Fixing the Brain

Researchers from Harvard Medical School and the University of Pennsylvania have developed a new way to treat brain lesions in mice, and the procedure may hold promise for treating a neurodegenerative disease in humans.

Dr. Evan Y. Snyder of the Neurology and Pediatrics departments of Children's Hospital and Dr. John H. Wolfe of the School of Veterinary Medicine at the University of Pennsylvania successfully corrected disease progression in afflicted mice serving as animal models for Sly Disease, an inherited human ailment characterized by mental retardation. The fatal disease afflicts fewer than one in 100,000 humans.

Snyder and Wolfe worked with mice whose brains lacked an enzyme necessary for breaking down metabolites and waste material in cells.

Without this enzyme, called beta glucuronidase, substances called glycoaminoglycans accumulate in the brain and other tissues, where they cause neural damage. Accumulation of this waste material leads to severe brain deterioration, retardation and ultimately death.

Snyder and Wolfe reversed the disease's progression by transplanting immature healthy brain cells, called progenitor cells, into the enzyme-deficient brains of newborn mice. According to Snyder, the young cells matured into normal healthy cells, migrating and engrafting themselves in the brain as the mouse grew older.

The findings, published in the journal Nature two weeks ago, is the first report about using this technique to treat a widespread genetic disease of the central nervous system.

The unique anatomical features of the brain made conventional treatments of its lesions ineffective.

Whereas other organs can make up for missing enzymes through contact with the blood, the brain is isolated from the bloodstream by a protective sheath of impermeable capillaries: the blood-brain barrier.

The barrier blocks the entry of drugs and therapeutic molecules into the brain, preventing the correction of brain lesions.

Researchers therefore decided to inject neural progenitor cells into the brain ventricles, chambers filled with cerebrospinal fluid surrounding the brain.

Progenitor cells give rise to two types of brain cells, the neurons (nerve cells) and the glial cells (nourishing cells), which develop into specialized brain structures.

"We recognized an inherent property of immature nerve cells and exploited it," Synder said.

Since the afflicted mice are born relatively healthy, the transplant therapy was able to be used on newborns, rather than embryos.

By the time the newborn mice reached maturity, the neural progenitor cells had secreted the missing enzyme, engrafted throughout the brains and appeared as normal constituents of the central nervous system.

Mice with transplanted cells who lived over eight months, the mouse's usual lifespan, showed a dramatic absence of pathology in their brains, suggesting a permanent cure without additional abnormalities, said Wolfe.

Human Therapy

The researchers' work suggests that neural progenitor cells could eventually be used to treat Sly Disease in humans.

"Our long-term hope is to produce a permanent treatment in patients, whether mice, dogs, or humans," Wolfe said.

Named after William Sly of St. Louis University, who discovered the human disorder in 1973, Sly Disease affects many body tissues, including the bone marrow, joints, heart tissue, liver, spleen and brain.

The progressive, debilitating pathology leads to heart and breathing problems, crippling, mental retardation and eventually death within one to two decades.

Although the disease is "individually rare" and affects fewer than 1 out of 100,000 people, it belongs to a broader group of inherited diseases, which together affect 1 in every 1,500 people, said Wolfe.

"All of the diseases have similar strategies for correction," he added.

Potentially, the neural progenitor strategy could be used to treat this wider group of genetic ailments, which include Tay-Sachs, Gaucher's disease, galactosemia and dozens of other maladies that affect millions of people worldwide.

In the future, Snyder and Wolfe plan to attempt the correction of a larger animal model: the dog.

But Wolfe said that because the dog brain is much larger than that of the mouse, it is unclear how much of the dog's particular inherited enzyme-deficiency disease can be corrected.

If the team of researchers are successful yet again, "there will be a strong impetus for us to try our neural progentor technique on humans," said Wolfe.

The first step in developping such a brain-transplant therapy will be to identify and clone neural progenitor cells in humans.

The researchers hope to "do a lot to try to understand the basic cell biology of the neural progenitor cells, the basic forces driving them to become specific cells, and their capabilities from a therapeutic point of view," Snyder said.