Portrait of Marianne Abi Fadel

Can you tell us about your academic background and what motivated you to pursue a career in biochemistry and molecular biology?

Born in Lebanon, into a French-speaking and Francophile family, I obtained my French Baccalaureate in Lebanon and studied pharmacy at Saint-Joseph University in Beirut, before completing a DES in medical biology with a specialization in clinical biochemistry. In 1999, I completed a DEA (post-graduate diploma) in Physiopathology of Human Nutrition at Paris Diderot, with an internship in the field of lipids at La Pitié, in one of the teams headed by Dr John Chapman, who went on to form the unit to which I now belong. I went on to do a doctorate at the Université Paris Descartes, in Prof. Catherine Boileau's team at the INSERM U783 unit headed by Prof. Claudine Junien at the Hôpital Necker Enfants Malades. It was there that I specialized in genetics and molecular biology, investigating the genetic basis of familial hypercholesterolemia, leading to the identification of a new gene and protagonist involved in this disease: PCSK9. My thesis was carried out under the joint supervision of Université Paris Descartes and Université Saint-Joseph in Beirut, Lebanon, where the incidence of familial hypercholesterolemia is one of the highest in the world.

I became a naturalized French citizen in 2006 and continued my doctoral and post-doctoral research between INSERM in Paris and the USJ Faculty of Pharmacy in Lebanon, where I was involved in teaching, diagnostics and research. After obtaining my HDR and the French equivalence of my medical biology diploma, I was elected Dean of the USJ Faculty of Pharmacy in Beirut in 2013, and founded the Biochemistry and Molecular Therapies Laboratory at USJ. My teaching focuses on biochemistry and molecular biology in pharmacy, nutrition and for medical laboratory technicians. I've always been keen to pass on my interest and passion for these fields to future generations. During the COVID crisis, I assumed responsibility for the Rodolphe Mérieux Laboratory-Lebanon (LRM), which became the reference laboratory for tuberculosis in Lebanon in 2018. It is a non-profit laboratory, supported by Fondation Mérieux and USJ, serving vulnerable populations.

I lived through the war during my childhood and adolescence in Lebanon, which in itself is quite painful. However, the hardest thing to live through during my deanship was the multiple crises that shook the country: the economic crisis, the COVID health crisis, the explosion in the port of Beirut and, more recently, the war once again. At the same time, I was responsible for the pharmacy and nutrition students, helping them to continue their studies despite the dramatic situation, to succeed and to be accepted into top universities around the world. They all integrated well and succeeded in their post-graduate studies at French, American and Canadian universities.  Despite the unstable and challenging situation in Lebanon, I have co-supervised several theses under joint supervision between the USJ Faculty of Pharmacy and French teams.

Biochemistry and molecular biology play a crucial role in diagnostic and therapeutic innovations. I am proud and happy to have contributed to the improvement of diagnosis and treatment of lipid and cardiovascular diseases with the identification of PCSK9 in familial hypercholesterolemia, which led in 2015 to the marketing of highly effective lipid-lowering drugs.

I'm just as proud and happy to train generations of pharmacists, nutritionists and researchers, and to consolidate the ties between my two countries: Lebanon and France, ties that are historic and unshakeable.

How did your research and discoveries evolve over the years, particularly with regard to the discovery of PCSK9 in familial hypercholesterolemia?

My thesis involved searching for a 3rd gene involved in familial hypercholesterolemia in families where genes known to be involved in the disease were excluded.

The story of the discovery of PCSK9 in familial hypercholesterolemia is a wonderful adventure that has given purpose and meaning to my life, as it is the basis for life-saving drugs.

When I joined Professor Catherine Boileau's team, I was asked to search for a new gene involved in familial hypercholesterolemia in a family from Nantes recruited by the Réseau de Recherche sur l'Hypercholestérolémie familiale, in which the two genes already known to be involved in the disease (LDLR and APOB), were excluded. My mission was to explore which genes were included in the genetic region of chromosome 1, common on the one hand to the region linked to the disease in this French family and published in 1999 before my arrival in the laboratory, and on the other hand to the neighboring region identified by an American team in a Utah family whose hypercholesterolemia was due to the 3rd gene still unknown in the region.

The work was particularly meticulous, a true work of goldsmith requiring continuous rigor and reflection. This was back in 1999, when genome sequencing had not yet been completed, and the genetic and physical maps of the region were incomplete. So I built these integrated maps of the genomic region, identified in silico the genes present in the region and sequenced them using the techniques available at the time, starting with candidate genes that might be involved in cholesterol metabolism or highly expressed in the liver, as the liver is at the center of metabolic reactions, particularly those involving cholesterol.

