Gene therapy breakthrough in ALS and frontotemporal dementia

By Katie Robinson | Medically reviewed by Alison Christy, MD, PhD
Published April 18, 2024

Key Takeaways

  • A gene therapy halted the progression of amyotrophic lateral sclerosis and frontotemporal dementia in a mouse study.

  • The single-dose genetic medicine, dubbed CTx1000, is expected to progress to clinical trials in 2–3 years.

  • Experts believe these findings could translate to other neurodegenerative conditions, including Alzheimer’s disease.

A new gene therapy is showing promise in amyotrophic lateral sclerosis (ALS), also known as motor neuron disease (MND), and frontotemporal dementia (FTD).

Neuroscientists at Macquarie University in Australia have developed a single-dose genetic medicine, dubbed CTx1000, which halted the progression of these fatal neurodegenerative diseases in mice. The study was published in Neuron.[] 

“In lab conditions, we saw CTx1000 stop MND and FTD from progressing even at very advanced stages, and resolving the behavioral symptoms associated with FTD,” explained lead author Yazi Ke, PhD, in a university press release.[] “We have great hopes that when this progresses to human trials, it will not only stop people from dying from both MND and FTD, but even allow patients to regain some of the lost function through rehabilitation.”

Treatment gap

ALS causes a progressive loss of motor neurons in the brain and spinal cord, leading to weakness and paralysis. Most people with ALS die within 2–5 years of diagnosis. The gene therapy tofersen (Qalsody) was approved in 2023 by the FDA for the treatment of ALS associated with a mutation in the superoxide dismutase 1 (SOD1) gene.[]

Of the few treatments available for sporadic ALS, which makes up 90% of all cases, the most effective can extend a patient’s life by a mere 5 months.

FTD is a rare form of dementia, but it is the second-most prevalent form in individuals younger than 65. As noted by the Alzheimer’s Association,[] FTD results in cognitive decline coupled with anxiety, personality change, and impaired judgment. While ultimately fatal, patients may live for more than 10 years after an FTD diagnosis. Medications may help with behavioral symptoms, but no specific treatments for FTD are available.

How the treatment works

The TAR-binding protein 43 (TDP-43) is found in the nucleus of neurons in the brain and spinal cord.[] In ALS, FTD, and other dementias, TDP-43 is misplaced and collects in the cytoplasm. This toxic form of TDP-43 interacts with the 14-3-3 protein and accumulates, eventually killing the neuron.

The gene therapy CTx1000 binds specifically to the toxic form of TDP-43, and tags it to be degraded by the cell and removed from neurons, restoring normal functioning TDP-43 and preserving neuron health.

In commenting on the research that led to the development of CTx1000, Lars Ittner, MD, co-author of the published study, said in the press release, “We discovered for the first time that where there is pathological TDP-43, there is also an increase in a second protein, 14‑3‑3. The two proteins interact, resulting in these build-ups in the cells. From this, we were able to isolate a short peptide that controls this interaction, and that’s what we used to create CTx1000."

When administered in the lab, CTx1000 dissolved the build-ups and tagged the pathological TDP-43 proteins for recycling, while preventing new ones from forming. Because the new genetic medicine targets only pathological TDP-43, the healthy version of the protein was able to be produced and perform its function in the body unhindered.

In the study, CTx1000 was tested in mice with symptomatic ALS or FTD. When compared with a non-treated control group, the gene therapy partially reversed the disease. There was a 63.9% delay in the onset of paralysis and a 38.5% increase in survival.

Potential use in other neurodegenerative conditions

Co-author Annika van Hummel, PhD, suggested that the findings could translate to other neurodegenerative conditions, including Alzheimer’s disease.

“While we are initially concentrating on MND and FTD […] about 50% of cases of Alzheimer’s also show TDP pathology,” Dr. Hummel said, “so it’s possible that in the future this treatment could be translatable to other neurodegenerative conditions.”

Macquarie University spin-out company Celosia Therapeutics, which has the exclusive license to the drug, is planning pre-clinical trials over the next 2–3 years, with clinical trials to follow.

What this means for you

In a mouse study, a single-dose genetic medicine halted the progression of ALS and FTD. The gene therapy is expected to progress to clinical trials in 2–3 years and, importantly, could help treat other neurodegenerative conditions.

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