Gene Therapy Holds Promise to Treat ALS Caused by SOD1 Mutations, Preclinical Study Shows

Gene Therapy Holds Promise to Treat ALS Caused by SOD1 Mutations, Preclinical Study Shows

An experimental gene therapy based on RNA interference (RNAi) shows potential to treat patients with familial amyotrophic lateral sclerosis (ALS) caused by mutations in the superoxide dismutase 1 (SOD1) gene, according to results of a preclinical study in nonhuman primates.

The study, “Safe and effective superoxide dismutase 1 silencing using artificial microRNA in macaques,” was published in the journal Science Translational Medicine.

About 20 percent of familial, or inherited, ALS cases worldwide are caused by mutations in the SOD1 gene. These mutations result in the production and accumulation of toxic SOD1 protein, leading to the progressive loss of motor nerve cells in the brain and the spinal cord.

Several studies have shown that reducing the levels of SOD1 in mice with SOD1 mutations — used as a model of SOD1-associated ALS — reduces nerve cell damage, improves their motor and respiratory function, and prolongs their survival.

So researchers have been working on the development of therapeutic approaches to reduce the levels of SOD1 in ALS patients with mutations in this gene.

RNAi is a natural process of gene silencing that regulates gene expression, in which microRNA (miRNA) molecules bind to a specific messenger RNA (mRNA) — the molecule generated from DNA that is the template for the production of a specific protein — targeting it for destruction, ultimately preventing the production of that protein.

Since specific miRNA molecules can be designed for any given gene and a single molecule is able to silence many target mRNAs, RNAi therapy has the potential to prevent or reverse neurodegeneration in SOD1-associated ALS.

Researchers have now evaluated the safety and effectiveness of an RNAi-based gene therapy targeting SOD1 mRNA levels in cynomolgus macaques, a type of primate. This therapy has the advantage of requiring only a one-time administration.

The therapy consisted of miRNA molecules designed to target the mRNA of the SOD1 gene (SOD1-miRNA) and delivered through a modified and harmless adeno-associated virus (AAV). The chosen AAV — rAAVrh.10 — was previously shown to work well in the central nervous system (brain and spinal cord) and to be safe in clinical trials.

Different versions of components inserted in the AAV and involved in the production of miRNAs were tested to identify the one inducing the higher levels of SOD1-miRNA molecules.

Researchers administered the therapy directly into the spinal cord (intrathecal administration) of the animals, and analyzed the mRNA levels, or the expression, of SOD1, in three distinct areas of the spinal cord.

The data showed that SOD1-miRNA molecules were successfully delivered not only to the spinal cord and brain, but also to peripheral organs, highlighting the therapy’s potential to induce widespread therapeutic effects throughout the body and achieve better overall results.

The high levels of SOD1-miRNA detected in the spinal cord led to a significant reduction of SOD1 expression throughout its length, and in motor nerve cells.

There was also a strong association between the levels of SOD1-miRNA molecules and the subsequent reduction of SOD1 expression (protein production), with the best AAV version achieving up to a 93% reduction of SOD1 mRNA levels in the spinal cord.

The intrathecal administration of this RNAi-based gene therapy was safe and well-tolerated by the primates during follow-up (up to 92 days) and was not associated with any safety concerns.

“These results support the notion that gene therapy with an artificial miRNA targeting SOD1 is safe and merits further development for the treatment of mutant SOD1-linked ALS,” the researchers wrote.

They also noted that the U.S. Food and Drug Administration recently approved an investigational drug application of this therapy to begin a pilot Phase 1 clinical trial in humans. The trial will evaluate whether the therapy’s safety profile in humans is similar to that found in nonhuman primates.

