Skeletal muscle laminopathies – natural history and clinical trial readiness, first (30-31 October 2020), second (19-20 February 2021), third (10 December 2021) and fourth meeting (24-26 June 2022)

Location: Virtual meeting

Title: 253 virtual ENMC workshop on Skeletal muscle laminopathies - natural history and clinical trial readiness

Date: October 2020

Organisers: Dr G. Bonne (France), Dr L. Maggi (Italy), Prof. S. Quijano-Roy (France), Prof. C. Bönnemann (U.S.A)

Participants: Kate Adcock (UK), Lindsey Armstrong (Scotland), Danielle Beaumont (NL), Rabah Ben Yaou (France), Anne Bertrand (France), Sylvia Bonanno (Italy), Gisèle Bonne (France), Carsten Bönnemann (U.S.A.), Cristina Cappelletti (Italy), Robert-Yves Carlier (France), Eleonora Cugudda (Italy), Adele D'Amico (Italy), Gustavo Dziewczapolski (U.S.A.), Reghan Foley (U.S.A.), Greta Gladney, David Gómez Andrés (Spain), Marta Gomez-Garcia de la Banda (France), Uday Khire (U.S.A.), Giovanna Lattanzi (Italy), Agnieszka Madej.Pilarczyk (Poland), Lorenzo Maggi (Italy), Sebastian Maldonado (Argentina), Soledad Monges (Argentina), Andres Nascimiento Osorio (Spain), Ignacio Perez de Castro (Spain), Aty Piedra, Luisa Politano (Italy), Susana Quijano-Roy (France), Eric Schirmer (UK), Benedikt Schoser (Germany), Anneke van der Kooi (NL), Karim Wahbi (France), Howard Worman (U.S.A.)

Translation of the reports:

German translation by Rüdiger Schlagowski, Prof. Carsten Bönnemann
Polish translation by Dr Agnieszka Madej-Pilarczyk
Italian by Dr Silvia Bonanno
Spanish by Dr Ignacio Perez de Castro Insua

Due to the COVID-19 SARS2 worldwide pandemic context, the 253rd ENMC international workshop on Striated Muscle Laminopathies scheduled initially in March this year had to be postponed. The organizers (G Bonne, S Quijano-Roy, L Maggi, C Bönnemann) proposed to split it into two sessions, one virtual during the fall this same year and the second to be organized early next year in the usual ENMC place if the conditions allow it.

The first virtual conference was held during two afternoons on 30^th and 31^st October 2020. This event gathered 30 participants from Europe and America, including healthcare providers and researchers from Argentina, France, Italy, Netherlands, Spain UK and USA, as well as patients' and representatives from four advocacy associations (Cure-CMD, Fundacion Marcio Contra las laminopatías (FAM), Muscular Dystrophy UK (MD-UK), Associazione Italiana Distrofia Muscolare di Emery Dreifuss (AIMED)).

The meeting was opened by G Bonne (Paris, France), who welcome participants and gave an overview of the meeting main objectives: to increase knowledge in these diseases, to improve their diagnosis, clinical management and follow-up, to facilitate the identification of biomarkers and to move forward in possible therapeutic strategies.

The first afternoon session was dedicated to parallel working group (WG) meetings performed in several virtual rooms: 1) The Basic science & outcome measures WG chaired by G Bonne (Paris) was focused on patho-mechanisms of the striated (i.e., skeletal and cardiac) muscle laminopathies, eventual therapeutic targets including CRISPR and potential biochemical and imaging biomarkers; 2) The Heart WG (K Wahbi, Paris, France) presented recently published studies in adult striated muscle laminopathies and available data in pediatric patients; 3) The Clinical pediatric WG (S Quijano-Roy, Garches, France, and C Bönnemann, Bethesda, USA) allowed to update cohorts of patients followed by the different participating teams and to present the results of a recent worldwide international retrospective study with clinical and genetic data from more than 150 pediatric patients; and 4) The clinical adulthood WG (L Maggi, Milan, Italy) presented retrospective data of the adults affected with striated muscle laminopathies and discussed the most frequent measurements and outcomes identified in several studies. In all clinical WGs patients, families and advocacy group representatives had a time to express their difficulties, needs and expectations. After these brainstorming sessions, all WG reconvened in a single virtual room and WG leaders presented the most important data and results, what allowed to state at best a state of the art.

The second afternoon session was important to structure and discuss about all presented data. Innovative therapies seem now to be closer and clinical readiness is becoming of great importance. Clinical and complementary motor, respiratory and cardiac outcome measures were listed by different teams to reach a consensus; potential biomarkers including biochemical and imaging techniques were described. The results of the retrospective pediatric worldwide study and other data in adult laminopathies provided a useful starting point to design prospective clinical studies in view of future therapeutic trials.

