Two parents’ quest to save the lives of their twin daughters from a rare, degenerative genetic disorder could ultimately save and improve the lives of millions.
After sifting through medical literature and piecing together bits of data, the non-medically trained couple contacted German researchers and suggested that a chemical called cyclodextrin may be able to treat atherosclerosis — the hardening of arteries with cholesterol-rich plaques, which is a precursor of heart attack, stroke and other cardiovascular diseases.
Following up on the parents’ hypothesis, the researchers, Eicke Latz of the University of Bonn, and colleagues found that in mice, cyclodextrin did indeed block plaque formation, melt away plaques that had already formed in arteries, reduce and revitalize atherosclerosis-associated inflammation. increase cholesterol metabolism – even in rodents fed high-cholesterol diets. In petri dish-based tests, the researchers found that the drug appeared to have the same effects on human cells and plaques.
The findings, published Wednesday in Science Translational Medicinesuggest that cyclodextrin – a drug already approved for use in humans by the U.S. Food and Drug Administration – may be highly effective in treating and preventing heart disease.
Currently, cardiovascular disease is the leading cause of death worldwide, and about 43 percent of Americans have high cholesterol, which can lead to atherosclerosis. Typical treatments include statins and other cholesterol-lowering medications, which are not always effective, especially when patients do not adhere to physician-prescribed cholesterol-lowering diets.
While Latz and co-authors stress that clinical trials are needed to validate cyclodextrin’s effects, the researchers note that it would be fairly easy to reuse the drug to treat and prevent cardiovascular disease.
But while the road ahead of cyclodextrin may be clear, the road to medical treatment has been strangely bumpy.
Sweet solution?
The chemical, which is simply a bunch of sugar molecules gathered in a ring, is already widely used in medicines and foods. Because the outside of the ring is hydrophilic (it mixes with water) and the inside of the ring is hydrophobic (it doesn’t mix with water), cyclodextrin can trap chemicals in the ring and help them mix into medicines and foods. In medicines, cyclodextrin acts as a ‘carrier’ that ensures that active medicines dissolve better in the body. Cyclodextrin is also used in foods, such as mayonnaise, candy and butter, to stabilize flavors and emulsifiers and to remove cholesterol. But beyond its role as an additive, it has been largely overlooked by researchers.
One of the first inklings of cyclodextrin’s therapeutic potential came in a 2004 scientific publication. Researchers were looking for a treatment for an extremely rare genetic disorder called Niemann-Pick type C disease (NPC), which is likely to affect only a few hundred patients in the US. The disease is caused by a genetic mutation that breaks down a protein responsible for carrying cholesterol into cells. Since cholesterol is an essential building block for cell membranes and various organic molecules, its transport through the body and cells is crucial to good health. In the absence of a functioning transporter, cholesterol gradually builds up in cells throughout the body, causing organ dysfunction, neurodegeneration and eventually death.
NPC is sometimes referred to as childhood Alzheimer’s disease because children with the disease are often diagnosed after they develop symptoms similar to dementia, including worsening memory, balance, and verbal skills.
In the 2004 study, researchers presented data that a neurosteroid — administered with the carrier cyclodextrin — appeared to help mice genetically engineered to have a broken cholesterol transporter. A single dose, the researchers found, doubled the life expectancy of the mice.
While other researchers rushed to repeat the experiment, confirming the finding, it took several years for researchers to figure out what was really going on: that the neurosteroid had no effect on the mice at all – it was the cyclodextrin.
Enter the Hempels
As researchers rolled out data on cyclodextrin, a couple named Chris and Hugh Hempel in Reno, Nevada, paid close attention. In 2007, their twin daughters, Addi and Cassi, then three years old, were diagnosed with NPC. With doctors repeatedly telling them there was nothing they could do, the parents continued to delve into the research and search for a cure.
They found cyclodextrin and initially tried using it in oral doses, which are known to be safe. However, the chemical could not effectively reach the brain that way. The couple made headlines for their tireless efforts to get drug companies, the FDA and doctors to try intravenous cyclodextrin treatments for their twins – and they won. Regular treatments gradually improved the twins’ condition, although she was not cured. Cyclodextrin is now in clinical trials to treat other children with NPC.
Meanwhile, Latz and colleagues published a study in 2010 Nature showing that cholesterol crystals, which build up along arteries when there is too much cholesterol in the bloodstream, can cause inflammation. The immune response then produces a snowball effect that eventually leads to the development of plaques — layers of cholesterol crystals, immune cells, and calcified lesions in the artery wall. After reading the study, Chris Hempel contacted Latz and told him about their experience using cyclodextrin to remove cholesterol from cells. Perhaps the sweet chemical can help clear it of plaques, too.
In mice fed a high-cholesterol diet, cyclodextrin cleared plaques and helped prevent more plaques from forming, Latz and his colleagues found. The chemical also activated cholesterol metabolism that increased the removal of the waxy substance from the arteries, plus dampened inflammatory responses that drive atherosclerosis.
Using blood vessel tissue from human patients with atherosclerosis, researchers found that cyclodextrin caused the same changes in the human cells as it did in the mice.
The study, co-authored by Hempel, shows that cyclodextrin is a promising new treatment for atherosclerosis in humans, the researchers conclude, all thanks to some motivated parents.
Science Translational Medicine2015. DOI: 10.1126/scitranslmed.aad6100 (About DOIs).