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Targeted Tau protein

The amyloid hypothesis is not only supported by numerous experimental data. From the point of view of new drug development, the amyloid protein hypothesis can also provide practical new drug targets, because whether it is to develop monoclonal antibodies targeting plaques or plaques or to design BACE inhibitors. None of the tasks are incompetent.

But because of the flourishing nature of the amyloid hypothesis, the Tau protein hypothesis has not received as much attention as the amyloid hypothesis for a long time. However, when the amyloid hypothesis was hampered, some proponents of the amyloid hypothesis began to turn to the Tau hypothesis.

Therapies based on the Tau protein hypothesis have several main directions: targeting tau protein-related kinases/phosphatases, or active and passive immunization, and using strategies such as anti-Tau protein aggregation inhibitors to reduce, stabilize, or inhibit Tau Protein aggregation.

In 1988, Claude Wischik and colleagues at the University of Cambridge discovered abnormal Tau protein in neurons in Alzheimer’s diseased brain. The accumulation of Tau protein tangles in this type of Tau protein is closely related to the development of dementia.

Wischik went to Aberdeen University in 1997 and continued to work on Tau protein research. In 2002, he established TauRx Therapeutics Inc., which specializes in the study of Tau protein aggregation inhibition, and advanced the clinical trial of the first drug, methylene blue, in 2004.

Maybe the blue sky was born with a halo. It was the first synthetic drug in human history. In 1891, Paul Guttmann tried to use the drug to treat malaria. The drug was then used to formulate Giemsa stain for chromosome staining.

In the early 20th century, methylene blue was used in the treatment of a range of other diseases, including depression, and led the development of chlorpromazine and tricyclic antidepressants. At the same time, it developed in the chemical and biomedical fields. It has a profound effect. Now methylene blue is mainly used for the treatment of methemoglobinemia and some inflammation. It sounds like a panacea, but can Methylene Blue treat Alzheimer’s disease?

In 2008, TauRx announced the phase II clinical trial results at a conference, but the results have caused much controversy: The data show that the two low-dose regimens of the drug are effective for moderate patients (non-early patients), and clinical design The program was also seriously questioned, and the company did not publish complete data on clinical trials after the meeting.

The company then recruited 111 patients and then published data on clinical trials in 2014 explaining that the problem of dose-effect relationship was caused by the acidification of methylene blue in the stomach. At this time, the company has also adopted the second-generation drug LMTM (which turns methylene blue into a stable reduced form to improve pharmacokinetic properties). TauRX did not disclose Phase I clinical information. Phase II clinical trials ended due to internal reasons. However, the company still conducted three phase III clinical trials. In 2016, the company announced that two of its clinical trials had failed.

True, the reality is so cruel. Alzheimer’s disease has been the hardest hit in clinical trials. Tau protein aggregation inhibition has not made good progress. Let’s look at other therapeutic strategies that target Tau protein.

The abnormal phosphorylation of Tau protein caused by the imbalance of phosphorylation and dephosphorylation may play an important role in the formation of neurofibrillary tangles, which can lead to the detachment of Tau protein and microtubules, and then aggregate with each other.

Abnormal phosphorylation may be due to increased kinase activity or decreased phosphatase activity. GSK-3 plays a critical role in the physiological and pathological Tau protein phosphorylation process. However, the development of GSK3 inhibitors is extremely difficult and it is difficult to obtain highly selective compounds, and it is difficult to control toxic side effects due to too much GSK3 substrate.

Despite this, there are still some inhibitors that have entered clinical studies. Noscira’s TideGlusib showed good safety in Phase IIa clinical trials, but the subsequent Phase IIb trial did not reach the clinical trial endpoint. While the development of phosphatase (such as PP2A) agonists theoretically has the potential to offset the failure of the development of kinase inhibitors, there is currently no drug in clinical trials.

As the detachment of microtubules and Tau protein causes abnormal microtubule function, which results in the obstruction of the transport process of cell bodies and axons and ultimately leads to impaired synaptic function, the development of microtubule stabilizers has become a potential treatment for the disease. Drug. Microtubule stabilizers are commonly used drugs in cancer chemotherapy. Similar to GSK3 inhibitors, the toxic and side effects of this class of drugs are also more difficult to control. In 2012, Bristol-Myers Squibb (BMS) began a Phase I clinical trial to assess the safety of microtubule stabilizer epothilone D, but BMS terminated the development of the indication after the clinical trial was completed.

Can we use the immune system to clear pathogenic Tau proteins just as we have developed targeted amyloid therapies? The answer is yes. And like amyloid therapies, Tau protein immunotherapy is also divided into active immunity and passive immunity. Active immunization uses antigen to activate the body’s immune cells to produce antibodies against a certain type of pathogenic Tau protein, while passive immunization uses monoclonal antibodies directly.

Active immunotherapy has two clinical vaccines: AADvac-1 from Axon Neuroscience SE and ACI-35 from Janssen. ACI-35 is undergoing Phase Ib clinical trials, while AADvac-1 will complete validation clinical trials by 2019. Ebavi’s monoclonal antibody ABBV-8E12 is undergoing phase II clinical trials in passive immunotherapy.

After the failure of Verubecestat, Merck bought an interest in Tau Monopoly in Teijin, Japan. The BMS-986168 purchased by Bianjian from BMS is also in Phase II clinical.

Although more and more therapies based on the Tau protein hypothesis have recently appeared, individuals believe that the therapy based on the Tau protein hypothesis cannot be considered as an advancement in the field of Alzheimer’s disease treatment, and may even be a helpless choice.

The Tau protein hypothesis has no obvious advantages over the amyloid protein hypothesis. On the contrary, even the current amyloid hypothesis still has numerous supporters. Although I am not personally optimistic about the research in this direction, whether clinical trials can succeed or not, I believe no one can accurately predict.

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