Many genes were in the region and I excluded them all, one by one. This is where I began to question the boundaries of the region initially published in the Nantes family. In parallel with the study of this family, I investigated other families not linked to LDLR or APOB. I was particularly interested in a family from Dijon that was crucial in the discovery of PCSK9. By studying microsatellite markers in this family, I was able to correct the bounds of the first genetic region reported before my arrival in the laboratory (which had been limited by a case of phenocopy), and identify a new common region more centromeric than the first on chromosome 1, and which showed good segregation with familial hypercholesterolemia in these families.

On the evening of this identification, I had a real tachycardia, as it rekindled hope in me, with new genes, new candidates and new hopes. Determined not to give up, with Catherine's agreement, I began sequencing genes in this new region that might be involved in cholesterol metabolism or those highly expressed in the liver. One of the genes present was PCSK9, which had another name at the time, NARC1, had just been released into the public databases, and was being studied by a researcher at the Institut de Recherches Cliniques de Montréal, Dr Nabil Seidah, who didn't know its function but contacted Pr Catherine Boileau because this gene was highly expressed in the liver and was on the short arm of chromosome 1. I therefore studied this gene along with the other liver-expressed genes present in this region.  On September 13, 2002, sequencing enabled me to identify the first two PCSK9 mutations: the same mutation in the two families with hypercholesterolemia and cardiovascular complications, and a 2nd in a new hypercholesterolemic French family whose index case had died of myocardial infarction at the age of 49.

This was the first result in the world of cholesterol involving NARC-1, which was named PCSK9 for the first time in our article by the Gene Nomenclature Committee, as the protein was the 9th member of the proprotein convertase family. It was a Friday, a day that will remain engraved in my memory, and I spent the weekend doing all the checks to prove that it was a causal mutation. The result was unequivocal: it was THE gene!

The collaboration with Nabil Seidah continued with functional and cellular studies, which contributed to our understanding of the role of PCSK9 in reducing the number of LDL receptors on the cell surface. The very convincing genetic results were accepted for publication in Nature Genetics, with a first agreement for a 'brief communication' in January 2003 and publication in May 2003. Other articles reporting the functional results were subsequently published.

A few months later, our result was confirmed by the American team in the Utah family. And two years later, the Dallas team identified healthy individuals with loss-of-function variations in PCSK9, associated with reduced cholesterol concentrations and cardiovascular risk. These results confirmed our own on the importance of PCSK9 in HF and cardiovascular disease.

Pharmaceutical companies then entered the race to find PCSK9 inhibitors, and the transition from gene discovery in HF to drugs was made in record time. Two monoclonal antibodies received marketing authorization in 2015, and an anti-PCSK9 Arn interferent in 2021. They are highly effective in lowering blood LDL cholesterol levels and reducing the risk of cardiovascular disease.

This work earned me the Chancellerie des Universités de Paris thesis prize in 2004, followed in 2011 by the Lebanese CNRS Scientific Prize. In 2021, I was awarded the Christophe Mérieux Prize of the Institut de France for my career, which included the discovery of PCSK9, but also all the diagnostic work carried out in Lebanon and the role I played during the COVID-19 pandemic. Given the economic crisis in Lebanon at the time, this prize enabled me to provide scholarships for my pharmacy and nutrition students. More recently in 2022, I was awarded the Italian Society of Cardiology SIC prize at its annual congress in Rome, recognizing the impact of this discovery in the fight against cardiovascular disease. In 2019, I was elected to the Académie Nationale de Pharmacie (in Paris).

Most recently, in 2025, in addition to the part-time chair at SU, I was appointed to the board of the International Atherosclerosis Society IAS, representing Lebanon and the Middle East region.

During my cotutelle thesis and all my years in France, my stays in Lebanon enabled me to recruit hypercholesterolemic families, or those with other rare dyslipidemias, especially as the rate of consanguinity is high in Lebanon, to characterize HF in Lebanon, to study PCSK9 as a phenotype-modifying gene, to include Lebanese patients in major international studies, particularly European ones, or in clinical studies with anti-PCSK9.  This research between two countries has been and continues to be fruitful and interesting.

They also enabled me to consolidate research between Lebanon and France, with 6 theses under cotutelle between the Paris Cité teams, INSERM U1148 at Hôpital Bichat and INSERM UMR1166 at SU.

Parallel teaching in Lebanon has been a driving force in my research career. Inspiring students, guiding them and helping them to give their best, without backing down in the face of difficulties, is very gratifying.

I always tell my students that hard work, tenacity, integrity, rigor and perseverance are the keys to success. Research is an exciting vocation that enables us to make discoveries, save lives and give real meaning to life.

The discovery of PCSK9 was a major breakthrough in the understanding of familial hypercholesterolemia. Can you explain simply what PCSK9 is and its role in cholesterol?

