‘Unprecedented’ survival boost seen with new gene therapy in ALS model

Treatment with a novel one-time gene therapy improved motor function and extended survival in a mouse model of amyotrophic lateral sclerosis (ALS) driven by mutations in the SOD1 gene, according to researchers from the University of Massachusetts Chan Medical School.

The results, the team noted, are “unprecedented.”

After a single injection into the bloodstream, the mice lived 100 more days than untreated controls, which the researchers deemed the “most substantial therapeutic benefit” seen with a single injection in this mouse model.

“No other studies have been able to achieve this kind of survival extension. This makes us very optimistic that our approach could have a meaningful impact for patients suffering from this horrible disease and warrants further clinical evaluation,” Guangping Gao, PhD, chair and professor of genetic and cellular medicine at the UMass school and a study coauthor, said in a university news story detailing the study findings.

Gao and colleagues, who developed the single-dose treatment, noted that the 100 days was more than triple the average survival time seen in models to date.

Titled “Intravenous administration of an engineered AAV9-gene-silencing vector suppresses human SOD1 and extends survival in an ALS mouse model,” the study was published in the journal Nature Communications.

Recommended Reading

Oct. 21, 2024 News by Margarida Maia, PhD

First SOD1-ALS patient dosed in trial of AMT-162 gene therapy

ALS is a progressive disorder in which motor neurons, the nerve cells that control muscle movement, become progressively damaged and die. Mutations in the SOD1 gene, which lead to the production of an abnormal SOD1 protein that is toxic to motor neurons, account for as many as 20% of all familial ALS cases — when the disease is seen in more than one person in a biological family — and as many as 2% of sporadic ALS cases, when there is no pattern in families.

People with SOD1 mutations have a treatment available, called Qalsody (tofersen), that’s designed to prevent the toxic SOD1 protein from being produced. However, this treatment approach requires a monthly injection into the spinal canal, which can be demanding for patients.

Researchers target ALS due to SOD1 gene mutations

With that in mind, the UMass research team set out to develop a new gene therapy that may be delivered just once via an intravenous, or into-the-vein, infusion. The approach basically aims to shut down the mutant SOD1 gene using a short sequence of genetic material called a microRNA.

When genes are read to make a protein, the genetic code is copied from DNA into a temporary molecule called messenger RNA, which then serves as a template for protein production. MicroRNAs are small molecules that can bind to specific messenger RNAs and target them for destruction, thus stopping protein production.

For this gene therapy, the researchers engineered a microRNA that specifically targets the messenger RNA of the SOD1 gene. The team engineered their treatment candidate with specific genetic sequences to ensure that the microRNA would be produced at high levels upon delivery to motor neurons.

To deliver the microRNA to motor neurons, the researchers used a viral vector, which is a virus engineered to deliver a therapeutic gene rather than cause infection. Specifically, they used a viral vector widely used in gene therapy called an adeno-associated virus serotype 9 (AAV9).

After creating the gene therapy, the researchers tested a one-time administration in a mouse model of SOD1-ALS. In this model, the median survival of untreated mice is about four months.

Recommended Reading

April 25, 2024 News by Steve Bryson, PhD

Qalsody slows ALS disease progression in real-world settings

Even after ALS onset, new gene therapy slowed progression

When the microRNA gene therapy was administered before symptoms developed, disease progression was markedly slowed, and median survival was extended by more than three months, the data showed.

The therapy also slowed disease progression when administered after symptom onset, the researchers noted. When given around the time symptoms first appeared, median survival was extended by about a month. When therapy was given later in the disease course, median survival increased by about two weeks, the data showed.

The survival extensions were accompanied by less weight loss, improved motor function, and greater preserved breathing ability compared with untreated mice, the researchers noted. Analyses of the mice’s tissues indicated that the gene therapy was shutting down the production of mutant SOD1 protein as intended. The scientists also noted that no safety issues were observed.

“Remarkably, administration near the disease onset delayed disease onset, as evidenced by a transient reversal of declines in body weight, motor function, and muscle strength. Even administration after disease onset significantly slows disease progression and extends survival,” the researchers wrote, noting also that, “in addition to the therapeutic efficacy, no treatment-related side effects were observed.”

According to the team, “these therapeutic benefits from a single [injection into the bloodstream] are unprecedented among gene-therapy approaches in this mouse model.”

The researchers cautioned that these data come from mouse models, so further testing is needed. Still, the scientists said their gene therapy offers a promising strategy for treating SOD1-ALS, which could plausibly be combined with Qalsody.

“If proven to be as powerful a treatment in clinical trials as it is in the mouse model, [the gene therapy] offers a once-and-done alternative to [Qalsody], which must be delivered repeatedly by invasive injections,” said Zuoshang Xu, MD, PhD, study coauthor at the UMass.

“A great advantage of AAV-delivered gene silencing could be that it can be implemented simultaneously or sequentially with [Qalsody], either as an alternative to those who cannot tolerate [Qalsody], or to improve further the clinical outcomes,” Xu added.