Marta Figueiredo holds a BSc in Biology and a MSc in Evolutionary and Developmental Biology from the University of Lisbon, Portugal. She is currently finishing her PhD in Biomedical Sciences at the University of Lisbon, where she focused her research on the role of several signalling pathways in thymus and parathyroid glands embryonic development.
Marta Figueiredo holds a BSc in Biology and a MSc in Evolutionary and Developmental Biology from the University of Lisbon, Portugal. She is currently finishing her PhD in Biomedical Sciences at the University of Lisbon, where she focused her research on the role of several signalling pathways in thymus and parathyroid glands embryonic development.
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  1. Letitia says:

    Great! Try anything! There’s nothing to lose here…
    But this genetic factor is only found in 3% of cases , I read…What about the other 97%???
    But I knew the key would not be in pharmaceuticals, but at the very basis of the cells…
    This gets triggered in people who have healed many injuries. It has to be inside the cells already…the potential…but I think everyone should be looking at the finding at the end of October at University of Colorado. The cells that mutate to start killing neurons are the same cells found in healthy, healing tissue. That’s what explains ME…and so many others who suddenly fall to this monster, having had lives filled with activity and many injuries. That’s it…right there…
    All I’m concerned with is stopping, and reversing this thing. I don’t have any illusions about anything happening fast enough, either. It destroys lives like nothing else does. I’m already starting out with 2 strikes against me with the knees bone on bone, and the tendons torn in the hand in which the ALS appeared, rendering it useless. I came through a complete reconstruction of a broken and infected jaw last year – and now the orthopedic surgeon is afraid to operate on me, because of what he saw happen to a patient who had shoulder injury, surgery, and the ALS appeared after the surgery and went crazy killing…It was 10 years ago, and that person died quickly. He won’t operate. He thinks it will do harm. The finding at the end of October shows he’s probably right…but what difference does it make, when the disease, itself, will freeze the body into a living trap, until it takes the last nerve pathway, unless it is stopped??
    I only intend to be here as long as I’m autonomous. It is all I am – and NOBODY should be getting in between an individual, and the INDIVIDUAL’S decisions regarding a disease that will disconnect the individual life from every voluntary function. It is a crime that individuals who fall to this disease, have to deal with wrongful power interjecting itself into individual decisions regarding life, and quality of life. It’s also a crime that insurance and money, and coverages, and GREED can deny people ANY chance at reversing or containing a disease that has no stopping point, and
    certainly no mercy in the way it will kill, left to its own devices. Those who make life more difficult, and stand in the way of decisions that offer the only chance at peace, available so far, to people who are faced with an unimaginably horrific endpoint of an unimaginably horrific disease…THEY’RE the only ones who deserve to face it…NOT the people who are struck down by it – by every account, people who have led active, happy lives that can be ripped apart in a few months by an undeserved monster of a disease that will take EVERYTHING – even the ability to say goodbye to loved ones that will be left behind too soon… Who should even have the audacity to interject their own opinions into the lives of people facing the ultimate monster…but they do…
    The stress this causes people like me, who consider freedom and autonomy sacred, has almost equal to the damage caused by the disease, itself…
    But I really want to be here longer, as I never thought I’d be up against such a tight timeframe…and there’s still so much I haven’t experienced… But I feel it closing in…There is a lot that’s failing now… If I could have gotten knees…I could have bought much more time…I started out strong, but it seems to kill people who had a lot of strength, faster…Maybe it has more cells it can attack in stronger people…
    I just wish all research would get on the same page, and be able to shove the greed, beauracracies, and empires out of the way…and just come up with something here that could bring concrete hope to people facing this monster right now…

  2. Joan Churchman says:

    You have said it so well. My childhood friend, who lives in Jamaica W.I. is battling this now. She was diagnosed in 2017 and now has three or four different equipment to keep her going. In Jamaica there is even less resources and you are right about all the things that goes on with insurance and all that. I feel for her and you. I wish there was something I could do. All the best to you!

  3. Chad Raymond Campbell says:

    Would anyone know where I can get more information on the phase 1 clinical trial that is mentioned in the last paragraph?

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