Drug Development Strategy: Three Points of Attack

Posted January 28, 2014

In view of an emerging consensus on how Alzheimer’s disease develops and progresses, the Cure Alzheimer’s Fund Research Consortium aggressively is focusing on three opportunities for possible intervention—at the early stage of the disease, the middle stage and the late stage. This comprehensive strategy addresses the whole picture of how Alzheimer’s disease develops and progresses, and attacks all three points simultaneously.

What we know

For too long, Alzheimer’s research has been distracted by arguments over “plaques” vs. “tangles.” Some thought the key to treatment was clearing plaques, while others argued that eliminating tangles would cure the disease. Most researchers now agree it is necessary to attack both plaques and tangles, as well as other elements of the pathology, to stop the disease’s progression.

The Research Consortium now shares the understanding that Alzheimer’s is a vicious cycle of destruction that begins with the production of excessive beta-amyloid peptides (Abeta) that aggregate into clusters called “oligomers,” then proceeds to the creation of tangles from the protein tau that originate inside cells but that recently have been shown to spread to other cells. Both of these create inflammation in the brain, which stimulates more creation of Abeta, thus continuing a cycle that is deadly for brain cells. This destructive cycle can be envisioned as follows:

Intervention point – A

Early stage

Ideally, this cycle would be stopped at what is thought to be its origin: the overproduction of the protein Abeta. This approach has been pursued broadly for a number of years, so far to little avail. Some drug candidates have proven too toxic; others were ineffective at safe doses. Recent research led by Robert Moir, Ph.D., of Massachusetts General Hospital (MGH) and funded by Cure Alzheimer’s Fund has shown the Abeta protein is an important and integral part of the innate immune system, and therefore maintaining an appropriate balance of the protein rather than eliminating it may be the right therapeutic approach.

Consortium researchers are pursuing a number of ways to control Abeta production and clearance. Perhaps the most promising research is taking place in the University of California, San Diego lab of Steven Wagner, Ph.D., and the MGH lab of Rudy Tanzi, Ph.D. Their approach has been to develop drugs to modulate an enzyme called gamma secretase, which is a critical contributor to Abeta production. Their effort has been so successful that the compounds they have developed have been adopted by the National Institutes of Health (NIH) as part of its fast-track, high-priority “Blueprint” program.

“We’re making excellent progress,” reports Wagner. “We have developed a number of compounds and are currently testing them with the hopes of narrowing the list down to one or two clinical candidates.” Tanzi echoes this optimism, saying, “We are hopeful that this project will lead to our gamma secretase modulators in clinical trials over the next year or so.”

Intervention point – B
Middle stage

In concert with efforts to contain Abeta in the earliest possible stage, consortium members also are pursuing strategies that would zero in on the formation and spread of tau tangles. Foremost among these is the effort led by consortium member David Michael Holtzman, M.D., based at Washington University in St. Louis, who recently demonstrated breathtakingly positive results in a proof-of-concept study aimed at stopping the aggregation and spread of tau in the middle stages of the disease.

Holtzman’s study, in collaboration with Washington University’s Marc Diamond, M.D., assembled a variety of potential tau antibodies and introduced them into the brains of genetically engineered mice. Based on a hypothesis that the toxic form of tau gets “spit out” of nerve cells and subsequently “infects” other nearby healthy neurons, the study demonstrated that the antibodies were able to conclusively stop this spreading process; this subsequently led to cognitive improvements in the mice. Their study was published in the journal Neuron in September 2013. The results were “fantastic,” commented the German Center on Degenerative Diseases’ Eckhard Mandelkow, Ph.D., to the Alzheimer’s Research Forum last September. “It explains why antibody therapy might work for tau pathology.”

Intervention point – C

Late stage

Consortium members also are pursuing efforts to curtail Alzheimer’s-related brain inflammation. One of the most promising efforts involves an attempt to inhibit the activity of a gene called CD33. In 2008, Tanzi’s group first discovered this gene’s relationship to late-onset Alzheimer’s in a large family-based, genome-wide association study (GWAS). In 2013, the group described in the journal Neuron the gene’s regulation of immune-response microglial (helper) cells in the aging brain. Microglia normally clear away damaged and unwanted cells in the brain; if they are not functioning properly, damaging inflammation can occur. When Tanzi’s group deactivated CD33 in AD mouse models, more Abeta was cleared away by the microglial cells, leading to diminished amyloid plaque burden and less inflammation.

The Tanzi lab is attempting to develop effective CD33 inhibitors by screening compounds and antibodies that inhibit CD33 function. The compounds showing the most promise will be tested in AD mouse models. “There’s still some work to do here,” says Tanzi, “but interrupting CD33 could turn out to be a powerful therapeutic strategy.”

Following the science

“We follow the science, wherever it leads,” says Cure Alzheimer’s Fund Chairman Jeffrey Morby. “Alzheimer’s is a complex disease and we’re proud to support our Research Consortium in this multipronged effort to defeat it at each stage.”

Want to learn more? David Holtzman, Rudy Tanzi and Steve Wagner will further discuss their research findings in an Alzstream video, moderated by David Shenk, available starting on March 20. The video will be posted at curealz.org and sent out via e-blast to everyone on our mailing list. If you would like to be added, please let us know by emailing us at [email protected].