SCIENCE/TECHNOLOGY
Bioinorganic Complex Is Possible Treatment for Rare Genetic Disease of biochemistry at the University of Tor onto, and coworkers. The paper reports on the group's 17 years of experience in treating seven Menkes disease patients with the complex. Menkes disease is a genetic disorder that causes devastating neurological de generation in young children. Infants with Menkes disease have repeated sei hemists in Toronto have devel zures, mental retardation, temperature oped copper-histidine, a bioinor regulation problems, connective tissue ganic complex, as a treatment for defects, skin that is underpigmented and Menkes disease, a rare neurological dis 'loose/' circulatory and bone abnormal order that generally kills children by age ities, and hair that is unusually brittle three. But although the researchers first and kinky. The incidence of the disease introduced copper-histidine therapy 17 is believed to be 1 to 2 per 100,000 births. years ago, the treatment's effectiveness Because Menkes disease is so rare and remains uncertain. many physicians are not familiar with it, Research on the treatment of Menkes many children are not diagnosed early, disease with copper-histidine was sum or die without having been diagnosed at marized in the November Journal of Pe all. Sarkar believes that early diagnosis is diatrics [123, 828 (1993)] by Bibudhen- essential and that patients must be treat dra Sarkar, head of the department of ed with copper-histidine in the first biochemistry research at the Hospital month of life to have any hope of avoid for Sick Children, Toronto, and professor ing irreversible and ultimately fatal neu rological damage. Menkes disease was discovered in 1962 by pediatric neurologist John H. Menkes and coworkers at Columbia University. A decade later, an Australian group found that it was caused by a widespread defect of copper transport. And earlier this year, three independent research groups reported the discovery of the gene for Menkes disease [Nature Genetics, 3, 7,14, and 20 (1993)]. The gene encodes a copper-trans porting adenosine triphosphatase. In Menkes patients, a defective version or a complete absence of this enzyme im pairs copper transport in a manner that is not yet completely understood. The gene's discovery could lead to the de velopment of convenient DNA diag nostic tests for Menkes disease to re place the current procedure—which takes several weeks and is performed at only a few centers worldwide. "The basic problem in Menkes disease is that the body is deprived of copper," Sarkar: early diagnosis is essential explains pediatric geneticist and Menkes
• But effectiveness of copper-histidine as a treatment for Menkes disease remains uncertain after 17 years of use
Proposed structures of copper-histidine
C
Sarkar and coworkers believe cop per-histidine adopts one of these two structures at physiological pH. disease clinician Stephen G. Kaler of the National Institute of Child Health & Human Development, Bethesda, Md. "Copper is not absorbed properly from the gastrointestinal tract. Levels in the plasma and in the brain are subnormal, and even the copper that does reach cells doesn't get directed to the proper com partments for normal utilization." One reason copper is an essential trace metal in mammals, says Kaler, "is it's a necessary component in certain enzymes—such as dopamine β-hydroxylase, superoxide dismutase, cytochrome c oxidase—enzymes that are pretty im portant for neurologic function. Menkes patients have low activity of those enzymes." Sarkar first got involved in Menkes disease therapy in 1976, when the late Andrew Sass-Kortsak, a pediatrician at DECEMBER 13,1993 C&EN 23
SCIENCE/TECHNOLOGY
the Hospital for Sick Children, diag nosed Menkes disease in a newborn whose sibling had died several years earlier from severe Menkes-associated neurodegeneration. Sass-Kortsak brought the case to the attention of Sarkar, whose group had long focused on studies of copper transport in blood, asking him, "How can we save this child?" In earlier work, Sarkar and coworkers had found that copper-histidine was a key circulating form of copper that pro moted copper uptake in cells. Because Menkes disease is a copper-deficiency disease, Sarkar suggested administering copper-histidine to the patient. The ther apy was approved by the hospital's clin ical investigation committee, and cop per-histidine treatment was initiated during the baby's first month of life. Sarkar believes this saved the pa tient's life. At about three years of age, the patient made remarkable develop mental gains, learning to walk, talk, ride a tricycle, and climb stairs. Today, at 17 years old, he is the world's long est surviving Menkes patient.