Familial hypercholesterolemia is one of the most common genetic diseases. This disease is characterized by increased blood levels of LDL-cholesterol (cholesterol carried by low-density lipoproteins, LDL), which, if left untreated, leads to cardiovascular complications.

These LDL particles, which bind to specific receptors called LDL receptors, are internalized, notably in hepatocytes, where they are subsequently degraded. As a result, concentrations of LDL cholesterol in the bloodstream are reduced.  Until 2002, two genes were known to be mutated in this disease: the first encoding the LDL receptor, and the second encoding apolipoprotein B, its ligand on LDL particles.

PCSK9 is the 3rd gene responsible for familial hypercholesterolemia, which I discovered to be involved in this disease, thanks to mutations identified in French families suffering from hypercholesterolemia (Abifadel et al., Nature Genetics 2003). This gene encodes a PCSK9 (Proprotein Convertase Subtilisin Kexin 9) protein, which is the 9th member of the proprotein convertase family.

To simplify matters, PCSK9's main function is to reduce the amount of LDL receptors on the cell surface of hepatocytes, thus playing a key role in regulating LDL-cholesterol concentrations in the blood.

Gain-of-function mutations in PCSK9 increase the activity of this protein, leading to a reduction in the number of LDL receptors on the hepatocyte surface, and less internalization of LDL into the liver. Excess LDL cholesterol accumulates in the circulation, deposits in the arteries, oxidizes and leads to cardiovascular disease (myocardial infarction, stroke...).

In short, PCSK9 is a protein that regulates the quantity of LDL receptors available to remove LDL-cholesterol from the blood.

His discovery has opened up new avenues for the treatment of hypercholesterolemia, notably through the development of PCSK9 inhibitors, drugs which reduce PCSK9, thereby preventing the degradation of LDL receptors, increasing LDL internalization and helping to considerably reduce blood LDL-cholesterol levels, in at-risk patients who do not respond sufficiently to conventional statin therapy.  Anti-PCSK9 monoclonal antibodies received marketing authorization in 2015, with PCSK9-targeted Arn interferents in 2021.

PCSK9 inhibitors represent a significant advance in the treatment of hypercholesterolemia and the prevention of cardiovascular disease.  Clinical studies have shown that PCSK9 inhibitors are not only effective in reducing LDL-cholesterol, but also improve clinical outcomes by reducing cardiovascular events.

New studies are currently exploring PCSK9 in other pathologies, including cancer, sepsis and autoimmune diseases.

What synergies do you hope to create between UMRS 1166 and current research projects, particularly in the field of cardiovascular disease?

My collaboration with UMRS 1166 and several of its members began many years ago. I took my first steps in research in France, during my DEA in one of the teams headed by Dr John Chapman, (INSERM Director Emeritus), who would later form this unit, before going on to do my PhD in Pr Catherine Boileau's team at Necker. However, this collaboration continued over many years, notably in the context of research into Tangier disease, with the identification of the first Lebanese patient suffering from this rare disease, as well as other patients with hypoalphalipoproteinemia recruited in Lebanon. Diagnostic genetic studies are being carried out in collaboration with Pr Alain Carrié, and cellular functional studies with Dr Wilfried Le Goff. Other collaborative studies concerning PCSK9 and HDL metabolism had already been initiated and led to joint publications. The investigation of PCSK9 using cutting-edge technologies such as omics, and in the various pathologies studied at UMRS 1166, will continue and provide a better understanding of the impact of PCSK9 and even PCSK9 inhibitors in cardiovascular pathologies, but also in autoimmune diseases, cancers and other pathologies in which it may be involved.

Collaboration on the familial hypercholesterolemia axis is continuing through the European project we recently obtained, which brings together 15 countries including Lebanon, with the aim of improving the diagnosis and management of this pathology, which is still largely under-diagnosed and under-treated worldwide. The existing collaboration between my laboratory at USJ and UMRS 1166 will enable the recruitment of additional dyslipidemic Lebanese families and patients of interest from a genetic point of view, and their inclusion in the studies being carried out at La Pitié as part of the European FH-EARLY study which has just begun. Synergies will also be pursued in the training of students, which began a few years ago with a cotutelle thesis with Lebanon, followed by a post-doctorate in 2023 and currently an internship for a master's student at Sorbonne University.  This will also encourage research training for young students with a passion for our common themes.

UMRS 1166, Sorbonne Université, INSERM and La Pitié provide the ideal scientific, human and technological environment for collaborations and the specialization of scientists enabling them to contribute to improving the diagnosis and treatment of familial hypercholesterolemia, dyslipidemia and cardiovascular disease.

