function,” explains Dr. Teckman. “Early in my medical training, the common consensus was that any reduction in liver fibrosis, or scarring, in patients with AAT deficiency was impossible. Now, we have found a way to reverse the process in humans with minimal side effects. I think it’s remarkable and a game-changer.”

News of fazirsiran’s effectiveness in the early clinical trials brought hope to many patients with AAT, including Jen Childress and her two daughters. For more than 12 years, the family has made a yearly 370-mile trip from Wauwatosa, Wis., to SSM Health Cardinal Glennon Children’s Hospital to receive care from Dr. Teckman and learn about the latest AAT clinical trials and research efforts.

Larger clinical trials are now under way with the hope that the earlier breakthrough results can be duplicated, and a drug finally can be brought to widespread use outside of clinical trials.

“It gives me great satisfaction and hope that there is a true cure for this disease that could be available to patients within the next few years,” says Dr. Teckman.

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