WaveBreak's WTX-245 Shows Promise in Targeting TDP-43 Pathology for ALS and FTD

WaveBreak has revealed innovative preclinical findings indicating that WTX-245, a novel small molecule identified by the company that targets TDP-43 aggregation for ALS treatment, enhances normal splicing for various mRNAs essential for the function and survival of motor neurons. This data from WaveBreak is highlighted in a poster presentation at the 35th International Symposium on ALS/MND, scheduled for December 6-8, 2024, in Montreal.

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“TDP-43's aggregation in the cytoplasm and depletion in the nucleus serves as a defining pathological trait of ALS, leading to widespread transcriptional irregularities that ultimately result in neuronal impairment and cell death. Although TDP-43 aggregation plays a crucial role in the pathogenesis of ALS, there are few effective methods to prevent this protein's aberrant behavior and thus remedy global mRNA mis-splicing,” stated Edward B. Lee, MD, PhD, co-investigator and Associate Professor of Pathology and Laboratory Medicine at the Perelman School of Medicine, University of Pennsylvania, where he also co-directs the Institute on Aging. “The findings highlighted in this poster hold significance on two fronts: Firstly, it showcases the initial evidence that TDP-43 aggregation closely mimicking patient brain pathology adversely affects transcription across multiple mRNAs in a neuronal cell model, thereby replicating the disease pathology seen in ALS; secondly, it illustrates that a small molecule can both inhibit this aggregation and swiftly restore normal transcription for numerous mRNAs.”

TDP-43 is critical for maintaining over 30% of the global transcriptome in motor neurons, playing a pivotal role in mRNA processing in the nucleus, including transcription, splicing, and trafficking. When TDP-43 aggregates accumulate, they lead to the loss of functional TDP-43 and disrupt its normal nuclear activities, causing extensive transcriptional disturbances and a significant loss of motor neurons in ALS and FTD. Data from patients' brains show a correlation between neuronal dysfunction, cell death, and TDP-43 aggregation, which progresses rapidly. WaveBreak is advancing its TDP-43 program to develop small molecules targeting the disease-specific mechanisms behind TDP-43 aggregation, aiming to protect and restore motor neuron functions in conditions related to TDP-43 proteinopathies.

“The growing body of scientific evidence linking TDP-43 aggregation to the progression of ALS has gathered momentum, yet there are still few drug discovery initiatives directly aimed at targeting TDP-43 dysfunction, along with limited preclinical models for assessing drug candidates intended to prevent TDP-43 aggregation pathology,” remarked Bart Henderson, CEO of WaveBreak. “We are encouraged by our promising preclinical findings, which indicate potential for our strategy to both safeguard and restore TDP-43 function by inhibiting the aggregation that leads to motor neuron dysfunction and cell death in these diseases. This progress stems from WaveBreak's advancements in protein biochemistry that facilitate proprietary neuronal cell models for TDP-43 aggregation and in physical chemistry for discovering small-molecule therapeutics designed to disrupt the aggregation of TDP-43 implicated in ALS and FTD.”

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According to the data provided by the Synapse Database, As of December 11, 2024, there are 36 investigational drugs for the TDP-43 target, including 21 indications, 29 R&D institutions involved, with related clinical trials reaching 3, and as many as 2613 patents.

Wavebreak Therapeutics Ltd. has developed a small molecule drug, Target TDP-43, which targets TDP43. The drug is intended for the treatment of nervous system diseases, endocrinology and metabolic disease, and other diseases, with a focus on amyotrophic lateral sclerosis and frontotemporal dementia. Currently, the drug is in the preclinical phase, indicating that it is still in the early stages of development.