OurScience
Translation medicine
Neurodegenerative diseases
Therapeutic Focus: Our program is designed to address the core pathology of neurodegenerative diseases, which involves multiple prions and aberrant physiological cross-β networks. Our therapeutic strategy is centered around the use of baicalein, a compound capable of restoring the cellular folding of disease-causing proteins like α-synuclein and TDP-43, and rebuilding the normal prion-like cross-β interactome (see the video)
Addressing Multiple Prions & Amyloid Hypothesis: In neurodegenerative diseases, the co-existence of multiple misfolded proteins forms the basis of disease complexity. Our approach acknowledges the limitations of the amyloid-specific treatments, which have shown limited success due to the multifaceted nature of protein misfolding. Baicalein-based Reprofold® targets not just a single type of protein aggregate but aims to address the broader spectrum of misfolded proteins, including amyloid beta, alpha-synuclein, TDP-43, and SOD1, which are intricately involved in various neurodegenerative conditions.
Mechanism of Action: Baicalein-based Reprofold®‘s mechanism involves refolding misfolded proteins back into their functional oligomeric states. This not only disrupts the pathogenic aggregation process but also reinstates the physiological cross-β interactions essential for cellular health (please see the figure below). This approach is critical in disorders like PD and ALS, where α-synuclein and TDP-43 aggregation is a key pathological feature. Our approach marks a significant shift towards a holistic approach in neurodegeneration therapy.
The dependent origination of proteinopathies and Reprofold®-based therapeutic strategy.The key focus of the Reprofold®-based therapeutic strategy is to restore the normal physiological functions of pathological proteins. Only through this strategy, loss-of-function and gain-of-cytotoxicity result from misfolded pathological proteins can be simultaneously addressed.
Validation in Disease Models: Our research demonstrates that baicalein can remodel TDP-43 aggregates in ALS models and restore the prion-like structure of SMN2 in SMA, counteracting the motor neuron dysfunctions. Moreover, baicalein's efficacy in disaggregating α-synuclein has been validated in PD models, supporting its potential as a universal therapeutic agent for neurodegenerative diseases characterized by protein misfolding.
Pilot Clinical Trial: Our pilot experiment reveals relieving the burden of misfolded alpha-synuclein improves forward leaning of the whole body, smaller steps, visual hallucinations, exhibited delirium and cognition decline (see the video).
After receiving Reprofold® treatment, the subject were able to spontaneously express gratitude to the doctor fluently. Prior to this, the subject had a Mini-Mental State Examination (MMSE) score of only 4, and were unable to engage in normal conversation with others.
Following Reprofold® treatment, the subject in the video demonstrated a return to normal levels for both TDP-43 and PD indicative biomarkers.
The improvement in symptoms is most likely due to the effect of baicalein on these biomarkers. Rather than slowing the cognitive decline of patients, as seen in trials with other agents, subjects treated with baicalein demonstrated significant cognitive improvements from baseline status over the course of treatment in terms of behavior and cognition. Most importantly, baicalein offers dramatic improvement only within 5 days. We thus will replicate the clinical trial of baicalein to confirm its safety and efficacy for DLB and optimize course of treatment.
Long term goals: Our treatment is distinguished by its lower toxicity, making it an invaluable option for use in the presymptomatic stages of disease for prevention. This feature is particularly crucial, as it allows for early intervention, potentially halting disease progression and even reversing damage caused by protein misfolding. Additionally, we have developed a precise diagnostic test to detect plasma levels of synuclein and TDP-43, enabling earlier and more accurate diagnosis. This combination of a safer, preventative treatment and advanced diagnostic capabilities offers immense value to patients, promising improved health outcomes, enhanced quality of life, and a decrease in long-term healthcare expenses.
Covid-19 therapeutics and preventative drugs
Right after the outbreak of COVID-19, GBS screened two SARS-CoV-2 inhibitors, DoublePlay-001 and DoublePlay-002, from their compound pool and has been working on a treatment for COVID-19 with the US National Institutes of Health (NIH). The inhibition mechanisms of the two compounds are different, but they both prevent viral replication. DoublePlay-001 has subsequently been chosen for further optimization due to its lower toxicity. Another advantage of DoublePlay-001 is it has been allowed to directly enter phase II clinical trials. Besides curing patients, it also has the potential of becoming the pre-exposure and post-exposure prophylaxis for high-risk population, such as healthy medical staff and patients with chronic diseases. It provides protective effects similar to vaccines and reduces the possibility of infection. More recently, GBS has also discovered a novel mechanism through which COVID-19 can cause high mortality in infected diabetic patients. As a result, GBS has designed related animal research for additional candidate treatments.
Research Papers
Wang IF, Chang HY, Hou SC, Liou GG, Way TD, Shen CK (2012). The self-interaction of native TDP-43 C terminus inhibits its degradation and contributes to early proteinopathies. Nat Commun. 2012 3:766.
Chang HY, Hou SC, Way TD, Wong CH, Wang IF (2013). Heat-shock protein dysregulation is associated with functional and pathological TDP-43 aggregation. Nat Commun. 4, 2757.
Ting CH et al., Prion-like Conformational Editing of SMN2 Proteins Rescues Spinal Muscular Atrophy.
https://doi.org/10.21203/rs.3.rs-606188/v1
Chang, HY., Wang, IF. Restoring functional TDP-43 oligomers in ALS and laminopathic cellular models through baicalein-induced reconfiguration of TDP-43 aggregates. Sci Rep 14, 4620 (2024). https://doi.org/10.1038/s41598-024-55229-9
Chang HY & Wang IF (2024) Unraveling the Complex Pathology of Neurodegenerative Diseases: Multiple Prions, Cross-β Networks and Baicalein's ReproFold.
