Krabbe disease or globoid cell leukodystrophy is a rare disorder that affects about one in every 100,000 infants. It's caused by a mutation in a gene called GALC, which encodes an enzyme called galactosylceramidase. This incurable condition, which destroys the insulation surrounding nerve cells, is usually fatal to patients before age two.
The disorder also affects dogs, who get symptoms starting around six weeks of age. It's also fatal for them; the dogs only survive for a few months after the onset of symptoms. Researchers have now used a canine model of Krabbe disease to show that gene therapy can eliminate the symptoms of the disease. Reporting in the Journal of Clinical Investigation (JCI), the scientists found that dogs that received the therapy lived to be at least four years old, apparently with no significant side effects.
"This disease has no good therapy," said senior study author Charles Vite, a professor of neurology. "We've been looking at this disease in dogs since the 1990s, but it was really the shift over to a new gene therapy vector that gave us a chance to treat it with a big effect on the nervous system."
Cells contain small organelles called lysosomes, they are sacs that contain digestive enzymes. Krabbe disease is a lysosomal storage disorder. Normally, the enzyme encoded by the GALC gene would break down lipids, but a mutated GALC enzyme cannot, so stuff builds up inside of the lysosomes. In the case of Krabbe disease, that disrupts the insulation or myelin surrounding nerve cells, which alters nerve signaling. The disorder leads to neurological symptoms, including blindness, deafness, and paralysis.
A risky bone marrow transplant in an infant patient's first month can help relieve the disorder, but it only works in thirty percent of those treated. "A new treatment is really needed," Vite said.
As with any gene therapy, getting the therapeutic materials to the right place in the body and cells poses a challenge. In this work, the scientists successfully used a viral vector that has been used in other gene therapies, the AAV9 vector, which seems likeliest to gain FDA approval. They tried using high and low doses of the therapy at various ages.
"We decided we would inject into the spinal fluid via the back of the head, which is the most effective means of getting to the brain," noted Vite.
The most benefit was seen in dogs that were given a high dose of gene therapy before they showed symptoms; they had more myelination in their brains, and the myelination in their peripheral nervous system was maintained (even though the therapy was injected into the central nervous system).
"That was a huge surprise for us; that injecting a gene therapy in the spinal fluid can positively affect both the central and the peripheral nervous system was really exciting," Vite said.
There was still a benefit for dogs that were treated after symptoms started. Though they had an intermediate form of the disease, they lived significantly longer than dogs that had not gotten any therapy. It shows that trials will have to be careful about the proper dose.
Follow-up studies will examine the molecular impacts of the therapy, as well as how to ensure both dogs and children receive the correct dose. Vite suggested that since this therapy triggered some improvement in the peripheral nervous system, the approach might be useful for other disorders.
"The hope is to use the model as a method to understand the mechanisms at work in peripheral nerves and how we can target peripheral neuropathies," said Vite.