New Screening Method Answers Why Alzheimer’s Drugs Fail


Drug growth for Alzheimer’s has lengthy been pushed by the speculation that amyloid plaques??shaped by the buildup of amyloid-beta proteins within the mind??are what kill neurons and trigger Alzheimer’s. As a consequence, many analysis efforts have centered on designing medicine that filter these plaques.

“But this approach has not led to a cure or improved dementia in patients. Sometimes it has made the disease worse,” mentioned senior creator Shankar Subramaniam, a professor of bioengineering on the UC San Diego Jacobs School of Engineering.

To perceive why, Subramaniam and his collaborators developed a drug screening methodology that appears at what illness mechanisms, or endotypes, change in sufferers’ neurons on account of therapy. The most generally studied Alzheimer’s endotype is amyloid plaque formation. But there are different endotypes??reported for the primary time by Subramaniam and colleagues in a earlier examine??that additionally warrant consideration. These embody de-differentiation of neurons to an earlier “non-neuron” cell state; suppression of neuronal genes; and lack of synaptic connections.

“This is a new test for measuring whether an Alzheimer’s drug works,” mentioned Subramaniam. “The key here is that we are using the endotypes that we discovered to see how current drugs fail. When drugs interact with human neurons, what endotypes do the drugs fix, and what endotypes do they not fix in the process?”

What’s additionally particular about this methodology is that it screens medicine on precise affected person cells. “The power of this is that you can do precision medicine and have a good model system to study Alzheimer’s,” mentioned Subramaniam.

The methodology includes taking human induced pluripotent stem cells derived from sufferers with familial Alzheimer’s illness, which is a hereditary type of Alzheimer’s, and reworking them into neurons. The researchers deal with these neurons with medicine and use subsequent era sequencing methods to guage what endotypes change earlier than and after therapy. The researchers additionally carry out this drug display screen on neurons derived from wholesome people as a management experiment.

In this examine, the researchers screened two experimental Alzheimer’s medicine that had been designed to cut back or stop progress of amyloid plaques. One was a drug candidate developed by Eli Lilly, referred to as semagacestat, which had failed late-stage scientific trials. The different was a drug candidate developed by Subramaniam’s collaborator and co-author on the examine, Steven Wagner, who’s a professor of neurosciences at UC San Diego School of Medicine.

The researchers discovered that the medicine solely repair some endotypes, such because the formation of amyloid plaques. The medicine additionally partly repair the de-differentiation endotype, by triggering “non-neuron” cells to rework again into neurons. However, this transformation just isn’t full, famous Subramaniam, as a result of the neurons nonetheless lack synaptic connections and subsequently can’t talk with one another.

“Now we have a prescription for what endotypes to target during drug screening,” mentioned Subramaniam. “What we are seeing that is fixing amyloid plaque formation does not reverse the disease in any way. It turns out that this endotype is way downstream, so it’s too late. Once neurons de-differentiate into non-neurons, they lose their synaptic connections , which leads to loss of memory and cognition and as a consequence, dementia.”

“I am very excited to use these novel screening strategies for the Alzheimer’s drugs that are being developed in my laboratory,” added Wagner. “In my experience in industry and now academia, this is the first effort to use multiple endotypes for overcoming the failures of drugs targeted only at amyloid plaques.”

Next, the researchers will consider their drug screening methodology on mind organoids. “We want to take this a step further to screen drugs on more realistic tissues, not just neurons in a dish,” mentioned Subramaniam. The crew may even work on creating new Alzheimer’s drug candidates and screening them with their methodology.

Paper: “Endotype reversal as a novel strategy for screening drugs targeting familial Alzheimer’s disease.”

This examine was supported by the Alzheimer’s Association New Investigator Research Award (NIRG-14-322164), the National Institutes of Health (grants P50 AGO5131, U01 NS 074501-05, U01 AG048986, R01 LM012595, U01 CA198941, U01 DK097430, R01 DK109365 , R01 HD084633 and R01 HL108735), the National Science Foundation (grant STC CCF-0939370), the Joan and Irwin Jacobs Endowment; the Cure Alzheimer’s Fund (CAF), the Veterans Affairs (RR&D 1I01RX002259), and the Chen Foundation.

Source: Eurekalert



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