Single-Dose Gene Therapy Could Prevent Fatal Brain Diseases

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Single-Dose Gene Therapy Could Prevent Fatal Brain Diseases

Single-Dose Gene Therapy Could Prevent Fatal Brain Diseases

Researchers have developed a single-dose gene therapy that can clear protein blockages that lead to motor neuron diseases (also known as amyotrophic lateral sclerosis, ALS, or Lou Gehrig’s disease) and frontotemporal dementia. In healthy neurons, TAR DNA-binding protein 43 (TDP-43) is naturally produced and crucial for neuronal health. However, TDP-43 undergoes changes after synthesis, leading to its improper localization and aggregation in cells, impairing their normal function.

These accumulations are associated with neurodegenerative diseases such as motor neuron diseases (MND), also known as ALS or Lou Gehrig’s disease, and frontotemporal dementia (FTD).

Multiple sclerosis is a rapidly progressing disease that affects the ability of the brain and spinal cord to communicate with muscles, leading to weakness and worsening over time. Progressive supranuclear palsy is a group of diseases characterized by the loss of neurons in the frontal and temporal lobes of the brain, leading to the degeneration of behavior, personality, and/or language expression or comprehension. Both diseases are incurable and ultimately fatal.

Researchers at Macquarie University in Sydney, Australia, have identified for the first time the mechanism by which pathological TDP-43 accumulates in MND and FTD, and have developed a gene therapy to clear blockages and prevent their reformation.

The study’s co-senior author, Lars Ittner, stated, “We have discovered for the first time that the second protein 14-3-3 increases where pathological TDP-43 is present. These two proteins interact, leading to these accumulations inside the cells. From this, we were able to isolate a short peptide that controls this interaction, which is the raw material we used to create CTx1000.”

Single-Dose Gene Therapy Could Prevent Fatal Brain Diseases

Researchers found that in mice, a single dose of CTx1000 targets only the “bad” TDP-43 without harming healthy TDP-43. It is not only safe but also effective even when symptoms are present during treatment.

Ittner added, “It is crucial that CTx1000 targets only pathological TDP-43, allowing the healthy TDP-43 protein to generate and work unimpeded. When we use it in the laboratory, it dissolves accumulated TDP-43 proteins, marks them for recycling by the body, and prevents the formation of new TDP-43.”

Breakthrough research: Dr. Annika van Hummel, Professor Yazi Ke, and Professor Lars Ittner hope their latest research can treat some of the most devastating neurological diseases. Image: Samantha Christensen

Researchers at Macquarie University spent 15 years to achieve this. The first author and co-senior author of the study, Yazi Ke, said, “It’s been over a decade of work, from discovery to potential treatment. In lab conditions, we see that CTx1000 can stop the progression of MND and FTD even in late stages, and address behavioral symptoms associated with FTD.”

They are eager to see if these findings will translate to humans. Ke stated, “We earnestly hope that when this technology enters human trials, it will not only prevent people from dying from MND and FTD but also allow patients to recover some lost functions through rehabilitation.”

Due to the researchers’ study of multiple mutations in the TDP gene in the lab, the application of this therapy may extend beyond these two conditions.

Co-author Annika van Hummel said, “We want to unequivocally prove that this approach works in different scenarios. While we initially focused on MND and FTD, about 50% of Alzheimer’s disease cases also show TDP pathology, so this therapy could potentially translate to other neurodegenerative diseases in the future.”

The study was published in the journal Neuron.