How To Correct Genes That Cause High Cholesterol

U.S. researchers have used nanotechnology plus the powerful CRISPR-Cas9 gene-editing tool to turn off a key cholesterol-related gene in mouse liver cells, an advance that could lead to new ways to correct genes that cause high cholesterol and other liver diseasesNanotechnology is the design and manipulation of materials thousands of times smaller than the width of a human hair.

We’ve shown you can make a nanoparticle that can be used to permanently and specifically edit the DNA in the liver of an adult animal,” said study author Daniel Anderson, an associate professor in chemical engineering at the Massachusetts Institute of Technology.

The study, published  in Nature Biotechnology, holds promise for permanently editing genes such as PCSK9, a cholesterol-regulating gene that is already the target of two drugs made by the biotechnology companies Regeneron Pharmaceuticals and Amgen.

In the study, the scientists were trying to develop a safe and efficient way to deliver the components needed for CRISPR-Cas9, a type of molecular scissors that can selectively trim away defective genes and replace them with new stretches of DNA.

The system consists of a DNA-cutting enzyme called Cas9 and a stretch of RNA that guides the cutting enzyme to the correct spot in the genome. Most teams currently use viruses to deliver CRISPR into cells, an approach that is limited because the immune system can develop antibodies to viruses.

To overcome this, the team chemically modified the CRISPR components to protect them from enzymes in the body that would normally break them down. They then inserted this material into nano-scale fat particles and injected them into mice, where they made their way to liver cells.

In tests targeting the PCSK9 gene, the system proved highly effective, . The PCSK9 protein made by this gene was undetectable in the treated mice, eliminating the gene in more than 80 percent of liver cells, which also experienced a 35 percent drop in total cholesterol, the researchers reported.

High levels of cholesterol can clog arteries, causing reduced blood flow that can lead to a heart attack or stroke.

Source: http://news.mit.edu/

Therapy Stops Atherosclerosis

In what may be a major leap forward in the quest for new treatments of the most common form of cardiovascular disease, scientists at Johns Hopkins report they have found a way to halt and reverse the progression of atherosclerosis in rodents by loading microscopic nanoparticles with a chemical that restores the animals’ ability to properly handle cholesterol.


cholesterol2Cholesterol
is a fatty substance that clogs, stiffens and narrows the blood vessels, greatly diminishing their ability to deliver blood to the heart muscle and the brain. The condition, known as atherosclerotic vessel disease, is the leading cause of heart attacks and strokes that claim some 2.6 million lives a year worldwide, according to the World Health Organization.

A report on the work, published online in the journal Biomaterials, builds on recent research by the same team that previously identified a fat-and-sugar molecule called GSL as the chief culprit behind a range of biological glitches that affect the body’s ability to properly use, transport and purge itself of vessel-clogging cholesterol.

That earlier study showed that animals feasting on high-fat foods remained free of heart disease if pretreated with a man-made compound, D-PDMP, which works by blocking the synthesis of the mischievous GSL. But the body‘s natural tendency to rapidly break down and clear out D-PDMP was a major hurdle in efforts to test its therapeutic potential in larger animals and humans. The newly published report reveals the scientists  have cleared that hurdle by encapsulating D-PDMP into tiny molecules, which are absorbed faster and linger in the body much longer. In this case, the researchers say, their experiments show that when encapsulated that way, D-PDMP’s potency rose ten-fold in animals fed with it. Most strikingly, the team reports, the nano version of the compound was potent enough to halt the progression of atherosclerosis. As well, the nano-packaged drug improved physiologic outcomes among animals with heart muscle thickening and pumping dysfunction, the hallmarks of advanced disease.

Our experiments illustrate clearly that while content is important, packaging can make or break a drug,” says lead investigator Subroto Chatterjee, Ph.D., a professor of medicine and pediatrics at the Johns Hopkins University School of Medicine and a metabolism expert at its Heart and Vascular Institute.In our study, the right packaging vastly improved the drug’s performance and its ability not merely to prevent disease but to mitigate some of its worst manifestations.”

Source: http://www.eurekalert.org/

Nanoparticles Mimic Cholesterol Transporter and Attack Lymphoma

C. Shad Thaxton, of the Robert H. Lurie Comprehensive Cancer Center at Northwestern and member of the Northwestern University Center of Cancer Nanotechnology Excellence, and Leo Gordon, of Northwestern’s Feinberg School of Medicine, led research team that developed a biomimetic High-density lipoprotein HDL – nanostructure. HDL is well-known for its role in protecting the body from developing coronary artery disease, but HDL also helps lymphomas and other cancers acquire the large amounts of cholesterol they need to maintain the structure of their cell membranes as they grow rapidly. Researchers at Northwestern University have taken advantage of this dependency on HDL to create an HDL-mimicking nanoparticle that starves lymphoma cells of cholesterol, triggering them to commit programmed cell death without the use of any other anticancer agent.To create their biomimetic HDL nanostructures, the researchers start with spherical gold nanoparticles that are five nanometers in diameter and add the human protein ApoA1 and two phospholipids found in native HDLs.
nanoparticle mimics cholesterol

Drs. Thaxton and Gordon and their collaborators then treated mice with human lymphomas with the biomimetic HDL nanoparticles. This treatment stopped tumor growth when the tumors were derived from lymphoma cells.

Source: http://nano.cancer.gov/