Children with lysosomal acid lipase deficiency appear in a collage to raise funds for LAL-D research. Credit: Hesh Hipp

Nicole Ward, 41, knows what it’s like to live with lysosomal acid lipase deficiency (LAL-D). A resident of Birmingham, Alabama, she was born in 1980 with a distended abdomen and was promptly diagnosed with Hirschsprung’s disease. 

It took 2 years of testing, a colostomy, and then a colostomy reversal, before doctors at Children’s Hospital in Birmingham finally figured out what her problem really was: cholesteryl ester storage disease, a form of LAL-D.

“My LAL-D journey began as an infant, before I ever left the hospital,” she said. “I was one of the first people diagnosed with it back in 1982. At the time, there were only 4 people alive in the world who had it. Presumably, all the others had passed away.”

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From that point until the age of 24, Ward participated in a cholesterol ester storage lipid study at the National Institutes of Health in Bethesda, Maryland. Growing up, she had constant digestive issues and has suffered chronic diarrhea every day of her life.

“To me, it was normal. I didn’t know anything different,” she said. “Sometimes, I couldn’t keep up with the other kids. I seemed to lack energy, and always wanted to go to bed really early.”

Nicole Ward, 41, of Birmingham, Alabama, has lysosomal acid lipase deficiency (LAL-D). Credit: Brad Ward

Ella Smith, 10, of Amherst, Massachusetts, also has LAL-D. She was diagnosed 2 years ago at Boston Children’s Hospital.

“We discovered it by accident,” said Ella’s mother, Anne Christa Smith. “She was sick with a virus and woke up very ill one night with a headache, throwing up. My husband and other daughter were away. I decided to take her to the ER. They did lots of tests and blood work and found that her liver enzymes were elevated.”

Enzyme Therapy Can Provide Relief

It would be 3 months before further tests confirmed that Ella had LAL-D. She was then immediately put on sebelipase alfa (Kanuma®), an intravenous enzyme replacement therapy developed by Alexion Pharmaceuticals that’s been on the market since it won approval from the US Food and Drug Administration (FDA) in 2015.

Gregory A. Grabowski, MD, professor emeritus at the University of Cincinnati College of Medicine in Ohio, helped develop sebelipase alfa. He began working on LAL-D in 1993 soon after joining the staff of Cincinnati Children’s Hospital Medical Center.

“At the time, nothing was being done in LAL-D research, so together with one of my junior faculty we created a mouse with LAL-D and developed systems to produce the enzyme in our lab,” he said. “We went from making this enzyme in insect cells to tobacco plants to chicken eggs. It took a long time to develop the therapeutic molecules. They worked very well in the mice, but it was very difficult to get a commercial entity interested in this enzyme therapy.”

Eventually, Synageva BioPharma recruited Dr. Grabowski as its chief scientific officer. He was part of the team that developed the drug which later became Kanuma, but by then, Alexion had acquired Synageva. 

“Although I originated the idea, it took 20 years for it to be a clinically useful enzyme,” he said, estimating that the combined frequency of infantile and later-onset LAL-D at between 1 in 150,000 to 1 in 200,000 live births. Other experts put the number at around 1 in 50,000.

“One of the issues has been the rarity of the disease,” Dr. Grabowski said. “The later-onset variant occurs with a broad spectrum of phenotypes ranging from children to people in their 40s and 50s. The problem is in detecting and treating patients who look like they’re fine, so nobody tests them.”

In Pursuit of Gene Therapy

Paul T. Martin, PhD, is principal investigator at the Center for Gene Therapy at Nationwide Children’s Hospital in Columbus, Ohio. He’s at the forefront of research into potential gene therapies for LAL-D.

Paul Martin, PhD, of the Center for Gene Therapy at Nationwide Children’s Hospital (NCH) in Columbus, Ohio. Credit: NCH

“The main advantage of gene therapy is because you’re putting the gene into the cells instead of the protein, the gene can produce protein and remain in the cell for a very prolonged period of time, perhaps even the lifetime of the patient,” he said, predicting that gene therapy could eventually prove effective for all LAL-D patients regardless of age.

“There won’t be an age at which treatment doesn’t work,” said Dr. Martin, who’s also a professor of pediatric medicine at The Ohio State University. “I think it’s safe to say that even patients who have had the disease for a long time should probably be able to benefit from gene therapy treatment.”

He added: “More and more companies are learning how to manufacture these medicines, and as that scales up and the technology develops, I think the cost with development for everybody will come down.”

Limited Options for Patients

Ella Smith, 10, of Amherst, Massachusetts, has LAL-D. Credit: Anne Christa Smith

For now, Smith said, the twice-a-month, hour-long infusions of sebelipase alfa are working wonders for her daughter.

“Ella has a really good attitude. She handles it pretty well,” she said. “Her liver enzymes have decreased a lot. They’re not at normal levels, but it’s much better. We’re lucky her liver has no scarring, and that this was caught in time.”

But the medication doesn’t work for everybody. 

For a time, Ward was taking lovastatin in order to lower her cholesterol, but it was not very effective. Then, following its FDA approval, Ward began receiving sebelipase alfa at a hospital, since her insurance wouldn’t cover home infusions. 

After 10 months, however, she discontinued the treatment after going into anaphylactic shock.

“It was horrible,” she recalled. “I was about 5 minutes into my infusion. I had never had a problem, but that day I sat down like always, and all of a sudden, my hands started tingling, my mouth felt swollen and I felt like I couldn’t catch a breath. I started vomiting.”

Since that incident, Ward — who runs an online store selling vintage knick-knacks and antiques — doesn’t take medications of any kind, and constant diarrhea still plagues her. Just about the only thing she can do is avoid greasy or fatty foods as well as dairy, which seem to aggravate her digestive issues.

“I don’t have a doctor who’s been able to help me with my LAL-D, though I do have a GP who monitors my blood levels,” she said. “I try to live a normal life as much as possible, even though I struggle with chronic pain and fatigue. We all have challenges we have to push through, and right now, this is my journey.”