New gene therapy shows promise for motor neuron disease and frontotemporal dementia

Macquarie University neuroscientists have developed a single-dose genetic drug proven to halt the progression of motor neurone disease (MND) and frontotemporal dementia (FTD) in mice – and could even offer the potential to reverse some of the effects of life-threatening diseases.

It could also provide opportunities to treat more common forms of dementia, such as Alzheimer’s disease, which is the second leading cause of death in Australia after heart disease.

The new treatment, called CTx1000, targets pathological accumulations of the TDP-43 protein in cells of the brain and spinal cord.

Cells like neurons naturally produce TDP-43, which is important for their proper functioning. Under certain conditions, it accumulates in the wrong place in cells, blocking them and preventing them from functioning properly.

Over the past 15 years, a Macquarie University research team led by Professor Lars Ittner has been investigating the causes of this pathological accumulation of TDP-43, as well as ways to clear the blockages and prevent their formation. .

The team’s latest findings are published in Neuron.

Professor Ittner says their research has deepened their understanding of MND and FTD and their causes.

“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,” he says. “The two proteins interact, which leads to these accumulations in the cells.

“From there, we were able to isolate a short peptide that controls this interaction, and that’s what we used to create CTx1000.

“When we administered it in the laboratory, it dissolved buildups, marking TDP-43 proteins for recycling by the body, and prevented new ones from forming. Most importantly, CTx1000 only targets pathological TDP-43, thus allowing the healthy version of the protein to produce and do its job unhindered.”

This makes the CTx1000 incredibly safe, and Professor Ittner claims to have seen no adverse effects in his studies.

Professor Yazi Ke, lead author of the new paper, says this milestone is particularly exciting for her because the original discovery was made early in her postdoctoral studies.

“This spans more than a decade of work and goes from discovery to potential treatment,” she says.

“In laboratory conditions, we have seen CTx1000 prevent the progression of MND and FTD, even at very advanced stages, and resolve the behavioral symptoms associated with FTD.

“We have high hopes that when this moves to human trials, it will not only prevent people from dying from both MND and FTD, but even allow patients to regain some of the lost function through the re-education.”

Researcher Dr. Annika van Hummel claims to have covered various mutations in TDP genes during laboratory tests.

“We wanted to prove beyond doubt that this would work in different situations, and it resulted in clear improvements in symptoms and brain pathology,” she says. “The fact that it was effective before and after the onset of symptoms makes it particularly interesting.

“Although we are initially focusing on MND and FTD, approximately 50% of Alzheimer’s disease cases also have TDP pathology. So it is possible that in the future this treatment may be translatable to other diseases neurodegenerative.”

A desperate need for treatment options

Also known as amyotrophic lateral sclerosis (ALS), MND causes the progressive loss of neurons that allow the brain and spine to communicate with muscles.

Initially, patients experience muscle weakness, but as the disease progresses, they gradually lose the ability to walk, talk, swallow and breathe without assistance. Most people with MND die within two to five years of diagnosis.

FTD is one of the rarest forms of dementia, but it is the second most common form in people under 65 years old. Actor Bruce Willis was diagnosed with FTD in 2023.

It does not always present with obvious physical symptoms, but it causes cognitive decline associated with behavioral symptoms, including anxiety, loss of inhibition, personality change, and impaired judgment. Patients can live more than 10 years after diagnosis, but this is ultimately fatal.

Although there is promising genetic therapy for a form of familial MND, there are few treatments available for sporadic MND which accounts for 90% of all cases.

Of these, the most effective can only prolong a patient’s life by up to five months. All require frequent doses and some have side effects that are difficult to manage.

There is currently no treatment for FTD.

Professor Dominic Rowe, Professor of Neurology at Macquarie University, is one of Australia’s leading MND clinicians and researchers. “I currently treat over 200 people with MND, but only five of them with a specific type of familial MND can currently access genomic therapy,” says Professor Rowe.

“Such treatment does not exist for anyone else. For most patients, all we can do is provide good quality multidisciplinary care.

“This new research is incredibly promising for slowing the progression of MND and FTD in the vast majority of our patients. I am hopeful that it will soon be available to our patients at the MND Clinic at Macquarie University Hospital.

The high cost of research

Professors Ittner and Ke hope to begin human trials of CTx1000 within two years and have already received a $1.2 million preclinical grant to help with this process.

The therapy is one of the key discoveries championed by Celosia Therapeutics, a Macquarie University spin-off company established in 2022 to help move the groundbreaking work of the university’s neuroscientists from the laboratory to patients.

Unfortunately, testing new therapies and offering them to waiting patients is incredibly expensive. In this case, the cost is estimated at $22 million for human trials.

Celosia CEO Dr. Brenton Hamdorf is actively seeking investment to move CTx1000 into clinical trials.

“There is a desperate need for new drugs for neurodegenerative diseases like MND, and this is an exciting new therapy with enormous potential,” says Dr. Hamdorf.

“MND is difficult to diagnose because there is no conclusive test. It is a process of elimination that can take up to 12 or 18 months, after which the disease has progressed significantly.

“We have the potential for CTx1000 to be a unique treatment that can help patients even at advanced stages of the disease. It would then literally be a light at the end of the tunnel that patients and their families simply do not have. NOW.”