How SHARE Can Help Find New Drugs
An article that appeared in the New York Times this week gave details of a series of studies that investigated two rare genetic mutations that reduce a type of blood fat called trigylcerides, far below normal levels. Carriers of these genes appear to be invulnerable to heart disease, even if they have other risk factors.
Scientists have been able to utilize this information to develop drugs that have the same effect, which many experts predict will become the next big treatment option for heart disease. Dr John Kastelein, a professor of vascular medicine at the University of Amsterdam, said that alongside existing treatrments such as cholesterol-reducers and blood pressure medications, these new drugs "will drive the final nail in the coffin of heart disease."
Currently these news drugs are in the early stages of development with human trials only just beginning. The positive predictions from the researchers involved comes from the fact that nature has produced strong evidence they should work, rather from clinical trial data.
Case evidence of nature at work comes from Mrs Anna Feurer from St. Louis who in 1994, gave a blood sample at a health fair organised by her employer, so that her cholesterol levels could be measured. The company doctor found that her triglyceride levels were abnormally low, along with her LDL (low-density lipoprotein) levels which raises the risk of developing heart disease, and he encouraged her to see a specialist.
Mrs Feurer recalled in an interview that "It was all an accident," that her single blood sample could lead to the development of new treatments. The specialist she ended up seeing was Dr Gustav Schonfeld at Washington University in Saint Louis. He asked whether she and others in her family would participate in a research study. Mrs Feurer agreed and so did her immediate family, plus a couple of her cousins and aunts.
The results were varied with some displaying the same extremely low levels of triglyceride, whereas others had normal levels, and others inbetween. Dr Schonfeld tried to locate the gene for years but failed and unfortunately passed away in 2011.
In 2009 Dr Schonfeld had sent Mrs Feurer's DNA to Dr Sekar Kathiresan, a cardiologist at Massachusetts General Hospital. He discovered that she carried mutations in both copies of a gene called ANGPTL3, which is involved in the metabolism of triglyceride. (Each individual carries two copies of a given gene, one from each parent.)
The results from the rest of the family showed that 3 of her 9 siblings also had no working copy of the gene and extremely low levels of triglyceride. Three others had one mutated gene and one normal gene which resulted in them having low triglyceride levels but not significantly low as those with no functioning gene. The last three members of her family that were in the study all had 2 normal copies of the gene and normal triglyceride levels.
The question that was asked by Dr Daniel Rader of the University of Pennsylvania, who is an author of 3 of the recently published studies was "Does this loss-of-function mutation translate into a reduced risk of heart disease?"
Dr Nathan O. Stitziel, a cardiologist at Washington University in Saint Louis, said that the evidence so far was that people with this gene mutation seemed to be protected from coronary events. Dr Stitziel and his team carried out scans and found that their coronary arteries were free of plaque and reported their findings in the Journal of the American College of Cardiology.
One of the siblings that had these mutated genes had risk factors that are normally associated with heart disease such as smoking, high blood pressure and Type 2 diabetes, yet there was no plaque in his arteries. Dr Stitziel went on to lead an international group of researchers who looked for mutations that destroyed the gene in 180,180 people. It was a rare event, occurring in just 1 in 309 people. But Dr Stitziel and his colleagues discovered the mutation reduced heart attacks by a third.
The second line of evidence for these new drugs originated with a study of Old Order Amish in Lancaster, Pa. About 5% appeared to have arteries that were clear of plaque and low levels of triglycerides. As it turned out, these people had inhherited a single copy of another gene related to triglyceride production called ApoC3. This led researchers to want to find people that had inherited 2 mutated copies to see whether short-circuiting the gene might be safe.
They began by searching genetic data collected from more than 200,000 people around the world but this approach did not prove fruitful. They then tried a different strategy by focusing on participants already enrolled in a heart disease study in Pakistan, where first cousins often marry and mutations such as the one they were looking for, are more easily inherited.
This approach was successful and the researchers identified more than 100 people in Pakistan who had mutations in both ApoC3 genes. This group were found to be healthy with low levels of triglycerides. These findings were reported in the journal Nature last month.
These discoveries have led companies to start testing experimental drugs that mimic a loss of ApoC3 by blocking the ApoC3 protein. In addition, 2 companies, Regeneron and Ionis Pharmaceuticals, are now testing drugs based on the mutations in the same gene that was found in the Feurer family, company scientists and academic resaearchers reported in The New England Journal of Medicine.
Both companies reported that in these initial tests, drugs that are based on these mutations reduced triglycerides in people with elevated levels. Both also reported that studies of the drugs in mice showed that the drugs protect the animals from heart disease.
What it comes down to is that "reductions in triglycerides with these things is pretty unprecedented," George Yancopoulos, President and Chief Scientific Officer at Regeneron explained. Still it is not yet clear to what extent this will prevent heart attacks.
Even more significant may be the way in which these drugs were identified. Finding people who are impervious to a disease like heart disease can open a door to letting the rest of the population share their genetic luck.
"It's a huge advance," said Dr Christie Mitchell Ballantyne, chief of cardiology and cardiovascular research at Baylor College of Medicine and a consultant for Regeneron (although not for the triglyceride studies). "That doesn't mean it's easy." Still, he added "what we are seeing is a new approach towards drug development."
You can help play your part in creating the treatments of the future by joining the SHARE register today.