UF Scientists Combine Experimental Therapies To Fight Gene Disorders

September 23, 2004

GAINESVILLE, Fla. — University of Florida scientists have combined stem cell therapy and gene therapy in a new strategy to correct inherited diseases, according to a study published this week in the online edition of the journal Hepatology.

Researchers removed a group of mouse liver cells that has the ability of stem cells to rebuild damaged organs and equipped them with a healthy human gene. The researchers then put the cells back into the mice, where they successfully began to rebuild the liver with cells that expressed the healthy gene.

The special cells are called progenitors, descendants of stem cells and natural builders in the human body, and the gene they delivered potentially would treat a common genetic disease that attacks the liver.

The findings help solve a problem that has hindered the use of adult stem cell therapy to treat genetic diseases — the stem cells rebuild the organ, but with the same flaw that caused the disease in the first place. UF scientists want to use gene therapy to fix the genetic blueprint of the stem cells, making them more viable as a remedy for patients.

“The idea is that if we use a patient’s own cells, then we don’t have to look for a donor or worry about medications that may be needed to prevent the body from rejecting the therapy,” said Bryon Petersen, an assistant professor of pathology, immunology and laboratory medicine at UF’s College of Medicine. “We’ve got the ability to basically take cells out of the patient, do our magic and put the corrective gene in, and then put those cells back into the patient. I think it goes back to the concept of self healing self.”

In experiments, researchers delivered the gene to correct alpha-1 antitrypsin deficiency, which affects about 100,000 Americans. People with a mutated alpha-1 gene often suffer from emphysema and severe liver disease because their livers cannot produce alpha-1 protein.

Scientists removed 70 percent of the liver tissue in mice, setting aside a relatively small amount of the progenitor cells, to which they added the gene to produce human alpha-1 antitrypsin. They returned the cells to the mouse livers and found that new liver tissue grew after 18 weeks. What’s more, 5 percent to 10 percent of the liver cells expressed human alpha-1 antitrypsin, suggesting that in people, the disorder that damages the liver would be treated, according to researchers at the UF Genetics Institute and the Program for Stem Cell Biology.

The experimental strategy to plant the corrective gene into the mouse liver cells relies on a molecular vehicle known as the adeno-associated virus, or AAV, which already exists without symptoms in many people.

“This is the first work to show that this virus can be used to deliver genes into liver progenitor cells,” said Sihong Song, the study’s lead author and an assistant professor of pharmaceutics at UF’s College of Pharmacy. “This work gives us real hope that we can do something in terms of delivering genes to modify the cells for the treatment of liver disease.”

Jayanta Roy-Chowdhury, the scientific director of the gene therapy facility at the Albert Einstein College of Medicine of Yeshiva University in New York City, said the strategy is in its early stages but is promising.

“In principle, the idea of taking progenitor cells, culturing them and transplanting them is viable, and I believe people will use it successfully in the future,” Roy-Chowdhury said. “Each component of it will need improvement. The main barrier to cross is to show transplanted stem cells will engraft and function to replenish the deficient enzyme for a long time.”