UF scientist: enzyme replacement restores muscle strength in mice with Pompe’s disease

GAINESVILLE, Fla.—University of Florida researchers have successfully restored normal muscle function in animals with a rare and fatal form of muscular dystrophy using a new form of enzyme replacement therapy.

In laboratory experiments, two doses of the enzyme strengthened the legs of a small sample of young mice with a muscle-wasting condition called Pompe’s disease, according to findings from a new UF study. The enzyme replacement, which was developed and produced by Oklahoma City-based Novazyme Pharmaceuticals, had no adverse effects in the mice and could be tested in people within the year.

“This is the first evidence that treatment for this disease has led to a functional correction of muscle strength,” said Dr. Barry Byrne an associate professor in the College of Medicine’s departments of pediatrics, and molecular genetics and microbiology. “The findings are preliminary and there’s still a lot of work to do, but we’re very encouraged.”

Byrne, who also co-directs UF’s Powell Gene Therapy Center, presented the results Sunday at the Federation of American Societies for Experimental Biologies conference in Orlando.

Pompe’s disease is a debilitating genetic condition that causes an enlarged heart and liver, severe muscle weakness, breathing difficulties and destruction of respiratory muscle function, which eventually results in ventilator dependence. It is caused by the body’s inability to manufacture any of the enzyme acid alpha-glucosidase, or GAA, also commonly called acid maltase.

Milder forms of the disease are caused by inadequate supplies of the enzyme. Infants with Pompe’s disease often die before age 2. Without the enzyme, a storage form of sugars and starches known as glycogen accumulates in and destroys muscle cells throughout the body, particularly those of the heart and respiratory muscles.

Though acid maltase deficiency diseases are rare, afflicting about 70,000 people worldwide, the UF research could lead to new treatments for as many as 50 other related genetic disease in which an important enzyme is missing or defective, Byrne said.

Enzyme replacement therapy to restore the missing enzyme is one of two current approaches currently being pursued to treat Pompe’s disease. Byrne and colleagues also are continuing to investigate genetic therapies to correct the faulty gene responsible for the disease.

For this study, Byrne treated a group of mice that had the faulty Pompe’s gene with high doses of Novazyme’s NZ-1001 enzyme replacement therapy, also called highly phosphorylated recombinant human acid alpha-glucosidase. NZ-1001 is generated in the laboratory to be nearly identical to human GAA and modified by adding high levels of phosphate and altering some of its sugar molecules. The alterations enable the protein to successfully reach the location in the cells where glycogen builds up. This type of enzyme formulation has higher potency than previously tested materials.

The mice received two doses of NZ-1001 over a two-week period, after which their leg muscles were just as strong as the leg muscles of healthy mice. Researchers tested strength by electrically stimulating isolated muscles. Because of their young ages, the mice had not yet displayed noticeable muscle weakness, “floppiness” or other outward signs of Pompe’s disease, but their muscle strength tests were abnormally low before the NZ-1001 was administered.

In addition, microscopic examination of skeletal and heart muscle and liver tissue of the treated mice revealed that glycogen levels in the cells had returned to normal levels.

“We saw complete restoration of the GAA enzyme activity in animals after two doses of the replacement therapy,” Byrne said. “That is particularly significant because the modification of the therapeutic enzyme seems to have improved its effectiveness.”

The results are preliminary findings from a broader study of 50 mice that is examining the effects of NZ-1001 replacement therapy, including long-term outcomes and alternate dosages. The therapy could be tested in human participants as early as this year.

“If we can replicate these results in children, we expect a dramatic improvement in their muscle function that, hopefully, will halt and perhaps even reverse progression of the disease and lead to measurable improvement in quality of life,” said John Crowley, president and chief executive officer of Novazyme and the father of two young children with acid maltase deficiency.

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• Paula Rausch