Catherine Boileau: Exploring Familial Hypercholesterolemia

For almost 40 years, biochemistry and genetics have fascinated Catherine Boileau, two disciplines which she brings together to further knowledge of conditions such as familial hypercholesterolemia and Marfan syndrome. The researcher was awarded the Lefoulon-Delalande Foundation Scientific Grand Prize for having co-discovered in 2003 the role of gene PCSK9 in cholesterol metabolism.

Some scientists are like explorers, keen to seek out new trails where others thought there was nothing left to find. Catherine Boileau*, cardiovascular diseases specialist, is that sort of scientist. In the 1990s, we thought we knew everything about cholesterol metabolism and familial hypercholesterolemia - a hereditary disease characterized by high levels of the "bad" cholesterol, LDL. When these lipoproteins are not eliminated correctly, they build up in the vessel walls and lead to the formation of deposits known as "atheromas", responsible for myocardial infarction and stroke.

Catherine Boileau
Catherine Boileau. Crédits : Inserm/François Guénet

 "Back then, the paradigm was that of a highly-elucidated disease. But a few of us colleagues felt that some of the puzzle pieces were missing", recalls the researcher. And they were right: in 2003, they discovered PCSK9, a new gene implicated in cholesterol metabolism. It ensures the synthesis of the enzyme of the same name - hitherto unknown - and whose neutralization reduces LDL levels. A cross-border discovery. In France, Boileau and her team follow up families affected by familial hypercholesterolemia and are studying, in particular, a region of chromosome 1.

"The human genome hadn’t yet been fully sequenced. To unearth an interesting gene, we had to do almost everything by hand, explore a given region of the chromosomes until we found what we were looking for... There were many failures, it was really frustrating. A PhD student of mine, Marianne Abi Fadel, now Dean of the Faculty of Pharmacy in Beirut, Lebanon, was of invaluable help in this thankless task", explains Boileau. Across the Atlantic, Nabil Seidah, biochemist at the Montreal Clinical Research Institute, had with his colleagues discovered an enzyme expressed in the liver, kidneys and intestines, and whose gene is present in a specific region of chromosome 1. A finding which him to Boileau. And bingo! PCSK9 (previously known as NARC-1) was indeed the gene which, when mutated, is implicated in familial hypercholesterolemia. The development of new treatments could begin.

A treatment undergoing a phase III clinical trial

Fifteen years later, it is almost a done deal: a therapy is being tested in a phase III clinical trial setting to compare its efficacy with that of a standard treatment on a broad population of patients. In May 2018 came the reward: Catherine Boileau, Nabil Seidah and Helen Hobbs, from the University of Texas Southwestern Medical Center in the US, were nominated joint winners of the Lefoulon-Delalande Foundation Scientific Grand Prize for their discovery of PCSK9. "Being able to make such rapid progress was to some extent thanks to a French particularity driven by Inserm, which is to facilitate interactions between research and the clinic. This connection meant we could study the genetic familial aspects of familial hypercholesterolemia more easily", comments the researcher.

To understand the "exploratory" approach of Boileau, we need to go back several decades to her university years. "I had an extraordinary biochemistry professor and I started to become captivated by organic chemistry and biochemistry. I liked the logic inherent to these disciplines, the way in which the metabolic pathways work, with a watchmaker’s precision: they’re the wonders of invention!" she says. But the researcher wanted to dig deeper: she was also fascinated by genetics and the "mathematical side" of the laws of gene transmission. Accepted for a pharmacy internship in Paris in 1980, she later became a clinical lecturer (AHU) at Ambroise-Paré Hospital in Boulogne-Billancourt, a role she held until 1989. "I thought I was going to devote my career to biological analysis, but two successive turns of events decided otherwise. First of all in 1987 when, alongside Philippe Sansonetti, currently a Unit Director at Institut Pasteur, I discovered what scientific research is. Then when I met Claudine Junien, specialist in medical genetics, who suggested I do a thesis… in human genetics!" explains Boileau. With the emergence of molecular diagnostics, the scientist chose to focus on the diagnosis of Duchenne muscular dystrophy, a genetic disease characterized by progressive muscle degeneration, and on Marfan syndrome, which affects the connective tissue and affects the cardiovascular, musculoskeletal, ophthalmological and pulmonary systems.

"Diseases were clearly what interested me", remarks the scientist. In 1996, she founded a multidisciplinary consultation, led by Guillaume Jondeau* and held at Bichat Hospital, for patients with Marfan syndrome, facilitating its complex diagnosis. In 1998, to federate the researchers working on the identification of new genes implicated in familial hypercholesterolemia, she launched a national research network dedicated to this genetic disease. This progressively became the CHOPIN project, driven by Bertrand Cariou** from University Hospital Nantes, which aims to institute individualized management of the condition. According to the familial hypercholesterolemia association ANHET, around 300,000 people currently suffer from this disease in France. "It’s a real public health problem. We shouldn’t wait for the first infarction to strike before it is detected. It is hereditary, and we have the means of diagnosing it well before it gets that far, and we have the means of conducting prevention initiatives aimed at patients. Yet only 1% of them are diagnosed! deplores Boileau. Cholesterol testing should be made obligatory but in France there is no longer a national campaign for the screening of hypercholesterolemia." For the scientist and her colleagues, her recent award serves an additional purpose: to shine the spotlight on a disease that is all too often overlooked.

Key dates

  • 1984-1989. Clinical lecturer (AHU) at Ambroise-Paré Hospital, Université Paris 5
  • 1993. Human genetics dissertation on Marfan syndrome and hypercholesterolemia
  • 1980-1984. Pharmacy internship in Paris
  • Since 1994. Director of a research group in various Inserm units (73, 383, 781, 698 and now 1148) Since 2014. University professor and hospital practitioner (PU-PH) in the genetics department of Bichat Hospital

Note :

*unit 1148 Inserm/Université Paris 13-Paris Nord/Université Paris Diderot- Paris 7, Laboratory for Vascular Translational Science (LVTS), Structural cardiovascular diseases team

**unit 1087 Inserm/CNRS/Université de Nantes – University Hospital Nantes, Thorax InstituteCIC 1413 Inserm/Université de Nantes