Recent developments in gene therapy

First in a two-part series

ST. LOUIS—Individuals suffering from Huntington’s disease face each day with the understanding that their ability to walk, talk, think and reason will progressively and irreversibly deteriorate until their genetic disorder takes their lives. Treatment options for Huntington’s patients are currently lacking, but two potential gene-therapy treatments recently discussed by researchers show promise for controlling the disease’s degenerative effects.

The two gene therapy treatment methods for Huntington’s disease, each developed by a separate research team, were among the topics presented earlier this month at the eighth annual meeting of the American Society of Gene Therapy. Other key topics included potential treatments for muscular dystrophy and a rare lethal childhood disorder called metachromatic leukodystrophy.

Researchers from around the world presented scientific abstracts summarizing their most recent studies at the meeting’s workshops, oral presentations and poster sessions. More than 1,100 abstracts were submitted for the meeting, which was held from June 1-5.

The first potential treatment for Huntington’s disease discussed at the meeting would reduce the toxic effects of the disease using RNA interference, a process that reduces the expression of a targeted gene. In a recent study, a research team led by Beverly L. Davidson used RNA interference to reduce the expression of mutant huntingtins, the proteins implicated in Huntington’s disease, by about 50 percent in the brains of mice.

Davidson, the Roy J. Carver professor of Internal Medicine, Physiology and Biophysics at the University of Iowa, said that RNA interference has been used in past studies to deliver genetic material to human brains, and she is hopeful that her team’s findings can be translated into future human therapies.

The symptoms of Huntington’s disease typically surface in affected patients between the ages of 30 and 50. Davidson said that the disease typically affects the region of the brain associated with motor coordination before affecting the regions that control personality, mood and complex thinking.

According to Davidson, suicide rates are high among individuals suffering from Huntington’s disease because many patients observe the debilitating and irreversible nature of the disease in family members before experiencing the symptoms themselves.

“How do you treat something that is just marching along eating away at your brain cells?” Davidson asked. “A lot of people have developed therapies that attack the downstream effects of this mutant protein, and what we’ve done is sort of nip it in the bud and just say, ‘let’s remove the dominant toxic protein from the brain.’”

Davidson said her research team is conducting a second set of studies to measure the effects of RNA interference in mice with one mutant huntingtin gene and one “good” gene—the gene pairing present in most human Huntington’s patients. If the procedure does more harm than good by interfering with the expression of the “good” gene, then the team’s next goal would be to develop a procedure that affects only the mutant gene, she said.

Dr. Sung-Rae Cho, a researcher from Dr. Steve Goldman’s lab at the University of Rochester Medical Center, discussed a second gene therapy procedure being studied for the treatment of Huntington’s disease. The procedure, called neurogenesis, is designed to induce the growth of new brain cells, thus delaying the progression of the disease.

To examine the effects of neurogenesis, a research team led by Goldman and Cho injected mice with an adenovirus containing two brain-derived growth factors. According to Cho, the mice underwent extensive neurogenesis, which delayed the progression of Huntington’s symptoms and extended survival.

“That observation alone is a major breakthrough, to show that in a living animal, the brain cells can be stimulated to divide and give us more neurons so that we’re not just [in a situation where] every brain cell that we lose is every brain cell that we don’t have any more,” former ASGT President Savio Woo said. “That used to be the way we think about the brain. This is now different.”

In addition to the research into potential gene-therapy techniques for Huntington’s disease, the ASGT meeting also featured a presentation summarizing a study by French researchers examining a potential treatment for muscular dystrophy.

According to a June 2 ASGT press release, the researchers injected genetic material called U7 into the legs of mice with muscular dystrophy. The degenerative muscle disease is characterized by a genetically determined absence of the protein dystrophin, which causes muscle cells to die and eventually become too weak to allow for normal breathing. The researchers found that the mice produced higher levels of dystrophin and exhibited normal muscle contractions after receiving the injections.

A procedure similar to the one tested on mice by the French researchers could potentially be used on humans in the future, the release stated.

Also at the meeting, a researcher from Italy discussed a treatment strategy that could potentially be used to treat metachromatic leukodystrophy, an untreatable deadly childhood disease that occurs in one out of every 40,000 births. Children affected by the disease produce abnormally low levels of an enzyme called arylsufatase A, which results in a buildup of toxins in the nervous system and elsewhere in the body.

Dr. Alessandra Biffi, a researcher at the San Raffaele Telethon Institute for Gene Therapy in Milan, Italy, said that a research team led by Luigi Naldini and herself delivered the therapeutic arylsufatase A enzyme to affected tissues in mice using hematopoietic stem cells, unspecialized precursor cells that eventually develop into mature blood cells.

According to Biffi, the bodily toxins associated with metachromatic leukodystrophy were significantly reduced in the mice that received the stem-cell transplants. She added that the transplants protected the mice from the disease’s major symptoms, which include learning and coordination abnormalities.

Next week: A history of gene therapy and the challenges of developing it for clinical use.

From the June 15-21, 2005, issue

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