The 4th PLN Info Day was held at UMC Groningen on Saturday 3 November. Over two hundred people, PLN carriers, family and friends came to Groningen this afternoon. One hundred of them donated blood that will be used to do research on the PLN mutation.
Pieter Glijnis, the chairman of the PLN foundation, kicks off. The most important news is the ongoing collaboration between AMC Amsterdam, UMC Utrecht, UMC Groningen and the American partners Mount Sinai NYC, Stanford University CA and the University of Cincinnati College of Medicine. Friday, November 2, 2018, the day before the PLN info day, researchers involved in the Leducq project met at the AMC in Amsterdam. Their project will start on January 1, 2019 with the ambitious goal to realize a treatment method for PLN that can be tested for the first time in humans in 2022/23.
Donations and activities
In addition to the financial support of the PLN foundation and other parties, a large donation was received from the Leducq Foundation. Pieter mentions the efforts of many people involved in all sorts of activities, such as:
- Trondheim-Oslo Monster Tour, which raised more than five hundred thousand euros,
- Paris-Deventer cycling tour,
- Amsterdam Marathon,
- Dam to Dam run.
There has also been publicity on t.v. about PLN last year. EenVandaag showed an item about PLN and Bas Westerweel (no PLN carrier) became our ambassador.
Mice with PLN gene
Prof. dr. Dr. Rudolf de Boer of UMCG talks about PLN and in particular the UMCG research in which mice with the PLN gene have been developed. In 2012 the PLN gene p.Arg14del was discovered in the Netherlands by (amongst others) Paul van der Zwaag (UMCG). The common ancestor probably lived around Dokkum between 575-825 years ago. By 2018, more than 1000 persons with this mutation have been identified, spread across more than 200 families. The initial clinical view is being adjusted in severity, as more and more information becomes available. For example, it seems that PLN carriers older than 75 years do not have a higher mortality risk than non-carriers. PLN can reveal itself through a deviant ECG showing low voltages. This can be caused by loss of myocardial tissue and/or fibrosis in the heart. There are also indications that the PLN protein is clotting, which is called PLN protein aggregation. Current treatments consist of the prescription of medication (ending on -pril, -lol or -none), placing an ICD, or LVAD (support heart) or, as a last resort, a heart transplant. Amongst others PhD Wouter te Rijdt attempts to trace early manifestations of PLN (especially manifestations of fibrosis) via MRI scans.
Another way is to compare presymptomatic carriers and non-carriers with Echocardiography. LVEF (the pump function of the left heart ventricle) is therefore also looked at. The problem here is that the LVEF can still be high, while the percentage of fibrosis is also high. The mice with PLN are similar in appearance to humans, which offers the possibility to test therapies on mice. The correct prevention model is not (yet) clear and requires much more research.
Litsa Kranias (University of Cincinnati College of Medicine)
Litsa Kranias has been researching Phospholamban for 40 years. She begins her contribution by saying that recently a scientific paper was published in a leading journal about the cooperation between researchers and the PLN Foundation. PLN plays a major role in contracting and relaxing the heart muscle through the calcium cycle. In 2006, the PLN mutation was first found in a Greek family. It appears that PLN has much more effect on the RV (right ventricle) than on the LV, in particular because the Calcium concentration remains high. The calcium pump of PLN carriers is less effective (less Calcium within and more leakages). Because the PLN syndrome develops slowly, many treatments can be tested. Other partners that Litsa works with are the Universität Göttingen and Biomedical Research Foundation, Academy of Athens.
“R14del-PLN in Cardiac function”
University of Cincinnati College of Medicine
Roger Hajjar (Icahn School of Medicine, Mount Sinai NYC)
Roger Hajjar discusses the possibility of gene therapy and gene editing. With gene therapy, a vector (the means of transport to get the right gene in the heart) is used to replace the defective gene. There are four stages:
- choice of vectors (e.g. mRNA, or AAV that has already been safely tested on more than 300 people)
- mode of Delivery (e.g. via catheterization via the groin)
- immune response
- clinical trials (testing)
In case of gene editing, the defective gene is replaced with a good gene by using a kind of scissors (this technique is called CRISPR-Cas). At cell level, skin cells from PLN carriers have already successfully been converted to stem cells and cardiomyocytes and subsequently repairing these cells Gene editing has also been successfully tested on a mouse model, but there is still a lot of work to be done to make it more efficient.
