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Addressing Unmet Needs: The Science Behind Rare Cholesterol Diseases

Translational Research in Action

Smilow Center for Translational Research

In the spring of 2011, Penn celebrated the opening of the Smilow Center for Translational Research – a new home for Penn Medicine's emphasis on translating breakthroughs in the lab to clinical therapies for patients. The story profiled here is just one example of such research at Penn.

See more stories in this series.

How the rare informs the common is becoming a – well – more common theme in biomedical research. Working with people who have rare genetic conditions provides researchers with a unique window into learning the role specific genes play in more common diseases.

“Relating insights concerning the genetic basis of disease to the identification of novel therapeutic targets and then developing new therapies that address unmet medical needs is one hallmark of translational medicine,” explains Daniel J. Rader, MD, professor of Medicine and Pharmacology, and associate director of the Institute for Translational Medicine and Therapeutics at the Perelman School of Medicine at the University of Pennsylvania.

He should know. In the past two years, using genome-wide approaches, Rader and colleagues have found many novel genes that are clinically relevant and important determinants of heart disease risk. For example, a region on chromosome 1 encoding a gene called sortilin is one of the strongest genetic determinants of blood levels of “bad” cholesterol and is also strongly related to risk of heart attacks.

But Rader’s research on a rare genetic disorder of extremely low cholesterol – abetalipoproteinemia – is already being translated into a new therapeutic approach for another rare inherited disease of extremely high cholesterol - homozygous familial hypercholesterolemia (FH).

What’s more, the study of homozygous FH provided a scientific foundation for developing statins, which remain one of the biggest advances in all of clinical medicine over the past two decades, adds Rader.

First, A Little Background
Homozygous FH patients have a five- to ten-fold increase in blood levels of low-density lipoproteins (LDL), the “bad” cholesterol, compared with the general population. They inherit two mutant genes for the LDL receptor, one from each parent. Receptors are proteins on the surface of a cell, which receive chemical signals that instruct a cell to complete a specific task.

FH patients do not respond effectively to the usual treatments for elevated cholesterol, such as statins, and heart attacks often occur in childhood or adolescence. 

In the 1970s, Joseph L. Goldstein and Michael S. Brown, from the University of Texas Southwestern Medical Center at Dallas, showed that FH is caused by mutations in the gene that encodes the LDL receptor. They went on to win the Nobel Prize in 1985 for this work. (Dr. Brown recently gave a talk, “Partnerships, Puzzles and Paradigms: A collaborative approach to cholesterol,” at Penn as part of the AstraZeneca Nobel Medicine Initiative Lecture Event on 12 May 2011.)

“We now take for granted that high cholesterol causes heart disease. However, this was not always the case, and translational research on homozygous FH proved the relationship between LDL and heart disease,” says Rader.

Statins lower LDL in most people. However, many people (dramatically emphasized by homozygous FH patients) need additional treatments because statins do not lower cholesterol enough. Also, says Rader, at least 3 to 5 percent of people on statins develop muscle pain and have to stop using them.

In healthy people, LDL receptors in the liver remove LDL from the blood. Standard drug therapies, such as statins, work by increasing the number of LDL receptors. Homozygous FH patients - who lack LDL receptors - do not respond well to statins. The only effective therapy for these patients is LDL apheresis, an invasive and time-consuming procedure that involves physically removing excess LDL from the bloodstream and must be repeated every one to two weeks. With over 30 patients, Penn has the largest LDL apheresis program in the United States, which is run by the Department of Pathology and Laboratory Medicine. LDL apheresis remains the standard of care for patients with homozygous FH. For an overview of the program read this issue of Penn Medicine

Without apheresis, many patients die before 30 due to cardiovascular disease. With LDL apheresis, some patients live longer, though still develop serious symptoms. But, LDL apheresis is far from a cure.

Daniel Rader, MD
Because Rader has cared for a few dozen patients with homozygous FH while at the NIH and Penn, he has always been interested in the concept of developing new therapies. Ironically, his work with patients with a different cholesterol disorder - abetalipoproteinemia - provided the impetus for the development of a new therapy for homozygous FH. This research led to the discovery of a protein that allows fats to be absorbed and transported in the body, which could potentially function as a therapeutic target for FH.

