3-drug combo shows promise for treating SOD1-ALS: Mouse study
Together at low doses, drugs improved outcomes better than any alone
A combination of three drugs — one of them the experimental therapy CuATSM — may be effective for treating amyotrophic lateral sclerosis (ALS) caused by mutations in the SOD1 gene, according to a new preclinical study.
In mice carrying SOD1 mutations, the combination of these three drugs — CuATSM, ebselen, and telbivudine — delayed symptom onset and improved survival better than CuATSM alone.
“We had been trialing different approaches with the drugs, but what we found was that a combination of all three, at a lower dose, was the most promising in producing better outcomes for [ALS],” Jeremy Lum, PhD, the study’s first author at the University of Wollongong in Australia, said in a university news story.
Importantly, per the study, this combination was found to be safe in testing.
Lum noted that, “in [the] mice, the drugs reduced the progression of [ALS], increased their survival rates, diminished levels of the unstable SOD1 protein and protected the motor neurons.”
The study, “A polytherapy approach demonstrates therapeutic efficacy for the treatment of SOD1 associated amyotrophic lateral sclerosis,” was published in eBioMedicine.
New SOD1-ALS combo includes experimental therapy CuATSM
In ALS, motor neurons, which are the nerve cells that control movement, sicken and die. The causes of ALS remain not fully understood, but some cases have been shown to have genetic underpinnings. Mutations in the SOD1 gene are responsible for as many as 10 in 50 cases of familial ALS and about 1 in 50 of sporadic ALS, when the disease occurs without any clear pattern.
The SOD1 gene provides instructions to make a protein of the same name. ALS-causing mutations in this gene lead to the production of an abnormal form of the SOD1 protein that is unstable and tends to form clumps in nerve cells, which is thought to drive neurological damage that ultimately gives rise to ALS.
Theoretically, drugs that could stabilize the mutant SOD1 protein and prevent it from forming clumps might be impactful as a treatment for ALS associated with SOD1 mutations.
CuATSM is an ALS treatment candidate that’s now in clinical testing, while ebselen is an experimental anti-inflammatory therapy. Telbivudine was a former hepatitis B treatment.
We believe that tackling [ALS] from multiple angles, with a combination of drugs targeting various aspects of its biology, holds greater promise than relying on a single treatment.
Preclinical studies have shown that all three of these drugs have the ability to stabilize the mutant SOD1 protein. Now, Lum and colleagues evaluated whether combining the three medications could produce more powerful effects than any one by itself.
“We believe that tackling [ALS] from multiple angles, with a combination of drugs targeting various aspects of its biology, holds greater promise than relying on a single treatment,” Lum said.
Using multiple medicines in combination is referred to as polytherapy, whereas using just one medicine is called monotherapy.
No safety issues seen with combo treatment in mice
In lab-grown mouse motor neurons carrying SOD1 mutations, the researchers found that polytherapy with the three drugs could effectively reduce mutant SOD1 protein clumping. It also was shown to improve the cells’ survival.
Importantly, according to the researchers, the combination of the three drugs with each at a relatively low dose was just as effective as a very high dose of CuATSM alone.
“Our results demonstrate that [polytherapy with CuATSM, ebselen, and telbivudine] reduces SOD1 [aggregates] formation, … and provides neuroprotection, compared to CuATSM monotherapy,” the researchers wrote.
The team next tested the treatment combination in mice. First, the researchers conducted a series of tests in healthy animals to ensure that the combination of therapies did not cause any safety issues. Also, the researchers ensured that all three medications were able to get into the brain and spinal cord, where the nerve cells most vulnerable to ALS live.
Then, the triple combo was tested in a mouse model of ALS caused by a SOD1 gene mutation. Similar to the cell data, experiments in mice showed that the three-drug combination reduced mutant SOD1 protein clumping and improved the survival of motor neurons.
The results also showed that the triple combo delayed the onset of ALS symptoms and lessened the severity of neurological symptoms more effectively than CuATSM alone. In addition, SOD1 mutant mice given the triple combination therapy lived on average 10% longer than untreated mice and 3% longer than mice treated with CuATSM alone.
The researchers concluded that the triple combination therapy “delayed disease onset, improved motor function and extended survival compared to both [placebo-] and CuATSM-treated [SOD1 mutant] mice.” According to the team, the findings “deliver a foundation to further identify more advantageous therapeutic options for ALS.”
“These data provide encouraging … evidence [in animal and cell models] for a polytherapy approach in the treatment of SOD1-associated ALS,” the researchers wrote.
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