Posts tagged sod1 gene
Articles and news from the latest research reports.
Therapy Slows Onset and Progression of Lou Gehrig’s Disease
Studies of a therapy designed to treat amyotrophic lateral sclerosis (ALS) suggest that the treatment dramatically slows onset and progression of the deadly disease, one of the most common neuromuscular disorders in the world. The researchers, led by teams from The Research Institute at Nationwide Children’s Hospital and the Ludwig Institute at the University of California, San Diego, found a survival increase of up to 39 percent in animal models with a one-time treatment, a crucial step toward moving the therapy into human clinical trials.
The therapy reduces expression of a gene called SOD1, which in some cases of familial ALS has a mutation that weakens and kills nerve cells called motor neurons that control muscle movement. While many drug studies involve only one type of animal model, this effort included analysis in two different models treated before and after disease onset. The in-depth study could vault the drug into human clinical trials, said Brian Kaspar, PhD, a principal investigator in the Center for Gene Therapy at Nationwide Children’s and a senior author on the research, which was published online Sept. 6 in Molecular Therapy.
“We designed these rigorous studies using two different models of the disease with the experimenters blinded to the treatment and in two separate laboratories,” said Dr. Kaspar, who collaborated on the study with a team led by Don Cleveland, PhD, at the University of California, San Diego. “We were very pleased with the results, and found that the delivery approach was successful in a larger species, enabling us to initiate a clinical translational plan for this horrible disease.”
There currently is no cure for ALS, also called Lou Gehrig’s disease. The Centers for Disease Control and Prevention estimates there are about 5,000 new cases in the U.S. each year, mostly in people age 50 to 60. Although the exact cause of ALS is unknown, more than 170 mutations in the SOD1 gene have been found in many patients with familial ALS, which accounts for about 2 percent of all cases.
SOD1 provides instructions for making an enzyme called superoxide dismutase, which is found throughout the body and breaks down toxic molecules that can be damaging to cells. When mutated, the SOD1 gene yields a faulty version of the enzyme that is especially harmful to motor neurons. One of the mutations, which is found in about half of all familial ALS patients, is particularly devastating, with death usually coming within 18 months of diagnosis. SOD1 has also been implicated in other types of ALS, called sporadic ALS, which means the therapy could prove beneficial for larger numbers of patients suffering with this disease.
Earlier work by Dr. Kaspar and others found that they could halt production of the mutated enzyme by blocking SOD1 expression, which in turn, they suspected, would slow ALS progression. To test this hypothesis, the researchers would not only need to come up with an approach that would block the gene, but also figure out how to specifically target cells implicated in the disease, which include motor neurons and glial cells. What’s more, the therapy would preferably be administered noninvasively instead of direct delivery via burr holes drilled into the skull.
Dr. Kaspar’s team accomplished the second part of this challenge in 2009, when they discovered that adeno-associated virus serotype 9 (AAV9) could cross the blood-brain barrier, making it an ideal transport system for delivering genes and RNA interference strategies designed to treat disease.
In this new work, funded by the National Institutes of Health, the researchers blocked human SOD1, using a technology known as short hairpin RNA, or shRNA. These single strands of RNA are designed in the lab to seek out specific sequences found in the human SOD1 gene, latch onto them and block gene expression.
In one of the mouse models used in the study, ALS develops earlier and advances more quickly. In the other, the disease develops later and progresses more slowly. All of the mice received a single injection of AAV9-SOD1-shRNA before or after disease onset.
Results showed that in the rapid-disease-progressing model, mice treated before disease onset saw a 39 percent increase in survival compared to control treated mice. Strikingly, in mice treated at 21 days of age, disease progression was slowed by 66 percent. Perhaps more surprising was the finding that even after symptoms surfaced in these models, treatment still resulted in a 23 percent increase in survival and a 36 percent reduction in disease progression. In the slower-disease-onset model, treatment extended survival by 22 percent and delayed disease progression by 38 percent.
“The extension of survival is fantastic, and the fact that we delayed disease progression in both models when treated at disease onset is what drives our excitement to advance this work to human clinical trials,” said Kevin Foust, PhD, co-first author on the manuscript and an assistant professor in neurosciences at The Ohio State University College of Medicine.
In addition to the potential therapeutic benefit, the study also offers some interesting insights into the biological underpinnings of ALS. The role of motor neurons in ALS has been well documented, but this study also highlighted another key player—astrocytes, the most abundant cell type in the human brain and supporters of neuronal function.
“Recent work from our collaborator Dr. Cleveland has demonstrated that astrocytes and other types of glia are as important if not more important in ALS, as they really drive disease progression,” said Dr. Kaspar. “Indeed, in looking at data from mice, more than 50 percent of astrocytes were targeted throughout the spinal cord by this gene-delivery approach.”
Ideally, a therapy would hit motor neurons and astrocytes equally hard. The best way to do that is to deliver the drug directly into the cerebrospinal fluid (CSF), which would reduce the amount of SOD1 suppression in cells outside the brain and reduce immune system exposure to AAV9—elements that would add weight to an argument for studying the drug in humans.
