Vol. 12 No. 2
New genes at work in patients
Gene therapy trial succeeds in spurring production of a protective protein
Robert Carlin Photography
Terence Flotte, MD
Researchers at the UMass Medical School and the University of Florida in Gainesville have safely given new, functional genes to patients with a hereditary defect that can lead to fatal lung and liver diseases, according to clinical trial findings that appeared in Proceedings of the National Academy of Science.
“This trial represents a very important step toward a potential gene therapy for the 100,000 or more Americans who suffer with alpha-1 antitrypsin deficiency,” said Terence R. Flotte, MD, dean, provost and executive deputy chancellor. Dr. Flotte, senior author on “Sustained transgene expression despite T lymphocyte responses in a clinical trial of rAAV1-AAT gene therapy," was formerly the chair of pediatrics at the University of Florida, where the study was conducted.
Patients with alpha-1 antitrypsin deficiency cannot produce a protective form of the protein alpha-1 antitrypsin, which is normally produced in the liver and protects the lungs from inflammation. Those lacking alpha-1 antitrypsin are vulnerable to infections or irritants in the air, such as cigarette smoke, and often develop life-threatening lung disease. Some people with the deficiency lead disease-free lives, never knowing they have defective genes. In others, the deficiency can lead to emphysema and cirrhosis, both progressive diseases that can be fatal.
When you deliver this therapy into the deltoid muscles of the arm,
the muscle becomes a factory for making the protein that these individuals are missing.
Mark L. Brantly, MD
In the clinical trial, three patients who received injections of a harmless virus containing copies of a correct gene for alpha-1 protein in their upper arms were able to produce trace amounts of alpha-1 antitrypsin for up to one year. Although the levels produced were not considered therapeutic, the study provided critical “proof of principle” that a corrected, functioning gene could trigger production of the protein. The National Heart, Lung and Blood Institute recently awarded a five-year, $2 million grant to Flotte for further clinical trials studying the use of an adeno-associated virus to deliver the alpha-1 antitrypsin gene.
“When you deliver this therapy into the deltoid muscles of the arm, the muscle becomes a factory for making the protein that these individuals are missing,” said Mark L. Brantly, MD, a professor of medicine and molecular genetics and microbiology at UF’s College of Medicine and first author of the study.
The trial established the safety of the adeno-associated virus used to “infect” patients’ cells with replacement genes, which then do the vital work of producing the alpha-1 protein. “I hope the alpha-1 community is as encouraged as I am that although this trial does not give us any guarantee, there is a fighting chance to develop a therapy using this method,” said Flotte.