Slowing Down ALS

Reprinted from PN/Paraplegia News November 2013

Researchers from Ohio and California encouraged by research findings.

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It’s not yet the long-sought cure for amyotrophic lateral sclerosis (ALS), but a group of researchers from Ohio and California may have found a way to slow it down.

Studies of a therapy designed to treat ALS suggest it dramatically slows onset and progression of the deadly disease. Researchers found a survival increase of up to 39% in animal models with a one-time treatment.

The researchers are being led by teams from The Research Institute at Nationwide Children’s Hospital in Columbus, Ohio, and the Ludwig Institute for Cancer Research at the University of California-San Diego.

Two Models

The therapy reduces expression of a gene called SOD1, which in some cases of familial ALS, has a mutation that weakens and kills motor neurons that control muscle movement.

Brian Kaspar, PhD

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, says Brian Kaspar, PhD, a principal investigator in the Center for Gene Therapy at Nationwide Children’s Hospital and a senior author on the research, which was published online Sept. 6 in Molecular Therapy.

“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,” says Kaspar, who collaborated on the study with a team led by Don Cleveland, PhD, at UC-San Diego.

Gene Blocking

Although the exact cause of ALS, also called Lou Gehrig’s disease, is unknown, more than 170 mutations in the SOD1 gene have been found in many patients with familial ALS, which accounts for about 2% 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, SOD1 yields a faulty version of the enzyme that is especially harmful to motor neurons.

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.

Earlier work by Kaspar and others found they could halt production of the mutated enzyme by blocking SOD1 expression, which they suspected would slow ALS progression.

Researchers had to come up with an approach that would block the gene and figure out how to specifically target cells implicated in the disease.

What’s more, the therapy would preferably be administered noninvasively instead of direct delivery via burr holes drilled into the skull.

Kaspar’s team accomplished the second part of this challenge in 2009. They discovered that adeno-associated virus serotype 9 (AAV9) could cross the blood-brain barrier. This makes it an ideal transport system to treat the disease.

Driving Excitement

In this new work, funded by the National Institutes of Health, 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 SOD1, 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% increase in survival. Strikingly, in mice treated at 21 days of age, disease progression was slowed by 66%.

Perhaps more surprising was the finding that even after symptoms surfaced in these models, treatment still resulted in a 23% increase in survival and a 36% reduction in disease progression.

In the slower-disease-onset model, treatment extended survival by 22% and delayed disease progression by 38%.

“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,” says Kevin Foust, PhD, co-first author on the manuscript and an assistant professor in neurosciences at The Ohio State University College of Medicine.

Laying Groundwork

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.

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.

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% in motor neurons and nearly 70% in astrocytes and no side effects were reported, laying the groundwork towards moving to human clinical trials.

This article was reprinted with permission from Nationwide Children’s Hospital. For more information, visit


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