Rubinstein-Taybi syndrome

RUBINSTEIN-TAYBI SYNDROME, a form of mental retardation accompanied by facial abnormalities and broad big toes and thumbs, accounts for 1 in 300 mentally retarded patients in institutions. in some people the syndrome has now been traced to breaks or tiny deletions in a particular region of chromosome 16. The region contains a gene that's involved in switching certain other genes on.

CATARACTS in infants (and occasionally in adults) are a side effect of galactosemia, in which the body lacks the enzyme it needs to use a sugar called galactose. In 1995 researchers found the gene for the enzyme on chromosome 17. When it is defective, a galactose derivative accumulates on the lens of the eye, causing cataracts.

PROSTATE CANCER is sometimes restrained from spreading by a gene identified on chromosome 11. The gene may code for a membrane protein that helps cells--including cancerous ones--stick together. The finding could eventually lead to a test to sort tumors that require aggressive treatments from those best left alone.

MALE INFERTILITY is due in about 10 percent of all cases to a sperm shortage. In 1995 a study of 89 men who can't produce sperm revealed that 13 percent of them were missing a particular region of the Y chromosome.

PARTIAL EPILEPSY is marked by seizures originating in specific regions of the brain and has been thought to result from injuries or tumors. But now it has been linked to genes on chromosomes 10 and 20. A mutation in one of the genes may lead to a faulty receptor for acetylcholine, a chemical that carries nerve signals.

ALZHEIMER'S was linked to two new genes, both of them for the virulent form that strikes before age 60. Though on different chromosomes, they appear similar in sequence. The proteins they code for might be involved in producing the amyloid plaques that clog the brains of Alzheimer's patients.

SCHIZOPHRENIA'S occurrence in 26S Irish families led researchers to a region on chromosome 6 that contains a gene of unknown function. it's probably one of several that interact to produce the disorder.

USHER SYNDROME is the most common cause of deaf-blindness. Most cases have now been traced to mutations in a gene on chromosome 11. The gene encodes a protein used by the ear's sensory hair cells and the eye's pigment cells.

BREAST CANCER runs in families in a small percentage of cases, and in 1994 those cases were linked to a gene called BRCA1. In November the gene was tied to most other cases as well. In familial cases the protein encoded by the gene is defective, but in the others it seems to be normal; for some reason, though, it may be unable to get into the nucleus to do its job, which apparently has to do with turning genes on and off and regulating cell division.

MATERNAL ACUTE FATTY LIVER OF PREGNANCY, a rare syndrome that strikes women during the third trimester, causes vomiting, liver failure, and sometimes death. It can often be cured by delivering the baby at once. In 1995 researchers linked the disorder to a gene on the fetus's chromosome 2 that codes for an enzyme that converts fatty acids into energy. Two mutant copies of the gene cause fat to build up in the fetus's liver. The fetus may then release a toxin that poisons the mother.

Gene Therapy: Special Delivery

As an experimental treatment for AIDS, cancer, and inherited genetic diseases, gene therapy--replacing, defective genes with working copies or adding genes that make cells better at fighting disease--is growing ever more fashionable. With hundreds of millions of dollars invested in research and 106 clinical trials approved, gene therapy would appear at first glance to be one of medicine's most promising fields.

Indeed, 1995 produced encouraging results from three highly publicized trials involving children with a form of severe combined immunodeficiency, or SCID. The children lacked an enzyme, ADA, that protects T cells from a toxin in the body. In the three trials--at the National Institutes of Health, Childrens Hospital in Los Angeles, and the H. S. Raffaele Scientific Institute in Milan, Italy--a virus carried a healthy gene for the enzyme into blood cells taken from the children, and the blood cells were then returned to the body. The researchers in charge of the trials reported this past year that in all the children, many of the T cells carried the healthy gene and that all the children were in good health. But that good health could not be conclusively linked to the gene therapy; for ethical reasons, the children were still given the old treatment for ADA deficiency, consisting of regular injections of a synthetic form of the enzyme. In other trials, too, there has been no unambiguous evidence that gene therapy has worked.

