Researchers have developed a single-dose genetic therapy that can clear protein blockages that cause motor neurone disease, also called amyotrophic lateral sclerosis, and frontotemporal dementia, two incurable neurodegenerative diseases that eventually lead to death.
In healthy neurons, TAR DNA-binding protein 43 (TDP-43) is naturally produced and important for their healthy function. However, TDP-43 can be modified after synthesis, leading to its accumulation and aggregation in the wrong part of the cells, preventing them from working properly. These build-ups are associated with devastating neurodegenerative diseases like motor neurone disease (MND), also known as amyotrophic lateral sclerosis (ALS) or Lou Gehrig’s disease, and frontotemporal dementia (FTD).
MND is a rapidly progressing disease that affects the brain and spinal cord’s ability to communicate with the muscles, causing weakness that worsens over time. FTD is a group of disorders characterized by loss of neurons in the frontal and temporal lobes of the brain, which causes a deterioration in behavior, personality and/or difficulty producing or comprehending language. Both conditions are incurable and eventually lead to death.
After uncovering, for the first time, the mechanism by which pathological TDP-43 accumulates in MND and FTD, researchers at Macquarie University, Sydney, created a genetic therapy to clear the blockages and prevent them from re-forming.
“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,” said Lars Ittner, a co-corresponding author on the study. “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.”
The researchers found that, in mice, a single dose of CTx1000 targeted only the ‘bad’ TDP-43, leaving the healthy version of it alone. Not only was it safe, it was effective even when symptoms were present at the time of treatment.
“Importantly, CTx1000 targets only pathological TDP-43, allowing the healthy version of the protein to be produced and go about its work unhindered,” Ittner said. “When we administered it in the lab, it dissolved the build-ups, tagging TDP-43 proteins for recycling by the body, and preventing new ones from forming.”
It’s taken Macquarie University researchers 15 years to reach this point.
“This spans more than a decade of work and goes from discovery all the way through to a potential treatment,” said Yazi Ke, the study’s lead and co-corresponding author. “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.”
They’re keen to see if the findings will translate into humans.
“We have great hope 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,” Ke said.
Because the researchers looked at a variety of mutations in TDP genes in the lab, the treatment may have applications beyond these two conditions.
“We wanted to prove beyond a doubt that this would work in different situations, and it resulted in clear improvements in both symptoms and brain pathology,” said Annika van Hummel, a co-author. “While we are initially concentrating on MND and FTD, … about 50 percent of cases of Alzheimer’s also show TDP pathology, so it’s possible that in the future this treatment could be translatable to other neurodegenerative conditions.”
The study was published in the journal Neuron.
Source: Macquarie University