Injections directly into CSF cannot be done easily in mice, so the team took the study a crucial step further by injecting AAV9-SOD1-shRNA into the CSF of healthy nonhuman primates. The results were just as the team hoped—the amount of gene expression dropped by as much as 90 percent in motor neurons and nearly 70 percent in astrocytes and no side effects were reported, laying the groundwork towards moving to human clinical trials.
“We have a vast amount of work to do to move this toward a clinical trial, but we’re encouraged by the results to date and our team at Nationwide Children’s and our outstanding collaborators are fully committed to making a difference in this disease,” Dr. Kaspar said.
The findings could impact other studies underway in Dr. Kaspar’s lab, including research on Spinal Muscular Atrophy, an often fatal genetic disease in infants and children that can cause profoundly weakened muscles in the arms and legs and respiratory failure.
“This research provides further proof of targeting motor neurons and glial cells throughout the entire spinal cord for treatment of Spinal Muscular Atrophy and other degenerative diseases of the brain and spinal cord, through a less invasive manner than direct injections,” said Dr. Kaspar, who also is an associate professor of pediatrics and neurosciences at The Ohio State University College of Medicine.
(Source: nationwidechildrens.org)
ALS trial shows novel therapy is safe
An investigational treatment for an inherited form of Lou Gehrig’s disease has passed an early phase clinical trial for safety, researchers at Washington University School of Medicine in St. Louis and Massachusetts General Hospital report.
The researchers have shown that the therapy produced no serious side effects in patients with the disease, also known as amyotrophic lateral sclerosis (ALS). The phase 1 trial’s results, available online in Lancet Neurology, also demonstrate that the drug was successfully introduced into the central nervous system.
The treatment uses a technique that shuts off the mutated gene that causes the disease. This approach had never been tested against a condition that damages nerve cells in the brain and spinal cord.
“These results let us move forward in the development of this treatment and also suggest that it’s time to think about applying this same approach to other mutated genes that cause central nervous system disorders,” says lead author Timothy Miller, MD, PhD, assistant professor of neurology at Washington University. “These could include some forms of Alzheimer’s disease, Parkinson’s disease, Huntington’s disease and other conditions.”
ALS destroys nerves that control muscles, gradually leading to paralysis and death. For treatment of the disease, the sole FDA-approved medication, Riluzole, has only a marginal effect.
Most cases of ALS are sporadic, but about 10 percent are linked to inherited mutations. Scientists have identified changes in 10 genes that can cause ALS and are still looking for others.
The study focused on a form of ALS caused by mutations in a gene called SOD1, which account for 2 percent of all ALS cases. Researchers have found more than 100 mutations in the SOD1 gene that cause ALS.
“At the molecular level, these mutations affect the properties of the SOD1 protein in a variety of ways, but they all lead to ALS,” says Miller, who is director of the Christopher Wells Hobler Lab for ALS Research at the Hope Center for Neurological Disorders at Washington University.
Rather than try to understand how each mutation causes ALS, Miller and his colleagues focused on blocking production of the SOD1 protein using a technique called antisense therapy.
To make a protein, cells have to copy the protein-building instructions from the gene. Antisense therapy blocks the cell from using these copies, allowing researchers to selectively silence individual genes.
“Antisense therapy has been considered and tested for a variety of disorders over the past several decades,” Miller says. “For example, the FDA recently approved an antisense therapy called Kynamro for familial hypercholesterolemia, an inherited condition that increases cholesterol levels in the blood.”
Miller and colleagues at the University of California-San Diego devised an antisense drug for SOD1 and successfully tested it in an animal model of the disease.
Merit Cudkowicz, MD, chief of neurology at Massachusetts General Hospital, was co-PI of the phase I clinical safety trial described in the new paper. Clinicians at Barnes-Jewish Hospital, Massachusetts General Hospital, Johns Hopkins Hospital and the Methodist Neurological Institute in Houston gave antisense therapy or a placebo to 21 patients with SOD1-related ALS. Treatment consisted of spinal infusions that lasted 11 hours.
The scientists found no significant difference between side effects in the control and treatment groups. Headache and back pain, both of which are often associated with spinal infusion, were among the most common side effects.
Immediately after the injections, the researchers took spinal fluid samples. This let them confirm the antisense drug was circulating in the spinal fluid of patients who received the treatment.
To treat SOD1-related ALS in the upcoming phase II trial, researchers will need to increase the dosage of the antisense drug. As the dose rises, they will watch to ensure that the therapy does not cause harmful inflammation or other side effects as it lowers SOD1 protein levels.
“All the information that we have so far suggests lowering SOD1 will be safe,” Miller says. “In fact, completely disabling SOD1 in mice seems to have little to no effect. We think it will be OK in patients, but we won’t know for sure until we’ve conducted further trials.”
The therapy may one day be helpful in the more common, noninherited forms of ALS, some of which may be linked to problems with the SOD1 protein.
“Before we can consider using this same therapy for sporadic ALS, we need more evidence that SOD1 is a major contributor to these forms of the disorder,” Miller says.
The trial was conducted with support from ISIS Pharmaceuticals, which co-owns a patent on the SOD1 antisense drug.