An experimental gene therapy to combat alpha-1 antitrypsin deficiency, a common hereditary disorder that causes lung and liver disease, has caused no harmful effects in patients and shows signs of being effective, University of Florida researchers say.
In a clinical trial, researchers evaluated the safety of using a so-called gene vector - in this case an adeno-associated virus - to deliver a corrective gene to 12 patients who are unable to produce a protein essential for health called alpha-1 antitrypsin.
"The primary end point in the trial was to see whether it was safe to give patients this gene transfer vector and then to try to begin to see if we could get the dose into a range where we would begin to replace the missing protein in the blood," said Terence Flotte, M.D., a pediatrician, geneticist and microbiologist with UF's College of Medicine and a member of the Powell Gene Therapy Center and the UF Genetics Institute. "We found that we can use this agent safely and we also saw evidence in the patients' blood that the higher doses successfully introduced the vector DNA. In one patient we saw evidence for a very brief period that some of the alpha-1 protein was being produced, but not at a high enough level to be beneficial."
The findings appear online today (Nov. 21) in the journal Human Gene Therapy.
Physicians injected doses of the virus containing copies of the gene for alpha-1 antitrypsin into the patients' upper arms. Essentially, the virus is intended to "infect" patients' cells with replacement genes that will do the necessary work to produce alpha-1 protein. UF scientists have successfully developed the technique in animal models.
The next step is to test the therapy with a different version of the adeno-associated virus; about 200 variations of the virus exist in nature.
"We have another version of the virus that appears in animal studies to be close to a thousandfold more potent at making protein," Flotte said. "That's very encouraging to us. So the next trial, which has already begun, is to use the new version of the virus and take patients through a similar range of doses, in a very similar scheme, and see if we can maintain the safety while pumping up the efficiency of the protein production."
In most people, alpha-1 antitrypsin is made in the liver and protects the lungs by counteracting inflammatory products that destroy lung tissue. But about 100,000 Americans have alpha-1 antitrypsin deficiency, according to the Miami-based Alpha-1 Foundation, a national not-for-profit organization devoted to finding a cure. In addition, medical authorities suspect less than 5 percent of affected individuals are diagnosed, often not until they are in their mid- to late-30s, after extensive lung damage occurs. Shortness of breath, wheezing, chronic cough and recurring chest colds are signs of the disease.
It is important that alpha-1 patients avoid cigarette smoke, said Mark Brantly, M.D., a professor of medicine and molecular genetics and microbiology at UF's College of Medicine who develops clinical research programs aimed at developing therapies for alpha-1 patients. Alpha-1 deficiency can in some patients lead to emphysema and cirrhosis, both progressive diseases that can be fatal.
Alpha-1 patients with symptoms of emphysema can be treated through weekly intravenous injections of alpha-1 protein derived from human plasma. The injections must continue throughout a patient's life, according to the American Lung Association. It does not cure, but it does appear to slow the progression of this disease.
Patients in the clinical trial - 10 men and two women who ranged from 42 to 69 - were asked to discontinue their replacement therapy 28 days before receiving the gene therapy.
One volunteer who had not been on protein replacement therapy exhibited low-level expression of alpha-1 antitrypsin, which was detectable 30 days after receiving an injection. However, residual levels of alpha-1 antitrypsin from the replacement therapy in the other patients obscured whether the alpha-1 gene had begun to express protein.
"As the authors conclude, the results set up the more interesting approach of using other AAV serotypes more suited for muscle delivery as an alternative with the same transgene in the next trial," said Richard J. Samulski, a professor of pharmacology and director of the University of North Carolina's Gene Therapy Center. "These studies are important milestones that allow the potential for gene correction of AAT to advance, as well as the (gene therapy) field in general. They also represent the step-by-step process established by the FDA and research community to ensure that safe and good clinical studies are employed in these early days, and I applaud Terry Flotte and his group for being cautious and thorough in their clinical design."