Prof. J.J.P. Kastelein MD PhD

All Publications

 Biography Prof. John J.P. Kastelein, MD PhD FESC

 

John J.P. Kastelein (1954) is Professor of Medicine at the Department of Vascular Medicine at the Academic Medical Center (AMC) of the University of Amsterdam, where he holds the Strategic Chair of Genetics of Cardiovascular Disease. Professor Kastelein has published over 820 research papers in peer reviewed journals, including Nature Genetics, Lancet, New England Journal of Medicine, JAMA and Circulation and has a Hirsch index of 99 in July 2016. His overall citatitions reached 45655 in July 2016 and were 5314 over the year 2015. He is listed among the 3000 Highly Cited Researchers 2015; Dr. Kastelein is on the 10th position for the Netherlands and on the 2nd position for the Unviversity of Amsterdam.

 

He received his medical degree in Amsterdam in 1980 where he subsequently received specialty training in internal medicine. Then, between 1986 and 1988, he was trained in medical genetics, lipidology and molecular biology at the University of British Columbia, Vancouver under the guidance of Prof. Dr. M.R. Hayden. In 1997 and 1998 he served a visiting Professorship at the Center for Molecular Medicine and Therapeutics at the University of British Columbia, Vancouver, Canada. Upon his return to the Netherlands, he was awarded a doctorate (Cum Laude) and in 1989 he founded the Lipid Research Clinic at the Academic Medical Center, AMC) in Amsterdam, which is currently serving as a tertiary referral centre and has become part of the department of Vascular Medicine.

The most important concept in Dr. Kastelein’s research career, developed initially at the University of British Columbia, by his mentor Dr. Hayden, and subsequently transformed into practice at the AMC in Amsterdam, the Netherlands, is the “extreme genetics” approach. This approach teaches that the study of rare human disorders that are associated with premature coronary disease have broader relevance for the understanding of the etiology of heart disease in general and will yield therapeutic targets that are valid for all patients.

This approach has been very successful, in so far that Familial Hypercholesterolemia is now internationally recognized as the paradigm for the relationship between LDL-C and heart disease, a relationship substantiated by at least 50 peer reviewed manuscripts and 10 postdoctoral theses in Dr. Kastelein’s curriculum vitae.

The same “extreme genetics” concept was applied to disorders of HDL-C and elevated triglycerides and lead to the discovery of the cholesterol efflux protein ABCA1 and later to gene therapy for lipoprotein lipase deficiency. These two innovative contributions to science have lead to important breakthroughs in the field of drug development for the prevention of cardiovascular disease (development of ABCA1 agonists) and in the area of gene therapy for hereditary disorders such as haemophilia, LCAT deficiency and others.

In 1995, Dr. Kastelein initiated a foundation for the active identification of patients with classical familial hypercholesterolaemia (FH) in the Netherlands (StoeH), for which he currently holds a position in the board of directors. This program has now been fully institutionalized and is operational under supervision of the RijksInstituut voor Volksgezondheid en Milieu (RIVM) and financially supported by the Ministry of Health with a total grant of approximately 30 million Euros. Since its inception, the StoeH has found over 25.000 individuals for whom a molecular diagnosis of FH could be made. The subsequent improvement of the treatment of these FH patients has saved many lives, as published in Lancet in 2001 and in the British Medical Journal in 2008.

Dr. Kastelein was president of the Dutch Atherosclerosis Society (DAS) and chairs the National Scientific Committee on Familial Hypercholesterolemia (EHC). He also is a member of the Royal Dutch Society for Medicine & Physics, the Council for Basic Science of the American Heart Association and the European Atherosclerosis Society and a Fellow of the European Society of Cardiology. He also is a boardmember of the International Task Force for CHD Prevention and was recently appointed to the Executive Board of the International Atherosclerosis Society (IAS) and is a recognized world leader in the significance of lipoprotein metabolism for the development of atherosclerotic vascular disease.

Dr. Kastelein was a principal investigator of the Bloodomics and CardioGenics consortia, two large European Union supported endavours under the Framework Programme 7, that aim to elucidate the molecular basis of atherosclerosis and premature coronary disease. Besides the scientific programmes aimed at the etiology of atherogenesis, Dr. Kastelein also served on a number of executive and steering committees of large cardiovascular intervention studies, including the IDEAL, TNT, CAPTIVATE, ENHANCE, ILLUMINATE, JUPITER, RADIANCE and numerous others of which TNT (2005), RADIANCE 1 (2007), ENHANCE (2008) and JUPITER (2008) are published in the New England Journal of Medicine, IDEAL (2006) in JAMA and RADIANCE 2 (2007) in Lancet.

