Home » Gene Therapy in Mice Holds Promise for ALS and Dementia

Gene Therapy in Mice Holds Promise for ALS and Dementia

by Nikos Kokkorakis

In animal models, a gene therapy known as CTx1000 has stopped the progression of both frontotemporal dementia and amyotrophic lateral sclerosis. Researchers studying neurology at Macquarie University in Australia have developed a single-dose genetic medicine that has stopped the progression of mice’s ALS and FTD diseases. The group feels that its method may also have promise for treating more prevalent types of dementia, like Alzheimer’s disease, and that it may even be able to reverse some of the consequences of the deadly diseases.

The novel therapy, known as CTx1000, targets abnormal accumulations of the protein TDP-43 in brain and spinal cord cells, which has been connected to dementias such as ALS and FTD. In as short as two years, the researchers, under the direction of Lars Ittner, PhD, want to see CTx1000 enter human clinical trials. Their research, “Targeting 14-3-3θ-mediated TDP-43 pathology in amyotrophic lateral sclerosis and frontotemporal dementia mice” was published in Neuron.

Nuclear TAR-binding protein 43 (TDP-43) is deposited in the cytoplasm in both frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). While TDP-43’s cytoplasmic re-localization is a crucial step in the ALS/FTD pathogenesis, the underlying processes are still unclear. The researchers reported that it was found a non-canonical connection that controls nuclear-cytoplasmic shuttling between 14-3-3θ and TDP-43.

The levels of neural 14-3-3θ were elevated in FTD and sporadic ALS patients with TDP-43 disease. Increased contact between pathogenic TDP-43 and 14-3-3θ led to cytoplasmic accumulation, insolubility, phosphorylation, and fragmentation of TDP-43, which mirrored pathological alterations in illness. Using the 14-3-3θ’s increased affinity for pathogenic TDP-43, the researchers developed a gene therapy vector that targets TDP-43 pathology. This vector reduced neurodegeneration and functional deficits in various ALS/FTD mouse models that expressed either mutant or non-mutant TDP-43, even in cases where the mice were already symptomatic when they began treatment. The results showed that 14-3-3θ plays a role as a mediator of cytoplasmic TDP-43 localization with implications for ALS/FTD pathogenesis and therapy. According to researchers, in lab conditions, CTx1000 stopped ALS and FTD from progressing even at advanced stages and resolved the behavioral symptoms associated with FTD.

In order to assist deliver CTx1000 from the lab to patients, Celosia Therapeutics, a Macquarie University spin-out business founded in 2022, is looking for funding to enable CTx1000 to advance to the clinical trial stage.

 

Reference: Yazi D. Ke, Annika van Hummel, Carol Au, Gabriella Chan, Wei Siang Lee, Julia van der Hoven, Magdalena Przybyla, Yuanyuan Deng, Miheer Sabale, Nicolle Morey, Josefine Bertz, Astrid Feiten, Stefania Ippati, Claire H. Stevens, Shu Yang, Amadeus Gladbach, Nikolas K. Haass, Jillian J. Kril, Ian P. Blair, Fabien Delerue, Lars M. Ittner, Targeting 14-3-3θ-mediated TDP-43 pathology in amyotrophic lateral sclerosis and frontotemporal dementia mice, Neuron, 2024, https://doi.org/10.1016/j.neuron.2024.01.022.

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