October 22, 2009
A chemical cousin of a drug used to treat sepsis dramatically slows the progression of amyotrophic lateral sclerosis, or Lou Gehrig's disease, in mice.
The results offer a bit of good news in efforts to develop a therapy to stop or slow the progression of a disease that generally kills its victims within just a few years.
In a paper published in the Journal of Clinical Investigation, scientists studied the use of an enzyme known as activated protein C (APC) to slow the cell death that occurs in ALS.
"We're able to significantly extend the lifespan of mice who have an aggressive form of ALS," says co-principal investigator Don Cleveland. "The compound also extended the length of time that the mice were able to function well despite showing some symptoms of the disease, and it reduced the pace of muscle wasting that is a hallmark of ALS."
While the investigators say that more research must be done before the enzyme is tested in people with the disease, they're encouraged that the work involves a compound that's already been proven to be safe and currently given to patients via a common injection for another condition. The team hopes to test a treatment in patients within five years.
The work was done by researchers from the Univ. of Rochester Medical Center, The Scripps Research Institute, the Univ. of Notre Dame, and a Rochester-based start-up biotech company, Socratech. First authors of the paper were Zhihui Zhong at Rochester and post-doc associate Hristelina Ilieva at UC San Diego.
The researchers studied mice with a mutation in a gene called superoxide dismutase 1 (SOD1), which plays an important role in keeping cells safe from damaging molecules known as free radicals. While the cause of most cases of ALS is unknown, scientists know that SOD1 plays a role in approximately 3% to 4% of cases-–providing an opportunity to study the disease's initial steps, which occur long before key nerve cells appear sick or die. In addition, recent studies have suggested that the accumulation of mutant forms of SOD1 is linked to most cases of sporadic ALS.
Cell death is central to the symptoms of ALS, a chronic disorder of motor neurons in the brain, brainstem and spinal cord, which results in a progressive paralysis that generally kills individuals within five years of onset. Currently there is no cure or even a treatment that can effectively slow disease progression.
In a surprising finding last year, a team led by Cleveland found that SOD1 mutations weaken the crucial natural barrier between blood and the spinal cord. In effect, blood vessels in the spinal cord become leaky, allowing toxic substances to flood into the spinal cord. Because of the defect, motor neurons are exposed directly to biochemical byproducts of hemoglobin such as iron, which forms reactive oxygen molecules that injure or kill neurons.
Now, the team has shown that APC dramatically lessens the activity of the SOD1 mutation. This protects neurons that are under assault by blocking the synthesis of aberrant forms of the molecule in motor neurons and other cells in the spinal cord. These include microglia cells, which the Cleveland laboratory has shown play a key role in the inflammatory response and progression of ALS. In addition to reduced SOD1 activity, the flow of dangerous byproducts of hemoglobin into the spinal cord was eliminated by APC, saving neurons.
Currently, the group is studying alternate forms of APC, in an effort to create the form that best quells the symptoms of ALS while causing fewer unwanted side effects, such as bleeding. The researchers say the form of APC currently used to treat sepsis carries an increased risk of bleeding and likely will not be appropriate for treating ALS in humans.
While other researchers are exploring the possibility of silencing SOD1 to treat ALS, Cleveland noted that most approaches would require invasive surgery and delivery by direct infusion into the spinal cord. APC, in contrast, is already approved as an injection.
Source: Univ. of Rochester Medical Center