This promotes the transfer of technology and skills, strengthening the French-speaking community and the special relationship between Lebanon and France, as well as opening up to a population with a homogeneous genetic background, with a prevalence of a founder-effect mutation in the LDL receptor, causing a high incidence of familial hypercholesterolemia, and favoring studies of genotype-phenotype correlations and modifier genes.

How do you perceive the evolution of health and research policies on cardiovascular disease and cholesterol?

The evolution of health and research policies on cardiovascular disease and cholesterol has been marked by several key trends over the last few decades.

In recent years, major advances in research and therapeutic innovation have revolutionized our knowledge and the arsenal of drugs available to combat metabolic diseases such as diabetes and hypercholesterolemia, particularly familial hypercholesterolemia, and their cardiovascular complications.

In the treatment of familial hypercholesterolemia, PCSK9 inhibitors have significantly lowered LDL-C concentrations, reduced cardiovascular disease and refined treatment recommendations.

Technological advances - next-generation sequencing, advances in genomics and other omics - have greatly facilitated diagnosis. Genetic data and biomarker studies aim to move towards a more personalized approach to the treatment of cardiovascular disease, attempting to take into account each patient's risk and tailor treatments to their individual needs (personalized medicine). The growing use of advanced technology, including telemedicine and artificial intelligence, is increasingly transforming the way cardiovascular care is and will be delivered.

National and international mobilization to ensure and improve diagnosis and treatment, with the establishment of patient registries, European studies such as that of the European Atherosclerosis Society Familial Hypercholesterolemia Studies Collaboration (EAS FHSC), which brings together more than 50 countries worldwide, and international recommendations for the diagnosis and management of lipid disorders and their cardiovascular complications, have enabled significant progress to be made in the fight against these pathologies.

 Prevention and awareness: There has been a growing emphasis on the prevention of cardiovascular disease, with awareness campaigns aimed at educating the public about risk factors such as high cholesterol, hypertension, smoking and obesity. Public health policies encourage healthy lifestyles, including a balanced diet and physical exercise.

It should be noted that patient associations in France, Europe, the USA and other countries are playing an increasingly important role in improving awareness, management and treatment.

In summary, the evolution of healthcare and research policies on cardiovascular disease and cholesterol reflects a more proactive, integrated and personalized approach, aimed at reducing the incidence of these diseases and improving patients' quality of life. France has been a pioneer on many levels, notably with its excellent familial hypercholesterolemia diagnostic and research network, and the PCSK9 story only goes to prove it.

Do you think that further advances are needed at political level to support research in these areas?

Familial hypercholesterolemia is the most common genetic disease, yet it remains under-diagnosed and under-treated worldwide. Despite major therapeutic advances in recent decades, access to treatment remains limited in many countries and regions of the world. The high price of treatments, particularly new ones, economic difficulties in various countries, and inaccessibility to care for the poorest, limit the availability of vital medicines. Many challenges remain, particularly in terms of equitable access to care and the fight against health inequalities.

In Lebanon, for example, which is going through an unprecedented economic crisis, homozygous FH patients' access to LDL apheresis has been severely restricted due to the cost of care no longer being covered by the state, jeopardizing the health of these patients with extremely high cholesterol concentrations and risk of cardiovascular disease. Genetic diagnosis is mainly carried out through research projects run by university laboratories, such as the Biochemistry and Molecular Therapies Laboratory that I run in Lebanon.

In countries such as France, the consolidation of research, the funding of innovative projects, and policies that facilitate screening, generalize diagnosis and encourage collaboration between universities, pharmaceutical firms and research institutions, are enabling therapeutic breakthroughs in this field to continue. International collaborations, particularly with low-income countries with interesting genetic backgrounds, are promising.

Can you tell me about the European project you're working on with Wilfred Legoff?

The innovative FH-EARLY project was officially launched on January 1, 2025, paving the way for earlier diagnosis, better risk identification and management to improve the diagnosis and care of familial hypercholesterolemia (FH). With a 4-year grant of 7.25 million euros from the EU's HORIZON program, the consortium brings together 15 global leaders in genomics, AI, clinical care and patient advocacy.

Key Innovations Include:

• A next-generation chip for faster, more affordable genetic testing
• A biomarker or omic signature for personalized risk stratification
• AI tools for actionable, reliable information

In a Patient-centered approach, FH-EARLY places patients and families at the heart of its work, co-creating practical, culturally appropriate and equitable solutions to overcome persistent barriers in FH-related care. By improving early detection and prevention, FH-EARLY aims to prevent cardiovascular disease, reduce heart attacks, and promote cardiovascular health.

Sorbonne Université, UMRS 1166, AP HP and Université Saint-Joseph de Beyrouth are core members of the consortium, which is led by the Faculty of Medicine at the University of Portugal.