How can Alzheimer's disease, a small molecule drug, turn the tide?

In November 1901, DrAlois Alzheimer, a German psychiatrist and neuropathologist, took over a rather difficult case: a 51 year old female patient named August deter had a series of strange symptomsShe would suspect her husband for no reason, forget the way home, and often talk nonsenseFour and a half years later, the patient died of a worsening condition< br / > with the consent of the patient's family, DrAlzheimer dissected the bodyAfter careful observation under the microscope, he found that the brain section of the patient had two obvious characteristics: amyloid deposition and neurofibrillar tangleIn November 1906, at a scientific conference in Tubingen, Germany, DrAlzheimer reported the case and his findingsIn 1910, psychiatrist DrEmil Kraepelin named the disease Alzheimer's disease (AD)< br / > as a serious neurodegenerative disease, ad is like an eraser, which will erase one's mind and memory little by littleAccording to statistics, there are about 50 million AD patients in the world and more than 10 million AD patients in ChinaWith the acceleration of population aging, ad not only makes the patients miserable, but also brings heavy disease burden to the whole societyIt is worrisome that ad is not easy to deal withIn the fight with it, a wave of therapies have been defeated< br / > however, the fire of hope has not been extinguished The Pittsburgh based company, alignment therapeutics, is now developing an innovative small molecule therapy, which is expected to make a comeback in this difficult battle This week, the National Institute of aging (NIA), a unit of the National Institutes of Health (NIH), funded nearly $76 million to carry out its phase 2 clinical trial of ct1812 in research for Alzheimer's disease In the communication with the content team of Wuxi apptec, Kenneth moch, former president and CEO of alignment therapeutics company, introduced their R & D ideas in detail, which brought us enlightenment worthy of reference What is the cause of ad? Mr Kenneth moch said that the problem is very complex, which may be affected by many factors, such as genetic susceptibility, environmental inducement, nervous system damage, etc., but the current knowledge is quite limited, and the evidence obtained is still in the early stage, which needs to be further explored < br / > although ad related research has shown a leap forward trend in recent years, and led to a sharp increase in the number of compounds in preclinical and early clinical development, Mr Kenneth moch pointed out that from the perspective of development, late clinical trials generally performed poorly, and almost all new therapies related to ad met Waterloo, so the development of new ad drugs is very difficult < br / > in order to avoid the crater that the predecessors stepped on, the company chose to take a new path: developing small molecule drugs to restore and protect brain health and function, the cornerstone of synapses "Synapse is the 'basic unit' of brain function In the brain, the structure of synapses determines who we are, how we act and perceive ourselves, how we learn and evolve Simply put, unlike other organ systems or tissues in the human body, the function of the brain is inextricably linked to synapses To some extent, the number of synapses in the brain determines the ability of memory and cognition The loss of synapses is like the end organ damage of other organ systems " Mr Kenneth moch said < br / > through unremitting efforts, the research team of cognition company has created an innovative oral small molecule drug ct1812, which is expected to protect synapses from the neurotoxic cascade reaction triggered by β - amyloid (a β) oligomer and improve cognitive ability < br / > ▲ in the brain of AD patients, the abnormal deposition of β - amyloid protein (image source: NIH) < br / > many genetic evidences reveal that β - amyloid protein is probably one of the potential culprits of AD, and its oligomeric form has strong synaptic toxicity Ct1812 is a small molecule with high permeability into the brain Unlike previous attempts to directly target a β oligomer (or its precursor), it chooses to bind to sigma-2 receptor complex The interaction between ct1812 and sigma-2 results in the replacement of a β oligomer in the receptor target of synapse < br / > Mr Kenneth moch further explained: "ct1812 can regulate the sigma-2 receptor complex, the key multi protein regulator of oligomer receptor, through allosteric effect This makes the binding site of a β oligomer unstable, which leads to the increase and substitution of a β oligomer and its rapid clearance to CSF It's a bit like a Newtonian pendulum, when a metal ball hits a ball, it moves the ball off the other side " < br / > In October 2017, the US FDA awarded ct1812 fast track qualification "We have observed positive results in preclinical mouse ad models, and have also conducted preliminary studies in patients with mild to moderate ad currently, we are conducting phase 2 clinical studies for further testing." According to Mr Kenneth moch, there are many challenges in the development of new ad drugs, such as the heterogeneity of patients, the subjectivity and inaccuracy of clinical end-point design, the difficulty for many elderly patients to participate in clinical trials for a long time due to their own reasons, etc < br / > how to improve the possibility of success of ad test drug under the pressure of layers? In his view, an important improvement might be to "set up new clinical endpoints": from the outside, they may be based on new digital tools; or from the inside, they may be based on a more accurate understanding of the components of learning and memory, such as the number of synapses As part of its efforts, cognition has formed a "synaptic health endpoints working group" to explore and evaluate the potential endpoints of new ad drugs based on synapses < br / > how will ad drug development develop in the next 5 to 10 years? What is the best treatment mode? In this regard, Mr Kenneth moch believes that with the deeper understanding of AD (just like the human understanding of cancer and the continuous evolution of cancer therapy), its treatment may be realized through drug combination The key early step is to identify the biomarkers and genetic markers of ad susceptibility, which will have a significant impact on the ability to develop new drugs to treat ad < br / > He concluded < br / > The furthest distance in the world may not be life and death, but mutual dependence, but no longer acquaintance Indeed, in many people's eyes, ad is the cruelest disease in human history, because it will deprive all good memories < br / > it is an undeniable fact that in the hundred years' struggle with AD, human beings have experienced too many failures and setbacks However, as long as we work hard, there will be hope We hope that cognition and its innovative small molecule therapy can bring more good news and turn the fortunes of millions of AD patients < br / > References: < br / > [1] alignment therapeutics: undated warrior in the battle against Alzheimer's retrieved January 14, 2019, from < br / > [2] alignment therapeutics receives fast track design from U.S FDA for first in class Alzheimer's candidate, ct1812 Retrieved October 16, 2017, from [3] [4] Cognition Therapeutics Receives $75.8 Million NIA Grant for 540-Patient Phase 2 Study of CT1812 in Collaboration with the Alzheimer’s Clinical Trials Consortium, Retrieved June 8, 2020, from ▽