Macquarie University neuroscientists have developed an innovative genetic medicine, known as CTx1000, which has demonstrated remarkable potential in halting the progression of both motor neuron disease (MND) and frontotemporal dementia (FTD) in mice. This groundbreaking therapy may even have the ability to reverse some of the effects of these fatal diseases and could hold promise for treating more common forms of dementia, such as Alzheimer’s disease.
The treatment targets the pathological accumulation of the protein TDP-43 in cells in the brain and spinal cord. While TDP-43 is essential for the healthy function of cells like neurons, under specific conditions, it can aggregate in the wrong cellular compartments, leading to blockages and impaired cellular function.
Over the past 15 years, a team of researchers led by Professor Lars Ittner at Macquarie University has been investigating the underlying causes of TDP-43 build-up and exploring ways to prevent its formation. Their latest findings, published in Neuron, have offered new insights into the mechanisms of MND and FTD, shedding light on the role of a second protein, 14‑3‑3, in the aggregation process.
By isolating a short peptide that controls the interaction between TDP-43 and 14‑3‑3, the researchers developed CTx1000. In laboratory experiments, the therapy effectively dissolved the TDP-43 build-ups, facilitated the recycling of pathological TDP-43 proteins by the body, and prevented the formation of new aggregates. Importantly, CTx1000 selectively targets pathological TDP-43, allowing the healthy form of the protein to function normally.
Lead author of the study, Professor Yazi Ke, expressed excitement over the milestone achievement, highlighting the potential of CTx1000 to not only halt disease progression but also improve behavioral symptoms associated with FTD. Results from lab studies showed that CTx1000 halted the progression of MND and FTD, even at advanced stages, and led to the resolution of behavioral symptoms associated with FTD.
Dr. Annika van Hummel, a Research Fellow involved in the study, emphasized the therapy’s effectiveness across various TDP gene mutations, showcasing its potential in different disease contexts. While the focus has been on MND and FTD initially, the researchers believe that CTx1000 could be applicable to other neurodegenerative conditions, including Alzheimer’s disease, which also exhibits TDP pathology in about 50% of cases.
MND, also known as amyotrophic lateral sclerosis (ALS), results in the progressive loss of neurons crucial for communication between the brain, spine, and muscles. FTD, a less common form of dementia but prevalent in individuals younger than 65, leads to cognitive decline and behavioral changes, ultimately proving fatal.
Despite promising advancements in genomic therapy for familial MND, treatments for sporadic MND, which accounts for 90% of cases, remain limited. Current therapies for MND only provide marginal benefits and come with challenging side effects, while there are no approved treatments for FTD.
With plans to commence human trials of CTx1000 in the next two years, Professor Ittner and Professor Ke have secured a pre-clinical grant of $1.2 million to support the process. The therapy is being championed by Celosia Therapeutics, a spin-out company from Macquarie University, formed to translate the cutting-edge research of the university’s neuroscientists into clinical applications.
However, the path to clinical trials presents significant financial challenges, with an estimated cost of $22 million to advance CTx1000 to human testing. Dr. Brenton Hamdorf, CEO of Celosia Therapeutics, is actively seeking investment to expedite the therapy’s progress to clinical trial stage, recognizing the urgent need for effective treatments for neurodegenerative diseases like MND.
The potential of CTx1000 as a one-time treatment option for MND offers hope for patients, even in advanced stages of the disease. Dr. Hamdorf emphasized the transformative impact that CTx1000 could have, bringing a ray of hope to patients and their families who currently face limited therapeutic options for these devastating diseases.
