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Translational research: a successful model
How PCSK9 went from an enzyme discovered in the lab to a drug target that could revolutionize the way we treat high cholesterol levels
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The “bench to bedside” approach, also known as translational research, denotes the transfer of knowledge obtained in basic research laboratories into the development of new methods to diagnose, treat and prevent diseases in patients. This increasingly important research model contributes to improving health by accelerating the application of scientifi c breakthroughs to patients in need.
In 1967, the IRCM (Institut de recherches cliniques de Montréal) became the fi rst independent academic research centre in Quebec to unite basic and clinical researchers under one roof, thereby establishing the ‘bench to bedside’ philosophy that has been largely responsible for its success.
At the time, IRCM founder Dr. Jacques Genest was determined to build clinical research departments in way that would promote frequent and close interactions between basic scientists and clinicians, as they were too often dispersed in various sections of a hospital or university campus. Thus, the IRCM was born from the notion that the future of Quebec medicine was in the hands of doctors who could most effectively treat patients by combining their clinical skills with the knowledge acquired from biomedical research.
“The fundamental idea was to take a problem at the bedside, bring it to the lab to fi nd a solution based on scientifi c insight, then apply that solution back to patients,” says Tarik Möröy, PhD, the IRCM’s president and scientifi c director. “We continue to respect these founding principles at the IRCM and, to do this, we foster an environment in which scientists can conduct fi rst-rate research projects in close collaboration with practising clinician-scientists who provide the necessary bedside knowledge and input.”
Imitated by numerous other research centres, the IRCM’s approach is proving to be extremely relevant and has led to several important discoveries, including that of an enzyme called PCSK9, the ninth member of a family of proteins called proprotein convertases, which were discovered at the IRCM in the early 1990s.
IRCM researchers Nabil G. Seidah, PhD, and Michel Chrétien, MD, are pioneers in the fi eld of research on proprotein convertases and, in 2003, were the fi rst to describe PCSK9. The same year, Dr. Seidah’s team, in collaboration with French researchers, discovered that PCSK9 plays a key role in regulating blood cholesterol levels. This was one of the most exciting discoveries in cardiovascular research in the last decade.
“We discovered that the PCSK9 enzyme leads to an accumulation of LDL cholesterol (or bad cholesterol) in the blood and contributes to the growth of plaque that eventually blocks arteries,” explains Dr. Seidah, who won the 2011 Wilder-Penfi eld Prix du Québec for his research on proprotein convertases. “Following numerous observations, we found that inhibiting the function of PCSK9 can signifi cantly lower LDL cholesterol levels.” In addition, Dr. Chrétien identifi ed three French Canadian families whose members have a uniquely potent PCSK9 mutation. “This mutation causes their blood cholesterol levels to decrease to levels unattainable by drug treatments alone, and these subjects have no obvious side effects,” mentions Dr. Chrétien. Lowering blood cholesterol is important as
arteries.” — Nabil G. Seidah
high levels are a major risk factor for cardiovascular disease and stroke. According to the World Health Organization, cardiovascular disease is the single leading cause of death worldwide, with annual deaths expected to reach 23.3 million by 2030.
Currently, statins are the most prescribed cholesterol-lowering drug. Nearly 30 million people are prescribed statin drugs because they suffer from high levels of cholesterol, have had a cardiovascular incident such as a stroke, or are predisposed to cardiovascular disease due to various risk factors. However, many statin users exhibit a resistance or inadequate response to the drug, and a signifi cant number of patients suffer from serious side effects to the point of having to interrupt their treatment.
New therapeutic approaches are crucial for those who are resistant or intolerant to statin drugs, as well as for the large number of patients unable to reach the recommended cholesterol levels with their current treatment.
Today, PCSK9 is considered to be an ideal therapeutic target for the development of novel cholesterol-lowering drugs that could eventually supplement or even replace statins. In an April 2013(1) issue of the science journal Nature, a feature article stated that PCSK9inhibitors could become “the next blockbuster heart drug.”
The news quickly generated great interest from the industry. Dr. Seidah and his research team received a substantial investment from AmorChen (a venture capital fund that helps research-stage projects
reach clinical proof-of-concept) and Univalor (a Quebec-based university technology transfer organization) to develop an innovative drug that could block the function of PCSK9 and, in turn, signifi cantly lower blood cholesterol levels. Pharmaceutical companies are also jumping at the chance to take part in this multi-billion dollar market, which is expected to continue rising in upcoming years, and are racing to commercialize their version of a PCSK9-inhibitor.
Only nine years after Dr. Seidah’s discovery of the role of PCSK9, inhibitors of this enzyme were being taken to the bedside by his IRCM colleague, Dr. Robert Dufour, who is now supervising phase 3 clinical trials in order to evaluate the new therapeutic approach. The trials are mainly conducted with patients who suffer from familial hypercholesterolemia, a hereditary disease characterized by extremely high blood cholesterol levels that affects over 35,000 people in Quebec alone.
“It is nearly impossible for these patients to reach recommended cholesterol levels with currently-available treatments,” states Dr. Dufour, MD, clinical researcher at the IRCM. “However, our research has shown that PCSK9-inhibitors can reduce LDL cholesterol levels by approximately 70 per cent, with no reported side effects. The next step will be to determine whether these positive results will
— Dr. Robert Dufour
translate into fewer cases of heart disease and stroke, which is the ultimate objective.” “We still have much to understand about the role of PCSK9 in hypercholesterolemia and cardiovascular disease,” adds Dr. Seidah. “To tackle this issue, I have assembled an international, multidisciplinary team of experts to address many of the current knowledge gaps surrounding the enzyme’s biology.” This team includes 16 basic and clinical scientists from six institutions in Canada, France and Sweden. By combining state-of-the-art technologies and extensive clinical expertise, the researchers will defi ne the functions and physiological roles of PCSK9 in relation to risk, manifestations and management of cardiovascular disease. In addition to Dr. Dufour, Dr. Seidah also invited IRCM researcher and proteomics experts Benoit Coulombe, PhD, to join the team. This collaboration will accelerate the development of more precise diagnostic tools to eventually offer patients personalized health care, an emerging fi eld that tailors treatments to “Our goal is to determine whether patients’ specifi c genetic information. “New technologies are already availthis information can be used to able to measure levels of PCSK9 in a predict a patient’s response to statins patient’s blood,” says Dr. Coulombe, director of the translational proteomics and evaluate cardiovascular risk after research unit at the IRCM. “Our goal is to determine whether this information statin or anti-PCSK9 treatments.” can be used to predict a patient’s response to statins and evaluate cardio— Benoit Coulombe vascular risk after statin or anti-PCSK9 treatments.” The transatlantic research project headed by Dr. Seidah recently received a $6-million investment from the Fondation Leducq. “The knowledge generated by this project will have an immense impact on the understanding and treatment of cardiovascular disease, and will be highly valuable to develop new therapeutic approaches,” says Dr. David Tancredi, Fondation Leducq’s scientifi c director. “This is one of the best examples we could hope for to demonstrate the success of translational research,” says Dr. Möröy. “The commercialization of a PSCK9-inhibitor, which can potentially benefi t millions of people, could not have been achieved so quickly without the synergy, collaboration and close proximity of both basic scientists and clinicians, within an institute like the IRCM that supports independent academic research.” To see this story online visit http://biotechnologyfocus.ca/translational-research-asuccessful-model