Another Menkes patient treated with er the treatment did much for them. copper-histidine in the first month of life There's a tremendous clinical variability." at the Hospital for Sick Children is cur For example, one patient lived to the age rently seven years old and is also doing of 14 without copper-histidine treatment, well. Five other patients treated begin says Menkes. Kaler, who is currently conducting ning at two to seven months old died. "The efficacy of early treatment with an 18-patient trial of the biochemical copper-histidine appears to be the re and clinical effects of copper-histidine sult of making copper available during treatment, also believes the drug's effi the critical period of myelination and cacy remains uncertain. For example, development of the central nervous he says, "We haven't found measur system," explains Sarkar. "The impor ably improved levels of cellular copper tant aspect of this treatment is to ad enzymes" in patients receiving copperminister copper-histidine [in] the first histidine replacement therapy. weeks of life and prior to the evolution However, some of Kaler's patients have of the major neurological impairment." made very modest clinical gains with cop But Menkes, who is currently profes per-histidine therapy. "Probably if s going sor emeritus of neurology and pediatrics to be somewhat of a complicated story at the University of California, Los An sorting out the precise pathophysiology," geles, remains uncertain about the effec he says. He speculates that children with a tiveness of copper-histidine treatment. "I certain type of Menkes-gene mutation saw the paper in the Journal of Pediat may respond to copper-histidine treat rics," he says. 'The problem with the ment, but that such patients are likely to work is that the variability in the natural be rare. "Maybe Sarkar's two patients course of children with kinky-hair dis have a mutation like that," he says. ease—that's what I call it—is so great Kaler believes copper-histidine injec that you really have trouble telling wheth tions will remain part of Menkes disease
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DECEMBER 13,1993 C&EN
treatment because copper-histidine bypasses the blockage in intestinal copper absorption that is a characteristic of the disease. But in terms of the intracellular processing of copper, he says, something more needs to be done. "Better therapies, I think, will emerge in the coming years/' Kaler says. "But copper-histidine can somewhat ameliorate the most profound neurological problems, and on that basis I think Sarkar's work is a valuable contribution.,, Sarkar concedes that there is much additional work to be done. But he points to a recent published study by German and Danish scientists showing neurological improvements from copper-histidine treatment and indicating that the therapy increases the activity of a key copper enzyme. Sarkar believes it would be very unfortunate if physicians jump to the conclusion that copper-histidine doesn't work. "It gives these kids a chance," he says. "There is nothing else right now, without this." Stu Borman
Signal used to direct ribozyme to RNA target Chemists at the University of Colorado, Boulder, have developed a method for directing catalytic RNA molecules, or ribozymes, to the place in a cell where a viral RNA target of the ribozyme is localized. The strategy could, the chemists believe, increase the efficacy of ribozymes as antiviral agents by increasing the rate at which the ribozyme finds its target in a cell. And because it is becoming increasingly clear that cells use a variety of signals to determine how particular RNA molecules are processed, the approach developed by the Colorado chemists may be useful in increasing the efficacy of ribozymes against nonviral targets. Thomas R. Cech, a professor of chemistry and biochemistry and an investigator in the Howard Hughes Medical Institute at the University of Colorado, and Bruce A. Sullenger, a postdoctoral fellow in Cech's lab, harnessed what is known as a "retroviral packag-
OXALYL AN
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ing signal" to direct a ribozyme to its target [Science, 262, 1566 (1993)]. The experimental results indicate that the ribozyme so targeted destroyed most of the viral genomic RNA that normally would have been packaged into new retroviruses. In their paper, Cech and Sullenger point out that "the ability to target ribozymes to cleave viral RNAs in vitro has led to speculation about their potential therapeutic value as antiviral agents in vivo. To develop ribozymes for this purpose, however, one must consider the characteristics that distinguish these two settings." In the test tube, they note, ribozymes and their RNA substrates diffuse freely so cleavage can occur as fast as the ribozyme and its substrate combine to form a duplex. "In cells, RNAs do not appear to diffuse freely but rather are sorted to specific cellular locations," they write. "Such compartmentaliza-
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