Help From Another Rare Disease
Abetalipoproteinemia is a rare inherited disease characterized by extremely low levels of blood cholesterol. Essentially LDL is absent in the blood. At the NIH in the 1990s, Rader cared for several patients with abetalipoproteinemia and was part of a collaborative research team that discovered the gene responsible for abetalipoproteinemia, the microsomal triglyceride transfer protein (MTP) gene.

They learned that a defect in both copies of the MTP gene prevents the liver from creating LDL. “It was not surprising to discover that these patients have overall low cholesterol and a total absence of LDL cholesterol,” explains Rader.  “The study of abetalipoproteinemia gave us tremendous insight into the human physiology of LDL production and the absolutely key role of the MTP protein in this process.”

Based on this finding, colleagues of Rader’s at Bristol Myers Squibb developed the first inhibitor of MTP and showed that it successfully reduced LDL levels in animal models, including a rabbit model of homozygous FH.

Rader collaborated with these investigators to test their MTP inhibitor in patients with moderately elevated LDL levels and showed that it was dramatically effective in reducing LDL. However, certain side effects led BMS to abandon development of the drug. At this point, Rader convinced BMS to donate the drug to Penn so that he could test it in patients with homozygous FH. Based on its mechanism and on the study in FH rabbits, Rader was convinced it would be effective in homozygous FH.

A donation of the drug by BMS and funding from the Doris Duke Charitable Foundation allowed for a Phase II proof-of-principle trial in six patients with homozygous FH. In contrast to previous studies, the drug was started at very low doses and gradually taken to higher doses. This trial was highly successful and was ultimately published in the New England Journal of Medicine in 2007.

Marina Cuchel, MD, PhD, research assistant professor of Medicine and co-investigator of the study, emphasizes that the MTP inhibitor lowered LDL cholesterol levels in six homozygous FH patients by about 50 percent, considerably greater reduction than any previous therapy for this condition.

“We were happy with these results, but needed to be cautious about the effects of the drug on the liver and patients’ overall ability to tolerate it,” says Cuchel. The success of this initial study led the FDA Orphan Drug Program to fund a larger long-term phase III drug trial of the MTP inhibitor, now called lomitapide, being led by Cuchel.

An international phase III study of lomitapide, co-funded by the FDA Orphan Drug Program and by Aegerion Pharmaceuticals, is evaluating the safety and efficacy of lomitapide in homozygous FH patients. Research sites are scattered worldwide in the United States, Canada, South Africa, and Italy and the trial is fully enrolled at 29 patients. Interim analysis suggests that the average reduction in LDL cholesterol is about 45 to 50 percent, similar to that seen in the phase II trial.

“So far the results are encouraging,” says Cuchel. The long-term efficacy of lomitapide was confirmed in this second trial, but it is still too early to say anything definitive about long-term safety. The researchers hope it will eventually receive FDA approval. For now they are developing it specifically as an ‘orphan drug.’

“I believe that lomitapide could have a potential benefit for a broader patient population when given at lower doses in combination with other treatments,” says Cuchel.

“The study of human genetics and the discipline of translational medicine and therapeutics are intimately linked,” says Rader. “Penn is poised to be an international leader to bridge these cutting-edge disciplines.” Musunuru K, Strong A, Frank-Kamenetsky M, Lee NE, Ahfeldt T, Sachs KV, Li X, Li H, Kuperwasser N, Ruda VM, Pirruccello JP, Muchmore B, Prokunina-Olsson L, Hall JL, Schadt EE, Morales CR, Lund-Katz S, Phillips MC, Wong J, Cantley W, Racie T, Ejebe KG, Orho-Melander M, Melander O, Koteliansky V, Fitzgerald K, Krauss RM, Cowan CA, Kathiresan S, & Rader DJ (2010). From noncoding variant to phenotype via SORT1 at the 1p13 cholesterol locus. Nature, 466(7307), 714-9 PMID: 20686566

Cuchel, M., Bloedon, L., Szapary, P., Kolansky, D., Wolfe, M., Sarkis, A., Millar, J., Ikewaki, K., Siegelman, E., Gregg, R., & Rader, D. (2007). Inhibition of Microsomal Triglyceride Transfer Protein in Familial Hypercholesterolemia New England Journal of Medicine, 356(2), 148-156 DOI: 10.1056/NEJMoa061189

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