Targeted therapies to treat high cholesterol

September is Heart Awareness Month and South Africans have real cause for concern, due to both lifestyle and genetic risk factors.

Cardiovascular disease, which could lead to a stroke or heart attack, is often associated with obesity, high blood glucose levels, high blood pressure and high cholesterol. These measurable symptoms are in turn associated with an unhealthy lifestyle that includes a diet loaded with sugar, salt and saturated fat, a lack of exercise and smoking.

Unfortunately, more and more South Africans have begun living a westernised, busy life with plenty of fast food and little in the way of exercise. In addition, South Africa has the highest incidence of inherited cholesterol, or familial hypercholesterolemia (FH), in the world, with Afrikaans and Indian populations worst affected.

Professor Derick Raal, an endocrinologist and researcher based at the Charlotte Maxeke Johannesburg Academic Hospital, has a particular interest in FH and new therapies that can be used to treat this genetic disease.

He also sees patients suffering from lifestyle-related high cholesterol daily, and has been involved in anti-cholesterol-drug trials since the introduction of statins in the 1980s.

“Statins are remarkable drugs,” says Raal. “They work by increasing the ability of cells to take up cholesterol from the bloodstream, by increasing the number of cholesterol receptors on the surface of the cell.”

Raal describes these receptors as tiny arms, which reach out to find and grab cholesterol molecules when the cell needs it.

But not all patients with high cholesterol respond to statins. For some, the drugs can cause muscle pain and other side effects. And for FH patients, who produce four times more cholesterol than what is considered normal, and whose cells may have deformed or no cholesterol receptors, statins don’t really work at all.

As a result, Raal and other cholesterol researchers have recently turned their attention to two novel and revolutionary drugs that offer targeted therapy for those who don’t respond well to traditional treatments.

Shoot the messenger

Cholesterol is made in the liver. From there, it is transported around the body in the bloodstream, packaged inside a protein sack called a lipoprotein (low-density lipoprotein, or LDL, is known as “bad” cholesterol, and high-density lipoprotein, or HDL, is the “good” cholesterol).

The body needs some cholesterol because it is an essential building block of other hormones and the lining of every cell, but too much in the arteries can lead to cardiovascular disease. One way to lower high cholesterol is to cut off production at the source – the liver.

“This is where anti-sense technology comes in,” says Raal.

The main component of the lipoprotein sack that transports cholesterol is a protein known as ApoB. Like all proteins, ApoB is manufactured by the cell’s transcription and translation machinery: the ApoB gene on the DNA is transcribed into messenger RNA (mRNA), which is translated into the final ApoB protein product.

Mipomersen, the first ever anti-sense drug to be approved for clinical use (in early 2013), works by finding and binding specifically to ApoB mRNA, thereby preventing its translation into the functional ApoB protein.

The result is that cholesterol cannot be transported out of the liver, so it is just broken down and expelled from the body.

The advantage of anti-sense technology is that it does not affect the transcription and translation of any other vital proteins in the body, thereby minimising side effects. FH patients who have inherited the condition from both parents, the so-called double-dose patients, show a cholesterol reduction of 30%. “This is huge for them, and the percentage may be higher for other types of patients,” says Raal.

However, Mipomersen is very expensive to produce, so regulatory bodies have recommended it only for double-dose FH patients and for those patients who don’t respond to statins. And, because it is a protein, it must be given by injection (once per week) rather than orally. Unfortunately, local inflammation similar to a bee-sting reaction still occurs at the site of injection.

Disconnect the brakes

A new route of treatment that overcomes many of the limitations of Mipomersen is a monoclonal antibody that seeks out and binds to a protein known as PCSK9.

“When you take a statin to increase cholesterol uptake, it’s like pushing the accelerator of a car to increase petrol uptake into the engine,” explains Raal. “But just like your car, your cells have a brake to prevent too much cholesterol from going into the cell. This brake is known as PCSK9.”

He says about 10 years ago, researchers discovered that some people have nearly undetectable cholesterol levels naturally. Upon further investigation, they realised these individuals did not produce PCSK9 at all, yet lived totally normal lives otherwise.

“So we thought, what if we knock out this brake in people with high cholesterol?” says Raal.

Monoclonal antibodies that hone in on and mark PCSK9 for destruction, much like a targeted missile, are now in Phase III clinical trials. These molecules are generally produced in animals or eggs by stimulating an immune response against the human PCSK9 protein.

This immune response is also genetically tweaked so that antibodies compatible with humans will be created, ensuring that there is no allergic reaction when the therapy is administered to human patients.

While these novel technologies are life-saving options for FH patients, they, along with statins, must not be considered a quick-fix option by the general population, warns Raal.

“People think they can just take a pill or get a jab. That’s why we see so much more diabetes and other diseases of lifestyle,” he says. “The best option is prevention through eating a healthy, balanced diet, obtaining an ideal body weight by exercising, and quitting smoking.”

Professor Derick Raal heads the Division of Endocrinology and Metabolism at the Charlotte Maxeke Johannesburg Academic Hospital, and runs the Carbohydrate & Lipid Metabolism Research Unit in the School of Clinical Medicine at the University of the Witwatersrand.