Combination treatment in mice shows promise for fatal neurological disorder in kids
Infants with Batten disease, a rare but fatal neurological disorder, appear healthy at birth. But within a few short years, the illness takes a heavy toll, leaving children blind, speechless and paralyzed. Most die by age 5.
There are no effective treatments for the disease, which can also strike older children. And several therapeutic approaches, evaluated in mouse models and in young children, have produced disappointing results.
But now, working in mice with the infantile form of Batten disease, scientists at Washington University School of Medicine in St. Louis and Kings College London have discovered dramatic improvements in life span and motor function by treating the animals with gene therapy and bone marrow transplants.
The results are surprising, the researchers say, because the combination therapy is far more effective than either treatment alone. Gene therapy was moderately effective in the mice, and bone marrow transplants provided no benefit, but together the two treatments created a striking synergy.
The research is online in the Annals of Neurology.
“Until now, this disease has been refractory to every therapy that has been thrown at it,” says senior author Mark Sands, PhD, professor of medicine and of genetics at the School of Medicine. “The results are the most hopeful to date, and they open up a new avenue of research to find effective therapies to fight this devastating disease.”
The combination therapy did not cure the disease, the scientists caution, but mice that received both treatments experienced significant, lasting benefits.
What is Batten Disease?
Batten disease is a fatal, inherited disorder of the nervous system that begins in childhood. In some cases, the early signs are subtle, taking the form of personality and behavior changes, slow learning, clumsiness, or stumbling. Symptoms of Batten disease are linked to a buildup of substances called lipopigments in the body’s tissues. Lipopigments are made up of fats and proteins. Because vision loss is often an early sign, Batten disease may be first suspected during an eye exam. Often, an eye specialist or other physician may refer the child to a neurologist. Diagnostic tests for Batten disease include blood or urine tests, skin or tissue sampling, an electroencephalogram (EEG), electrical studies of the eyes, and brain scans.
Is there any treatment?
As yet, no specific treatment is known that can halt or reverse the symptoms of Batten disease. However, seizures can sometimes be reduced or controlled with anticonvulsant drugs, and other medical problems can be treated appropriately as they arise. Physical therapy and occupational therapy may help patients retain functioning as long as possible.
Mice that got gene therapy and a bone marrow transplant lived nearly 18.5 months, more than double the lifespan of untreated mice with the disease. (Healthy laboratory mice live about 24 months.) And for a significant portion of their lives, motor skills in mice that got both therapies were indistinguishable from those in normal, healthy mice.
While bone marrow transplants carry significant risks, especially in children, the researchers say they may be able to combine gene therapy with another treatment to achieve the same results. This same approach potentially could be used to treat other forms of Batten disease.
Batten disease is an inherited genetic disorder that strikes fewer than five of every 100,000 U.S. children but is slightly more common in northern Europe. There are several forms of the disease, diagnosed at different ages, and all are related to the inability of cells to break down and recycle proteins.
Batten disease Symptoms
Symptoms of Batten disease generally begin between ages 5 and 10 years. Initial symptoms are loss of vision or seizures. Over time, loss of muscle control (ataxia), moderate wasting of brain tissue (cerebral atrophy), progressive loss of sight, and dementia occur.
Batten disease Diagnosis
Batten disease is diagnosed based on the symptoms the child is experiencing. Parents or the child’s pediatrician may notice that the child has begun to develop vision problems or seizures. Special electrical studies of the eyes, such visual-evoked response or electroretinogram (ERG), may be done. In addition, diagnostic tests such as electroencephalogram (EEG, to look for seizure activity) and magnetic resonance imaging (MRI, to look for changes in the brain) may be done. A sample of skin or tissue (called a biopsy) may be examined under a microscope to look for the buildup of lipofuscins.
The infantile form is caused by mutations in the PPT1 gene that codes for an enzyme needed to remove these proteins from cells. Without a working copy of the gene, the proteins build up in cells, causing seizures, brain atrophy and dementia. The disease progresses most rapidly when it is diagnosed in infants. By age 2, most live in an unresponsive, vegetative state.