Alpha-1 antitrypsin deficiency (AATD) is among the most common life-threatening genetic diseases to affect adult Caucasians worldwide. Yet for years, there’s only been one way to treat it: augmentation therapy.
All 4 augmentation therapy products approved by the US Food and Drug Administration (FDA) involve taking alpha-1 antitrypsin protein (AAT) from the plasma of healthy human donors and infusing it intravenously — on a weekly basis — into the blood and lungs of AATD patients diagnosed with emphysema.
But several new treatments, including potential gene therapies, are now on the horizon for people with dangerously low levels of AAT. Those, along with COVID-19 and its impact on the Alpha-1 community, will be on the agenda at the Alpha-1 Foundation’s Virtual Alpha-1 Education Day slated for August 28, 2021.
The Miami, Florida-based charity was started just over 25 years ago by three “Alphas” with guidance from several scientists specializing in AATD, which can result in serious lung disease in adults, as well as liver disease at any age.
“The concept was to basically take donated dollars and turn them into research for a cure for antitrypsin deficiency. It’s been very successful, and more than $81 million has been devoted” to researching AATD, said Mark Brantly, MD, the foundation’s scientific director.
Research projects have been conducted at 119 institutions in North America, Europe, the Middle East, and Australia, and of the $1.5 million in Alpha-1 Foundation grants awarded this year, 50% are lung-focused, 30% are liver-focused, and 20% cover both areas.
Rare Care Podcast: Dr. Mark Brantly on Treating AATD and the Work of the Alpha-1 Foundation
Augmentation therapy may soon involve subcutaneous injection, inhaled antitrypsin, and pills in addition to the current intravenous infusion delivery method.
“Indeed, there have been some early studies in dogs giving inhaled antitrypsin that were very successful, and that spurred us on from that standpoint,” said Dr. Brantly, a professor of medicine, molecular genetics, and microbiology at the University of Florida in Gainesville. “I’ve been particularly interested in inhaled antitrypsin because it makes sense to directly deliver the drug to the affected organ by an aerosol, where we can get much higher doses of antitrypsin than we can give by IV antitrypsin.”
Dr. Brantly first became involved with AATD during his medical residency, when he treated a 35-year-old man with devastating emphysema.
“It was really hard to explain that he’d only smoked for about 7 or 8 pack years at the time, and I became fascinated with this clinical case,” he said in a recent interview. “We discovered that he had antitrypsin deficiency, and I fell in love with the concept of being able to treat this condition at the time. I went to the National Institutes of Health, which was just starting an antitrypsin study on individuals, and really have not looked back since then.”
The foundation’s Alpha-1 Education Day — sponsored by AlphaNet, CSL Behring, Grifols, Takeda, and Vertex — begins with a research and registry update by Jeanine D’Armiento, MD, PhD, who chairs the organization’s board of directors.
Separate panels follow on AATD lung disease, presented by Karina Serban, MD, medical co-director of the Alpha-1 Clinic at National Jewish Health in Denver, Colorado, and on AATD liver disease, by Robert A. Sandhaus, MD, PhD, the foundation’s clinical director.
There’s also a presentation on pulmonary rehabilitation by Barry J. Make, MD, director of National Jewish Health’s Pulmonary Rehabilitation and Respiratory Care division.
Dr. Brantly said he’s seen a wide spectrum of lung damage among AATD patients he has treated.
“As you lose lung function, quality of life tends to diminish over time with people’s inability to accomplish some of the things they want to,” he said. “I find it quite remarkable, particularly in this group of individuals, where oftentimes, even with lung function of 20% predicted, some people are still working and have lived quite full lives. In my space, I see very courageous patients. Every day, they have a smile on their faces, even though their lung function is substantially down.”
Gene therapy also shows some potential, though the disease has been resistant to gene therapy up until now, said Dr. Brantly, who’s been working on such efforts since 1983.
“We will probably move more into gene therapies related to CRISPR and a number of other things that are basically direct changes of an individual’s genes,” he said. “It’s more tricky to use viral vectors, which are the most advanced gene therapy tools that we have, because antitrypsin is a bulk protein. We need a lot of it. Gene therapy is really good at getting small amounts of protein to replete people. The hemophilias are probably the best example of that, but there are other ones as well.”
One huge concern in the Alpha-1 community, as with all rare disease patients, is the worsening COVID-19 pandemic, currently fueled by a dramatic spread of the Delta variant.
Since the pandemic erupted in early 2020, about 500 people with AATD have died of coronavirus in the United States, though the vast majority of those with the disorder have managed to avoid infection, Dr. Brantly said.
“That’s probably because they were on very high alert for COVID-19, would routinely mask anyway, and took the recommendations very, very well to basically isolate during the first stages of the pandemic,” he said.
In fact, the Virtual Education Day will wrap up with a “COVID-19 & Vaccine Townhall” led by Dr. Brantly, along with Dr. D’Armiento, Dr. Sandhaus, and Benjamin Miko, MD.
A recent survey conducted by the Alpha-1 Foundation showed that “the vast majority” of AATD patients have received either the Pfizer-BioNTech, Moderna, or Johnson & Johnson vaccine.
“Compliance is extremely high,” Dr. Brantly said, adding that he hasn’t encountered any vaccine resistance among AATD patients to date. “They might be afraid to talk to me because I’m pretty strong on that. But I think we’re not going to be able to let our guards down regarding this until we’ve got everybody vaccinated.”