Lysosomal storage diseases account for a significant portion of the instances of mental retardation in children. Examples include Tay-Sachs disease, Hunter disease and Pompe disease. In a lysosomal storage disease, cellular debris accumulates within storage areas of cells called lysosomes.
The cats used in the study were born with a genetic disorder directly analogous to alpha-mannosidosis or AMD, an inherited disease in humans that causes severe mental retardation and skeletal abnormalities.
Although the disease itself is rare, In the case of AMD, children are born with a faulty version of the gene for an enzyme called lysosomal alpha-mannosidase or LAMAN. Children born with the worst form of the disease rarely survive into their teens.
Lysosomal storage diseases are good candidates for gene therapy because along with LAMAN, active enzymes from genetically corrected cells will be secreted into brain tissue and taken up by neighbouring cells.
"Through gene therapy, we replace a 'broken' gene responsible for alpha- mannosidase with the correct, functioning copy, to dramatic results," said John Wolfe, a neurology researcher at The Children's Hospital of Philadelphia.
He added: "The treated cats were markedly improved compared to diseased cats, with better balance and muscle control and fewer tremors." MRI scans also revealed that white matter tracks (myelin) in the brain had been largely restored.
Dr Wolfe said the brain of the cat was much closer in size to the human infant brain compared to mice. He thought it might be possible to achieve similar results in humans with as few as 20-30 injections in each of the two hemispheres of the brain.
He added there was the possibility of further limiting the number of injections by the use of strong promoters that could increase the amount of enzyme that comes from corrected cells.
"Shortly after birth, brain tissue is still physically maturing, which means that there is a particularly important window of opportunity for gene therapy in infants," Dr. Wolfe said. "In our study, we could see that gene therapy used during this particular time led to a restoration of damaged neurons, even though the lesions that represent the disease were already extensive."
While this latest discovery bodes well for the clinical use of this therapy in humans, an additional problem appears in developing and utilising non-invasive methods to monitor the regression of the disease following treatment. Previously, to allow the clinician to see improvement in brain pathology needed a brain biopsy. However, the ability to monitor the improvement in brain myelination in alpha-mannosidosis using imaging is clearly the way in order to quantify the effectiveness of this treatment.
The animal study also demonstrated that only a limited number of injections are necessary to introduce the working LAMAN gene, one of the first steps that will prepare this particular gene therapy for practical use in humans. The gene is transported via a neutralised virus that "infects" cells with the functioning gene. Since the blood-brain barrier would block the virus carrying the gene if it were circulating in the bloodstream, the researchers injected the virus directly into the brain.
Although encouraged by their findings, the researchers note that any clinical trials in humans might be years in the future.
With the advent of gene therapy, considerable effort has been put forth to attack the source of the problem and replace the enzyme itself. One way to replace the enzyme is to put a normal gene into the body that can make the enzyme. This approach can be accomplished by giving the affected individual normal genes from the bone marrow or blood of an unaffected person (called a bone marrow or stem cell transplant) or by making special cells in the laboratory that contain a normal gene and injecting them into the affected individual (gene therapy).
Bone marrow transplantation (BMT) has been successful in several LSDs and allowed long term survival with less severe symptoms. However, there are significant risks to the BMT procedure, it does not always work and the beneficial effects sometimes wear off.
Another approach to replacing the defective enzyme is to manufacture it in a laboratory and give it directly to the patient. This method, called enzyme replacement therapy (ERT), is now available for several of these disorders and its availability is a direct result of the Orphan Disease legislation mentioned above. ERT has been available for patients with Gaucher disease for over 10 years and has provided significant benefit.
However, there are some drawbacks to this therapy as well. The manufactured enzyme does not get into the brain and so does not treat the mental retardation that is associated with some LSDs. Because these drugs are so new the true long-term benefit of ERT for these disorders remains to be seen. Finally, despite the benefits of legislation that defrays the cost of development and allows drug exclusivity for 7 years after its approval, yearly infusion costs for these drugs approach or may exceed more than $200,000 (€149,000).
The members of the research team, from The Children's Hospital of Philadelphia, published their findings in this month's issue of the Annals of Neurology.