Part of the problem may be the gene-delivery method. Ninety-two of the 106 clinical trials have used crippled viruses to carry genes into cells, and though this method seems to have worked in the SCID trials, in other cases die viruses have caused trouble. Some have provoked inflammation and an immune response that destroyed both the virus and the cells to which it delivered genes; some threaten to damage parts of the cells' chromosomes.

So even as some researchers are charging ahead with clinical trials, others are trying to perfect better methods of gene therapy. Here are three ideas now under investigation.

A More Careful Virus

MOST GENE-THERAPY TRIALS use viruses to deliver genes to a patient's cells, and most of those viruses are retroviruses, which have the ability to neatly splice their genes--and the human gene they're carrying--into a cell's chromosomes. Although the viruses are crippled so that they can't reproduce, they can still cause problems. "Retroviruses are promiscuous," explains molecular geneticist Suzanne Sandmeyer of the University of California at Irvine. "They can insert in the middle of a gene, knocking out the structural sequence for a protein." In their quest for a safer retrovirus, Sandmeyer and her colleagues are studying "retrotransposons": bits of a cell's own DNA that, like retroviruses, can copy and slot themselves into other sites in the cell's genome. A yeast retrotransposon called Ty3, the researchers have found, is especially judicious: it always inserts itself in safe places, outside genes rather than inside them, and only near genes of which a yeast cell has many copies. Somehow, says Sandmeyer, it may be possible to confer that selectivity on a retrovirus that is being used to ferry, a healthy human gene into a patient's cells. One approach might be to insert into the virus the proteins coded for by Ty3, which the researchers have found are crucial in guiding Ty3 itself to the right spot.

The Subtle Approach

INSTEAD of USING some fancy virus, why not just blast genes into cells with a gun? That's the approach taken by cancer immunologist Wenn Sun of Northwestern University and her colleague Ning-Sun Yang of Agracetus, Inc., in Middletown, Wisconsin. They've used a gun powered by pressurized helium to fire microscopic gold bullets, coated with genes, into skin cells surrounding tumors in mice. The cells then produce more of what die genes code for: cytokines, which are messenger molecules that circulate in the blood and activate immune cells. Sun thinks these particular cytokines may activate killer T cells, which poison tumor cells, as well as macrophages, which gobble them up. In any case, she and Yang have found that a week of gene shots three to five times daily not only shrinks the tumors but lengthens the lives of the mice. Unlike viruses, the gene bullets don't seem to cause inflammation, and die genes they carry aren't permanently integrated into the cell's DNA--their effects last only a few days or weeks. That's a disadvantage when it comes to treating inherited diseases, but it means that diseases like cancer can be treated with less risk of side effects. "There's a fear that with viruses, you create something that hasn't existed before, with potential consequences that nobody can predict right now," says Sun. Once the Food and Drug Administration approves the gene gun as a medical device, Sun and Yang hope to aim it at human tumors, particularly those beyond the reach of a scalpel.

Gentle Bullets

LIPOSOMES--hollow, microscopic spheres that fat molecules spontaneously form when they're in solution--are a gentler type of gene bullet. Natasha Caplen and her colleagues at Royal Brompton Hospital in London are experimenting with liposomes as a gene-therapy vehicle for cystic fibrosis. People with CF have a defect in the gene for a protein that regulates the flow of chloride ions in and out of cells; as a result, chloride ions become trapped in the cells of the respiratory tract, as does water, and the lungs become clogged with dry, sticky mucus. In two separate gene-therapy trials, the healthy gene has been successfully delivered to cells in the lungs and nose by a virus. But some patients have suffered inflamed lungs or swollen, itchy nostrils, which just worsens their breathing problems.

In Caplen's experiments, liposomes were coated with the healthy CF gene and sprayed into patients' nostrils. Cells lining the nose absorbed the liposomes by forming membrane pockets (called endosomes) around them, and some copies of the gene made their way into the cells' nuclei. Measurements of the patients' chloride ion levels indicated that the liposomes had delivered the gene--and without the side effects caused by viruses. "With the virus, they saw inflammation at the therapeutic dose," says Leaf Huang, a pharmacologist at the University of Pittsburgh who collaborated with Caplen's team. "We don't." To actually treat CF, the researchers will have to deliver the liposomes to the lungs by having the patients inhale deeply from a breathing mask.

COPYRIGHT 1996 Discover
COPYRIGHT 2004 Gale Group