MassGeneral Hospital for Children News

“This is the largest collection of familial Alzheimer’s whole-genome sequences in the world,” Dr. Tanzi says, comprising half a petabyte of data, equivalent to the entire contents of the Library of Congress. “This is as big as big data gets.” 

Alzheimer’s Disease Gene Discovery & Drug Discovery

11/Dec/2013

For Top Alzheimer’s Researcher, Drug Discovery Follows Gene Discovery

Rudy TanziRudy Tanzi, PhD, co-discovered the first three genes for familial Alzheimer’s Disease, and as Director of the Genetics and Aging Research Unit at Massachusetts General Hospital, he has spent the past 20 years finding yet more clues to the causes of the disease. He is now embarked on the largest gene hunt the Alzheimer’s field has ever seen: poring over the entire genome sequences from almost 1,500 familial AD patients, searching for gene variants that tilt toward risk or protection in those most at risk for developing the disease. “This is the largest collection of familial Alzheimer’s whole-genome sequences in the world,” Dr. Tanzi says, comprising half a petabyte of data, equivalent to the entire contents of the Library of Congress. “This is as big as big data gets.” 

The data were generated as part of the Cure Alzheimer’s Fund Alzheimer’s Genome Project, headed by Dr. Tanzi at MGH. The Alzheimer’s Genome Project is only the latest from Dr. Tanzi’s lab, a world leader not only in the discovery of AD genes, but also in understanding their mechanisms and translating that understanding into therapeutic strategies. “With every gene we find, the next step is what is the defect, or what is the change that protects you,” Dr. Tanzi says. “Based on that, we do drug discovery, to fix the defect or mimic the protective effect.”

Amyloid Targeted from Multiple Directions

He is also currently developing two drugs based on his earlier discoveries. Beta amyloid is generated from the amyloid precursor protein (APP) when it is serially cleaved by beta- and gamma-secretase. But inhibiting gamma-secretase altogether is not a viable strategy for AD, since the enzyme has many other substrates whose products are needed for normal brain function. Instead, Dr. Tanzi is developing enzyme modulators, which will allow it to cleave its other substrates, while reducing the cleavage of APP that produces the most toxic peptide, a-beta 42. With support from the National Institutes of Health, Dr. Tanzi and colleagues at the University of California at San Diego are currently shepherding these modulators through the preclinical stages of drug development.

The second drug targets the interaction of beta-amyloid with copper. “The mechanism we discovered is that copper drives aggregation of beta-amyloid, and also mediates its toxicity by driving the generation of free radicals”. The drug, PBT2, has already completed one successful phase II trial in 2008, and is currently in a second phase II trial in AD. Specifically, it disrupts the interaction of beta-amyloid with copper, stripping copper away from beta-amyloid to redistribute the metal to its normal tissue locations, while also neutralizing the toxicity of beta-amyloid. The same mechanism is at play in Huntington’s Disease, where a phase II trial has just been completed, with results expected in early 2014. The drug is being developed by the Australian company, Prana Biotechnology.

Dr. Tanzi has also studied the alpha-secretase ADAM10, showing that in addition to its known site of cleavage within the amyloidogenic region, it also cleaves APP in the middle of the protein. This follows on his recent discovery that certain rare ADAM10 mutations elevate levels of beta-amyloid in some cases of late-onset familial AD. In a more recent paper, these mutations were validated to be pathogenic in animal models of AD. These are the first new AD mutations to be validated as pathogenic since those in the original early-onset AD genes in the 1990s. “We are using those mutations to learn how to modulate the enzyme, to favor the good clip. We don’t have a drug there yet; we are just beginning that road to drug discovery.”

Successful treatment of Alzheimer’s Disease is likely to come from multiple drugs given at different stages of the disease, he says. Gamma-secretase modulators are likely to be most useful very early, to prevent build-up of amyloid. Drugs that break up or detoxify amyloid could be useful for the early to middle stages. But recent work from Dr. Tanzi’s lab indicates that later in the disease process, neuroinflammation is a major mediator of neuronal loss, possibly more so than amyloid.

Tanzi’s genome-wide association study identified the microglial transmembrane protein CD33 as a risk factor for AD in 2008. It is now clear from work by Dr. Ana Griciuc in Tanzi’s lab that CD33 is a signaling molecule that triggers microglia to switch from neuroprotective to neurotoxic activity. Increasing expression of the protein leads to accumulation of a-beta 42, and knocking out the protein reduces the levels of insoluble a-beta 42 and amyloid plaque burden in mice. “A drug that safely blocks CD33 should be particularly useful for a patient with full-blown Alzheimer’s Disease,” Dr. Tanzi predicts, and a drug screening program to do just that has begun.

“Since our inception, we have operated by asking what genes and proteins matter in the molecular and biochemical basis of the disease.” And now the hunt moves to the next level, searching through whole genomes for subtle genetic changes that influence disease risk, not just in genes, but in the vast majority of the genome that doesn’t code for protein. Results from these studies are likely to begin emerging from Dr. Tanzi’s lab in 2014.


E-mail Us: NeuroBlast@partners.org | Follow us on Twitter | Request a Neurology Consultation or Referral (PDF)

patient

U.S. News and World Report Best Hospitals 2014-2015

U.S. News & World Report ranks Mass General #1 in New England and #2 in the nation based on our quality of care, patient safety and reputation in 16 clinical specialties.

Search the Mass General news archive

Search the archive for previously published news articles, press releases and publications.

View all departments

Departments and Centers at Mass General have a reputation for excellence in patient care. View a list of all departments.