In the 1980s, Ronald G. Crystal, chairman of Genetic Medicine, Weill Cornell Medicine, developed a treatment for one of the most common hereditary disorders in Caucasians: Alpha-1 Antitrypsin (A1AT) Deficiency. The inability to produce normal levels of the A1AT protein makes patients susceptible to emphysema and liver disease and is often fatal. Crystal and his team were able to purify the deficient protein from normal blood samples and deliver it back to patients with the disorder. More than 6,000 people around the world are using this treatment today, but Crystal says there’s a catch.
“Proteins have a very short half-life,” he says. “For A1AT, they last about one week, so you have to administer the therapy with intravenous infusions every week.”
In 1989 with prompting from a former postdoctoral student and collaborator, Crystal saw an opportunity to develop a one-time treatment for A1AT deficiency. By using a virus to deliver the gene that produces the protein, researchers could in theory give a patient the lifelong machinery to make their own A1AT. “It was this eureka moment of realizing that if we had the right virus, we might be able to take a hereditary disorder and use the virus one time to cure the disease,” says Crystal. “That’s what got me started on gene therapy.”
Gene Therapies, Licensed and Ready for Clinical Trials
Almost 30 years and many contributions later, Crystal may finally have the gene therapy for A1AT deficiency that would require just one dose. He licensed this technology, along with two other therapies, to a startup he cofounded in 2014, Annapurna Therapeutics. Annapurna recently merged with another company to form Adverum Biotechnologies, which will independently carry out a large clinical trial of Crystal’s gene therapy for A1AT deficiency. Crystal is an advisory board member and a paid consultant for Adverum.
The Technology—How It Works
Crystal’s lab focuses on in vivo gene therapy, whereby genes are delivered directly to the patient. “The problem and the challenge of the technology has been how do you get genes into human cells? How do you get them to go where you want them to go?”
The answer is viruses. Viruses have evolved to transfer their genetic material to the cell, usually to the nucleus, and they can target certain organs or tissues. Once there, “they basically hijack the cell’s genetic machinery to reproduce themselves,” Crystal explains. In the gene therapy field, researchers essentially empty these viruses of their own genetic information and replace it with genes that a patient needs expressed.
“We use the structure of the virus like a Trojan horse,” Crystal says. “The idea is then to directly administer the virus to the brain or heart or liver, and the virus will deliver the genetic information to the nucleus of the cell. There, it uses the cell’s genetic machinery to transcribe the gene, make a protein, and then that protein either functions within the cell or is secreted.”
A good deal of the work in Crystal’s lab therefore involves finding and modifying viruses and genes for target organs, inserting therapeutic genes into viruses, and carrying out the studies in animal models and in small clinical trials. The therapies licensed to Adverum include the A1AT deficiency therapy as well as a therapy for another genetic disorder: hereditary angioedema. In patients with hereditary angioedema, blood vessels leak fluid and cause excessive swelling, which can lead to premature death. The third treatment is a gene therapy for severe allergy such as peanut allergy. “We can cure the diseases in mouse models in one dose,” says Crystal. “Whether they’ll work in humans, of course, we don’t know—yet.”
The Partnership of Academia and Industry for Conducting Large-Scale Clinical Trials
When it comes to the kinds of large-scale clinical trials that are necessary for drug approval, academics often don’t have the resources, Crystal says. “In the academic world, we can carry out early phase I studies, studies in 20 or 30 patients, but we don’t have the infrastructure or the funds to carry out the large studies that are required.”
“We use the structure of the virus like a Trojan horse,” Crystal says. “The idea is…to directly administer the virus to the brain or heart or liver…the virus will deliver the genetic information to the nucleus of the cell."
One answer is to partner with biotech and pharmaceutical companies, Crystal continues. “In our lab, we’ve made the initial viruses, shown that they work in animal models, in some cases shown safety, in some cases not yet,” he explains. “The concept then is to partner the academic environment—with new ideas, new therapies, and early data—with industry. They will take it over and run the clinical trials, and turn it into a drug if it works.”
To avoid conflicts, Crystal won’t be involved in the clinical trials. “I think it’s a very good paradigm, a good way that we in the academic world can get the ideas and the creativity that we have and move it towards curing patients.”
Foresight: Linking Technologies to Clinical Problems
As a pulmonary doctor by training, Crystal has always had an eye on clinical problems and how his research can address them. When he began working in the gene therapy field, he followed the technology to the problems that this technology could address.
“It’s really a kind of opportunism, in terms of understanding how the technology can be married to a clinical problem,” he says. “It’s a combination of seeing the advantages and limitations to the technology and being lucky enough to have training in medicine—so we can see how to use this technology and where best to apply it.”
While the technology has guided Crystal to certain problems, the underlying goal has always been to improve human health. At the National Institutes of Health, where he worked for 23 years before joining Weill Cornell Medicine, his group was the first to carry out a human gene therapy in vivo to treat cystic fibrosis. With his collaborators, he has also worked on therapies for cardiac ischemia, cancer, and central nervous system disorders, and he is developing vaccines for addictive substances such as cocaine as well as other projects.
Fusing Basic Science and Clinical Medicine
“I decided a long time ago to focus my career on that interface between basic science and clinical medicine,” Crystal says. “I think if you ask my colleagues, physician-scientists who do similar kinds of things, probably the most satisfying thing is to at least have the opportunity to develop therapies for human disease. When we can do something and play a role in its success, that’s very satisfying.”
Weill Cornell Medicine, Crystal continues, is a great place for the kind of work that brings basic science to clinical problems. “As a clinical scientist, it’s very important to have access to individuals who are willing to participate in clinical trials, and 10 percent of the population lives within 50 miles of Weill Cornell Medicine,” he explains, “and we have Weill Cornell Medicine, The Rockefeller University, Memorial Sloan Kettering Cancer Center, Hospital for Special Surgery—it’s a very high density of clinical and scientific talent. That’s a wonderful milieu to be in.”