U.S. medical scientists, working together, have found that a genetically engineered enzyme can significantly help children and young adults with a rare disorder that involves storage of materials within cells, resulting in the cells swelling to the point of bursting and killing those cells.
In its most severe form, the disease, mucopolysaccharidosis 1, causes progressive developmental delays, corneal clouding, lung obstructions, heart disease, severe joint stiffness and death, usually by age 10. In milder forms, known as Hurler-Scheie syndrome and Scheie syndrome, patients suffer many of the same medical problems, but they develop more slowly, and victims die by their 20s or live a nearly normal life span.
A report on the new study of 10 patients with intermediate disease, which documents the effectiveness of recombinant enzyme treatments, appears in the Jan. 18 issue of the New England Journal of Medicine. Authors include Dr. Emil D. Kakkis of Biomarin Pharmaceutical in Novato, Calif., Dr. Joseph Muenzer, associate professor of pediatrics at the University of North Carolina at Chapel Hill, and 15 others.
"We gave patients back an enzyme called iduronidase that they were missing and that was made in the laboratory," Muenzer said. "We saw significant improvement in their ability to get around, they had more energy and their oversized liver and spleen shrank dramatically. Six patients we treated prior to puberty also showed an increased growth rate."
MPS 1 is a recessive disorder with an estimated incidence of one in 100,000. About one in every 200 to 300 people in the United States may carry the defective gene for MPS 1 so that when two carriers have children, about one in four of their offspring are born with the disorder. The most severe form, Hurler's syndrome, causes patients to die by age 4 or 5 on average.
"Until now, the only treatment alternative was bone marrow transplantation, and besides complications associated with transplantation, doctors can't find matching donors for all children who need one," Muenzer said. "For that reason, this work is exciting. It's also exciting for me personally because the first patient we treated was a young child I met when I was a postdoctoral fellow 18 years ago, and I have known him ever since."
Doctors gave the purified laboratory-generated enzyme to patients intravenously each week for a year and evaluated them extensively at six, 12, 26 and 52 weeks before analyzing and reporting their findings.
Because numerous comparable lysosomal storage diseases like MPS 1 have been identified, each with its own missing enzyme, the new work "is really the beginning of a whole new therapeutic possibility for rare genetic disorders like this one," Muenzer said.
In lysosomal storage diseases, organelles inside cells called lysosomes get clogged with complex carbohydrates known as mucopolysaccharides that the missing enzymes would otherwise break down for recycling.
"Since the lysosome is a recycling center, I liken it to a garage people keep putting stuff in," the physician said. "If you never take the items out to the curb, over time your garage becomes non-functional."
The researchers now are conducting a second study known as a Phase III, double-blind, placebo-controlled trial at six centers across North America and Europe. Other centers involved in the study reported Thursday were Vanderbilt University Medical Center, the University of Texas Southwestern Medical Center in Dallas, Baylor College of Medicine in Houston, Harbor-UCLA Medical Center in Torrance, Calif., and UCLA School of Medicine in Los Angeles.
The chief sponsor of the clinical trial was Biomarin Pharmaceutical, and it also was supported by the Ryan Foundation for MPS Children, the Harbor-UCLA General Clinical Research Center and UNC-CH's General Clinical Research Center.
"The fact that researchers and companies are willing to get involved in this disorder to me is very encouraging because we're talking about a market in the U.S. of only 500 to 1,000 patients," Muenzer said. "This work not only gives them a working product they can show investors, it also allows them to develop technical expertise they can eventually use in disorders with much bigger potential markets."
By David Willamson
UNC-CH News Services
Note: Muenzer can be reached at 919-966-1447, or via paging at 216-0921, Kakkis at 415-884-6700.
Contact: David Williamson, 919-962-8596.
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