Research

Transatlantic collaborative project, 2017 – 2022

The PLN Foundation was founded in 2012 by people and family members affected themselves by the negative consequences of the PLN gene mutation. During the first years, scientific research projects were mainly initiated and financially supported in The Netherlands in order to gain more insight in this disease. During the last years, a global study was done to trace where knowledge and experience was available in the field of the PLN mutation in order to develop a treatment for this life-threatening disease.

The conclusion is that there is knowledge about the PLN mutation in The Netherlands and that several studies are currently ongoing at the academic centers in Groningen, Utrecht and Amsterdam. They jointly treat almost all Dutch PLN patients.

In the United States of America, a number of technological innovations took place which can be used to conduct further research projects on finding a treatment method.

Based upon the above, the PLN genetic heart disease Foundation came up with the plan to establish a transatlantic collaborative project in order to try and find a treatment method for this life-threatening disease.

The project involves the establishment of a unique collaboration between 3 academic medical centers in The Netherlands (Amsterdam UMC, UMC Groningen and UMC Utrecht) and 3 academic medical centers in the United States of America (Mount Sinai Hospital New York, Stanford University, California and the University of Cincinnati College of Medicine). This way, the best of the best in the field of knowledge and experience with the PLN mutation and the most technologically innovative institutes are brought together. Initial they were be working in parallel on 3 possible solutions:

Gene therapy: by inserting genetic material in human cells, one will try to replace the defective PLN protein by adding a healthy one.

Drug therapy: investigating whether existing drugs or specific molecules have a favorable impact on the PLN mutation. The advantage of this therapy is that the valuable time of development, testing and having a new drug approved could be saved. For this purpose, an ultramodern robotized laboratory is availablein the USA.

Stem cell therapy: inserting healthy stem cells in the heart muscle so that new and active heart muscle cells can be formed there. Stem cell therapy did not give the wanted results and therefor it was  decided to focus on the other two therapies and gene silencing. Gene silencing is is the regulation of gene expression in a cell to prevent the expression of a certain gene.

An important part of the research project will take place in America and will be supported by sending talented young medical scientists from The Netherlands who also will be financially supported. The other part will take place in The Netherlands.

When a solution is found in these therapies, it will be tested through animal proofs and after that the “First in Man” therapy will be tested. Of course after all approvement from the involved organizations and regulations.

An important argument for this project, is the spin-off which largely consists of a deeper understanding of the heart muscle cell operation and particularly the functioning of the calcium balance which makes the heart muscle contract and relax. This may possibly also be applied when finding treatment methods for heart failure, one of the main causes of death worldwide.

The management of the research project is conducted by the Netherlands Heart Institute, an unique collaborative platform of the Cardiology departments of all academic medical centers in The Netherlands. Within this institute, Prof. Dr. Doevendans is responsible for the project supervision.

CURE-PlaN, 2019 – 2024

Mid 2018, Fondation Leducq awarded USD 6 million for a PLN-focused international research plan, the CURE-PLaN. This project officially started on January 1st, 2019. The team is a transatlantic team brought together by our Foundation, consisting of researchers from UMC Groningen, Amsterdam UMC, UMC Utrecht, New York Mount Sinai Hospital, University of Cincinnati and Stanford University (Mercola Lab). This team was further strengthened with researchers from Greece and Germany.

A start was already made in the last quarter of 2018: The Netherlands Heart Institute and our Foundation took the initiative to organize a researchers day. Almost fifty researchers from The Netherlands, America, Germany, Italy and other countries took part. Timelines were discussed and agreements were made.

This project has led to some duplication with our existing project. In recent months The Netherlands Heart Institute has been working with us to remove these duplications from the project and to coordinate the two initiatives. Our goal is to support efficient initiatives that strengthen and accelerate the overall project.

Crazy Idea sessions

Because the medical world is evolving rapidly, we want to remain flexible with the research project and also take advantage of new developments. That is why our PLN Foundation organises a “Crazy Ideas” session twice a year: during this session we ask medical scientists to come up with alternative ideas to make the disease caused by the PLN mutation treatable. For each session, we make a budget available to follow up on the best idea. At the end of a “Crazy Ideas” session, it is immediately announced which researcher is granted the budget.