“The Promise of Gene Therapy and Genome Editing for PLN R14 Del Cardiomyopathy”
Icahn School of Medicine at Mount Sinai New York
Mark Mercola (Cardiovascular Institute, Stanford University)
Mark Mercola is testing the effects of medicine on cells with the PLN mutation. Cells of PLN carriers are transformed into cardiac muscle cells, which are used to grow cardiac muscle tissue. With a robot, the effect of existing medicines can then be tested on the cardiac muscle tissue. For example, medication can be tested for the effect on contraction. Another line of research is to test the grown cells for fingerprints. The PLN gene can lead to the formation of more protein aggregates, because the formation of more unfolded and misfolded protein leads to accumulation. A possible therapy is reactivation of the folding process, or the prevention of the incorrect folding.
“A development route for a medicine for the PLNR14del disease”
Icahn School of Medicine at Mount Sinai New York
Parallel session PLN Childhood age
The contribution of pediatric cardiologist Freek van den Heuvel (UMCG) has the title “PLN cardiomyopathy at childhood age. Problem or no problem? He asks four questions:
Is it a medical problem?
No, probably not because studies (among others by Paul van der Zwaag) showed that the youngest carriers with symptoms were 20 years old and the youngest with heart failure was 31 years. Cardiac tests show abnormal results with many children, and it is unlikely that it is due to the PLN gene.
Does PLN have consequences for children?
Only top sport practice (four or more intensive training sessions plus competitions per week) may not be advisable. Some professions are excluded for PLN carriers.
When and how to check children?
Only if there are symptoms, and with an individual approach; no lifestyle advice for children with PLN without symptoms. The basic check, from 10-12 years, consists of an ECG (to detect abnormal electrical activity), an Echocardiogram (to diagnose any widening of the heart chambers, heart muscle reduction, reduced heart function) and 24-hour ECG (Holter).
A comprehensive check, starting from 15 years of age, includes an exercise test (on the bike) and an MRI scan (heart function, reduction of myocardial tissue, fibrosis connective tissue). Medical data is stored for scientific purposes. In case later or more is known about individual cases it can be retrospectively reviewed to identify whether something has been overlooked.
Whether or not to genetically test during childhood?
Considerations that play a role here are removing uncertainty, social consequences (insurance, loans / mortgages), and the psychological burden of being a carrier or not. There is also the possibility to do the basic checks without testing on PLN. Using your phone whilst cycling is a bigger risk than being a PLN carrier at a child’s age.
Parallel session PLN and sport
Freyja van Lint, physician-researcher at the Department of Clinical Genetics AMC, has the following research question: Why does one carrier become ‘sick’ and the other does not? And more in particular: the role of physical exercise such as sports. The PLN gene can lead to DCM (dilated heart muscle) and ACM (for example caused by connective tissue, especially in RV). ACM is relatively common among athletes. Athletes have been researched relatively often). If there is a tendency for ACM, a sports restriction is recommended in the USA. The question is whether this is also good advice for PLN carriers. Her research results are still provisional (more than 195 carriers have been interviewed by telephone). The preliminary conclusion is that there is no proven effect of sports or physical effort on PLN. It is of course advisable to exercise less intensively after heart rhythm problems. More information can be found on the websites erfelijkehartziekten.nl and youngheartz.nl.
Do not ask what the PLN Foundation can do for you, ask what you can do for the PLN Foundation
The information afternoon is continued plenary with a forum where the three American researchers, together with Rudolf de Boer from the UMCG, will answer questions from the audience. The day ends with a call from the moderator of the day: ‘Do not ask what the PLN Foundation can do for you, ask what you can do for the PLN Foundation’. We can only make the PLN mutation cease to exist if we all commit ourselves. By donating money or collecting funds in your network more research can be done. The more research can be done, the greater the chance that a treatment will be found. The PLN Foundation consists entirely of volunteers.