$7.9 Million NIH Grant Funds 'Disease in a Dish' Genomic Research to Find Root Cause of Heart Attack

Researchers looking to find a root cause for heart attacks and coronary artery disease will soon begin using a novel investigative approach as they work toward preventing the nation's number one killer.

The National Institutes of Health (NIH) has awarded a $7.9 million grant to the Scripps Translational Science Institute (STSI) of The Scripps Research Institute and Scripps Health in San Diego and Sangamo BioSciences (NASDAQ: SGMO) of Richmond, CA, to conduct the nation's first-ever, heart-based "disease in a dish" research.

The study will involve the use of induced pluripotent stem cells (non-embryonic stem cells created from mature cell types, such as skin cells) to recreate participants' own heart artery-lining cells in a dish, along with genome-editing technology aimed at potentially directing certain cells away from a disease state.

Medical research confirms that the human genome's 9p21 "gene desert" region, which everyone possesses, is strongly linked to people's risk of developing heart disease. But researchers don't understand what takes place in this trouble spot that causes some people's cells to eventually become diseased. This portion of genetic code is known as a "gene desert" because there are no genes in this region.

"We're trying to figure out for the first time how this region works and which other parts of the genome or genes it's interacting with to make some people's cells become diseased," said Scripps Research Professor of Translational Genomics Eric J. Topol, the study's principal investigator and director of STSI.

In the study, scientists will recreate artery-lining cells for two distinct patient groups, each totaling approximately 1,000 people. The first group includes those who already have coronary artery disease, which is a precursor to heart attack. The second cohort comprises those who have lived to at least age 80 without any heart disease or other major illnesses.

"We'll take people whose 9p21 region of the genome says they're at risk for coronary artery disease, and then compare the stem cells from that individual to a healthy elderly person who may also have risk in that region, but somehow doesn't have the disease," said Samuel Levy, the study's lead investigator, director of genomic sciences with STSI and professor of molecular and experimental medicine at Scripps Research. "The crux of our research is to figure out which genes, or which other parts of the genome, are interacting with the 9p21 region. There are no genes in the 9p21 region, which is a big part of our challenge."

The "disease in a dish" heart study brings together two emerging research strategies that, to date, have largely developed separately—induced pluripotent stem cells to create relevant cells and a sophisticated genome-editing technology, which acts like scissors to cut and replace pieces of the genome. The research will also leverage extensive data from genome-wide association studies.

"Genome editing allows us to do an experiment no one has ever tried; that is, if you change someone's genetics, can you make their cells revert away from acquiring a disease?" said Levy. "Using zinc finger nucleases (ZFNs) that act like molecular scissors, we can actually take this risk region out of a person's genome and see what happens to his cells if that region is present or absent. This editing allows us to basically recreate the disease or take it away."

Scientists will take skin or blood cells from participants and reprogram them to create induced pluripotent stem cells, which have the capacity to become any cell type in the body. These stem cells then will be transformed into three different types of heart artery-lining cells: smooth muscle cells, endothelial cells, and cardio myocytes.

Researchers will characterize participants' artery-lining cell types as a way of trying to understand how someone with the 9p21 allele of risk ultimately goes on to acquire cells that are diseased. Once scientists understand the cells' underlying biology, they'll employ a genome-editing process using zinc finger proteins to cut the genome and replace parts of it with DNA with a different sequence. This will enable researchers to decipher how this gene desert region functions.

Learning the root defect in the genome would open the door to potentially developing new drugs or identifying existing ones that could help a person's cells revert away from the path of developing a heart attack or coronary artery disease later in life.

According to Topol, this study will address the biggest deficiency in genomics today. "We don't know the so-called functional genomics," he said. "We only know there's this zip code in the genome that's a problem spot, but we don't know what's going on in this zip code of hundreds of thousands of letters. We don't know which is the offending letter or group of letters. Genome editing will allow us to edit each one and analyze which ones are the culprits."

Send comments to: mikaono[at]scripps.edu

"We're trying to figure out for the first time how this region works and which other parts of the genome or genes it's interacting with to make some people's cells become diseased."
— Eric J. Topol