S.D. Scientists Claim Progress on Hemophilia : Genetics: UC San Diego, Salk researchers say they have made a major laboratory advance toward treatment of the inherited disease.

A San Diego-based research team has implanted modified genes into mice, for the first time prompting the sustained production of a key clotting substance that is missing in one form of hemophilia, according to a report in today’s Proceedings of the National Academy of Sciences.

Other researchers have successfully implanted modified genes into laboratory animals. But for unknown reasons, the implants stopped producing the desired substances after short periods of time.

Researchers at the Salk Institute and UC San Diego are reporting sustained production of factor IX, the substance that is missing in one kind of hemophilia. Mice bearing the genetically modified material are continuing to produce low levels of the clotting factor for as long as 11 months.

That long-term production of the clotting factor portends “real possibilities for human applications,” said Inder Verma, a professor in the Salk Institute’s Molecular Biology and Virology Laboratory.

“I think it is an important step for gene therapy,” said Yifan Dai, a Salk researcher. “We have (achieved) long-term expression. . . . Before, it was only for a very short time.”

The San Diego team’s report underscores the rapid pace of advances being made in the search for a genetic treatment of hemophilia, an inherited disease that affects 20,000 Americans.

“I think we are going to see human trials even faster than we thought back in March,” when the National Institutes of Health sponsored an update on research into a genetic treatment for the disease, said Frederick R. Rickles, chief of the Division of Hematology and Oncology at the University of Connecticut School of Medicine.

Scientists are using genetic engineering to seek an effective treatment for hemophiliacs who lack the single gene that prompts the liver to produce blood-clotting factors. Absent the required genetic coding, hemophiliacs are subject to spontaneous--and potentially deadly--internal bleeding.

Treatment, through natural or synthetic blood clotting agents, is expensive. The most severe cases require as many as 50 infusions annually at a cost ranging from $60,000 to $100,000.

Because hemophiliacs receive blood products culled from donors, they run the risk of contracting potentially deadly viruses. About half of the nation’s hemophiliacs test positive for HIV because they received tainted blood products before widespread testing for the AIDS virus.

“Compared to the promise of gene therapy, current treatments remain sub-optimal” because of health risks and costs, Rickles said.

Despite gains, significant barriers remain in their quest for a genetically engineered treatment for hemophilia.

The amount of clotting substance produced so far in laboratory mice is far too low for effective treatment. Production of the clotting factor must be enhanced “by 5-fold, or maybe 25-fold to be effective,” Rickles said.

And, researchers must tackle the tougher task of genetically engineering a solution for the absence of factor VIII, which causes the most common form of hemophilia. Researchers have focused on factor IX because it is a smaller gene that is easier to insert into cells.

A genetic treatment for factor VIII and IX hemophilia would address the medical needs of a large majority of hemophiliacs. To be effective, a genetic treatment would need only to increase the level of clotting factors in hemophiliacs, not fully restore production of the missing substance.

“If you convert someone from less than 1% clotting factor, which defines severe hemophilia, to 5%, which is mild hemophilia, you have done a tremendous job,” Rickles said. “You have taken someone from severe, spontaneous bleeding to a point where he . . . requires extra clotting factor only under special circumstances.”

While the liver normally produces clotting factors, researchers have turned to other tissues as potential hosts for the genetically engineered packages. Researchers in San Diego and at the University of Michigan have successfully inserted modified genes into the muscles of laboratory mice.

But in previous laboratory experiments, production of factor IX mysteriously ceased after a short period of time. “It is hard to fool God,” Rickles said. “He made (the body) in such a way that it works right.”

The San Diego team managed prolonged production of factor IX by encapsulating its genetic code in a complex but safe virus that also incorporates a body material that normally thrives in mice muscles. That concoction made the insert “more at home” and, apparently, helped to maintain production of factor IX, Rickles said.

Results achieved in San Diego bode well for researchers around the world who are exploring gene therapy as a potential treatment for thousands of diseases--including hemophilia, cystic fibrosis, diabetes--that are caused by a defect in a single gene.