Crazy Ideas 2019 – Curing Cardiac Fibrosis

Tom Bracco Gartner and Renée Maas won the European Crazy Idea Call. They will try to establish a human in vitro 3D model for cardiac fibrosis.

Crazy Ideas 2018 – Early detection

In December 2018 a Crazy Idea Session was held. The emphasis was on “early detection”. The winner was the project “Early Detection of contractile dysfunction in Phospholamban mutation carriers with echocardiographic deformation” by Karim Taha and Arco Teske. Using algorithms and image recognition software, the researchers will analyze echo images at certain places in the heart that are missed by the human eye. This technique will allow ultrasound images from the past five years to be analyzed again to see whether the onset of the disease could have been detected earlier. By now, we know better where in the heart the disease usually develops. With this software it is possible to look at this even more specifically. The software can also be used in the future, when the first therapies are tested on patients. Echocardiogram is a simple and less stressful examination for patients and one that could measure the effect of the therapy in this way.

Crazy Ideas 2018 – Antisense

In 2018, a Crazy Idea Call was awarded to Niels Grote Beverborg for a project with Antisense therapy. Antisense is a treatment that inhibits the creation of the entire PLN gene (both the good and the mutated part). His research focuses on an experimental drug from the manufacturers AstraZeneca and Ionis. In the UMC Groningen a special variant of the drug has been tested on the homozygous PLN-mice. We will keep you updated!

Crazy Ideas 2017 / 2018 – Inflammation

Patricia van den Hoogen (PhD student, Experimental Cardiology @UMC Utrecht) has a theory that the inflammatory reactions in the heart play an important role in causing PLN carriers to fall ill. For her research, she uses the blood that we have collected during the last PLN days.

Crazy Ideas 2017 – Silencing

Dr. A. Tijsen works in Amsterdam UMC with the silencing technology. They try to label the mutated cell so they can interfere.

Crazy Ideas 2017 – Istaroxime

Treatment of people (with other heart problems) with Istaroxime is already permitted, but because the half-life of the drug is short, it must be infused. Long-term treatment causes (fatal) poisoning symptoms, which means that it can only be used for a short period of time. Prof. Antonia Zaza approached us from the University of Milano Bicocca in Italy. In collaboration with the manufacturer of the drug, he has developed analogues of Istaroxime that have a longer half- life and no longer have a toxic side effect. For additional research with these analogues, heart muscle cells from Stanford have also been made available to him.

Heart Bank 

Various researchers have informed us that they would very much benefit from working with hearts in the early stages of the PLN disease. Until now, the hearts available to the researchers have belonged to patients who have been transplanted or who have died from the consequences of PLN. On this basis, in collaboration with the Durrer Centre, a project was started to set up a Heart Bank.

Hearts can be stored in this Heart Bank and pieces of them can be made available to researchers. Such a system now exists for the brain and its founders have made a great deal of information available to us to use for this project. We hope to have everything in order by 2020 to be able to call on PLN carriers to donate their hearts in the event of death. By using these hearts, we hope to gain more insight into the origin and development of the PLN gene mutation.

Biomarkers Project

The Biomarkers project aims to measure certain substances in the blood in order to predict whether a person will become ill from the PLN mutation (or remains “only” a carrier without complaints). During the last PLN information days, many participants have donated blood.  This is used to build a “biobank” of blood, which can be used to investigate what alters in the blood if the PLN heart disease develops. This blood is used, among other things, for the Biomarkers-examination.

Together with MD-PhD Manuel Mayr, Professor of Cardiovascular Proteomics at the Kings College in London, we will expand this project even further. Mayr is a global expert in protein research.

 

This overview is far from complete, but gives a good impression of what is happening and where our PLN Foundation is involved. In order to achieve a treatment method for PLN, a lot of work still has to be done and a lot of money is needed.