Dr. Kastelein has directed 55 postdoctoral theses and currently, he works in a team of 7 internists, 6 postdoctoral fellows, 26 MD PhD students, and a large number of laboratory technicians and clinical trial / study coordinators

Dr. Kastelein is invited regularly to important meetings on vascular disease for invited or keynote lectures, at least 5 meetings per year (American Heart Association, American College of Cardiology, European Society of Cardiology, International Atherosclerosis Society, European Atherosclerosis Society, etc.). Overall, his invited lectures can be numbered in hundreds.

Dr. Kastelein was in 1997 a co-founder of Xenon Genetics Inc., a drug discovery company that has now changed its name into Xenon Pharmaceuticals Inc., listed on the Nasdaq, and is based in Vancouver, Canada. One of Dr. Kastelein’s concepts of using “extreme genetics” to clone human validated disease genes that can than be turned into useful therapeutic targets, was an important basis for the rise of Xenon and also lead to the cloning of the ATP-binding cassette A1 (ABCA1) gene, as published in Nature Genetics 1999.

Professor Kastelein was also one of the founders of Amsterdam Molecular Therapeutics Inc. (AMT), a gene therapy company based on the concept of gene replacement in hereditary lipoprotein disorders. AMT has enjoyed a successful Initial Public Offering (IPO) at EuroNext in Amsterdam in the summer of 2007. The results of the first successful human gene therapy trial were widely publicized in the media and are published in ATVB in 2008. Furthermore, this gene therapy (Glybera) has now been approved by the European commission and constitutes the first approved gene therapy worldwide. Amsterdam Molecular Therapeutics has now changed its name into UniQure, listed on the Nasdaq, and Prof. Kastelein is the major consultant for Glybera. The review article on the history of Glybera as published in Human Gene Therapy in 2013 belonged to the 10 most referenced manuscripts in this journal.

Recently, Prof. Kastelein also founded Dezima Inc, a pharmaceutical company that develops assets for the treatment of dyslipidemia and has developed a cholesteryl ester transfer protein (CETP) inhibitor DEZ-001 (formerly TA-8995), inlicensed from Mitsubishi Tanabe Pharma Corporation (MTPC). Dezima Pharma was acquired by Amgen in 2015 in one of the largest private equity deals in biotechnology history of the Netherlands.

Last, Dr. Kastelein received the first Lifetime Achievement Award of the Dutch Heart Foundation in 2010 as well as the ZonMW Parel price and has received the Anitschkov Price from the European Atherosclerosis Society for the best atherosclerosis research in Europe in June 2014. In 2014, Dr. Kastelein was also awarded the No.1 position among the Top Worldwide Expers in Hyperlipidemia Research and Treatment by Expertscape. He also was a recipient of the Huibregtsenprice 2014 for the best academic researcher in the Netherlands. He is listed on the worldwide list of the 400 most influential biomedical researchers, Eur J. Clin Invest 2013; 43: 1339-1365. Last, Thomson Reuters has ranked Dr. Kastelein among the top 1% of researchers for the most cited documents in his field and top 100 of the most influential clinical researchers globally in 2015.

 

Prof. MD PhD J.J.P. Kastelein (Vascular Medicine)

Since lowering systemic risk factors can only prevent 35% of cardiovascular events, novel interventions are needed. Two approaches are being pursued:
1. Directly increasing vessel-wall resistance against atherogenic insults.
2. Identifying inflammation-modulating pathways to attenuate atherogenesis

With respect to the first, efforts are being made to target the endothelial glycocalyx as therapeutic target.

With respect to the second, HDL-increasing agents are being evaluated as novel targets to attenuate pro-inflammatory changes.

Themes: Metabolic Disorders, Cardiovascular Diseases

Faculty
MEng PhD G.M. Dallinga-Thie
MEng PhD J.C. Defesche
Prof. MD PhD G.K. Hovingh
PhD S.J. Pinto-Sietsma

• R.J. Roelants