The meeting ended with a contribution of the patients’ group representatives, where they and their relatives could share their experiences in daily life and highlighted their difficulties, unmet needs and expectations.

Although it was the first time that this ENMC workshop was run online, participants found it a successful experience which allowed experts in clinical and basic research, and patients and associative representatives to review updated data, interact in real-time and identify priorities and face future perspectives.

This virtual meeting has been an excellent opportunity to update and deepen our knowledge of natural history of laminopathies, promoting the international research and collaborative studies to better characterize and follow our patients, while we wait to be able to meet again in the face-to-face meeting in 2021.

A full report will be published in Neuromuscular Disorders.

Date: 19 – 20 February 2021, second meeting
Due to the COVID-19 SARS2 worldwide pandemic context, the 253rd ENMC international workshop on Striated Muscle Laminopathies scheduled initially in March 2020 had been postponed.
After a first virtual conference held during two afternoons on 30th and 31st October 2020, the organizers (G Bonne, S Quijano-Roy, L Maggi, C Bönnemann) proposed have a second round of virtual session on 19-20 February 2021 in order to progress in the preparative work necessary to reach the initial aims of the workshop which are 1) to share available data on natural history in adult and pediatric SMLs among experts and 2) to create working groups focused on the identification of clinical outcome measures and biochemical, molecular and imaging biomarkers useful for natural history studies and future clinical trials.
Before this second event, a survey was circulated among all the workshop participants to collect the current status of the basic science research as well as the available data and knowledge related to clinical management of SML patients.
This second virtual session gathered 30 participants from Europe and America, including healthcare providers and researchers from Argentina, France, Italy, Netherlands, Spain UK and USA, as well as patients' and representatives from four advocacy associations (Cure-CMD, Fundacion Marcio Contra las laminopatías (FAM), Muscular Dystrophy UK (MD-UK), Associazione Italiana Distrofia Muscolare di Emery Dreifuss (AIMED)).
The meeting was opened by G Bonne (Paris, France), who welcome participants and gave an overview of the main objectives of this second session organized in 3 separated working group sessions with the aim to synthetize the answers of the survey. Three main topics were addressed:
1) Clinical aspects: classification/deep phenotyping, standards of care and clinical trial readiness.
2) Biomarkers and basic science axes: pathophysiology questions (target) to be addressed, therapeutic approaches under development, biomarkers for natural history and therapy monitoring, logistic aspects of collaborating projects: biobanking, shared expertise/technologies, organization of collaboration/complementary project(s).
3) Perspectives of patients and patient representatives: patient empowerment, how to share information (care/research) via social media (FB, Website….) and how to best “use” patient “resources”.
The meeting ended with proposition to hold regular short virtual sessions of 1h30 every two other months to allow each working group to further exchange and advance on preparative work on specific topics that would be presented at the face-to-face scheduled on December 10-12, 2021.

Round of virtual sessions were held on April 16th, June 18th, September 3rd and October 22nd 2021
As agreed on February 2021, a round of short virtual sessions were held on April 16th, June 18th, September 3rd and October 22nd with working group breakout sessions, one dedicated to clinical aspects and the second to basic science and biomarkers. The clinical working group exchanged on: i) phenotyping classification of SML, ii) standards of care related to cardiac, stroke, spine and respiratory involvement, motor defects and contractures, gastrointestinal, nutritional and metabolism problems, iii) psychologic and cognitive impact of SML, iv) potential interest to use corticoids and v) trial Readiness. The basic science and biomarkers working group had explored the following topics: i) how to identify and validate biochemical, molecular, imaging biomarkers for diagnostic, prognostic, monitoring clinical trial outcome, ii) pathophysiological mechanisms of fibrosis and contractures, iii) stem cells and muscle growth and regeneration and iv) role of modifier variants in the clinical variability of SML.

Date: 10 December 2021, third meeting
On December 10th 2021, once again the COVID-19 SARS2 worldwide pandemic context did not allow to meet in person as scheduled. Therefore, once again the 253rd international ENMC workshop was converted in a virtual session on December 10th 2021 and the in-person meeting was re-scheduled once again for June 24-26th, 2022.
The virtual session on December was dedicated to the patients’ perspectives, with reports from patient representatives on patients’ expectations and needs and time of exchanges between clinicians, researchers and patient’s representatives that highlights the difficulties faced by patients and their families to get correct diagnosis and adapted care once diagnosed. These discussions highlighted the patient needs and helps to prioritize the scientific and clinical questions that need to be tackle for SML. Non-clinical biomarkers were also further discussed with focus on how to define, select and validated them.
After almost 2 years of COVID-19 SARS2 worldwide pandemic context, all participants have learnt how to use and contribute virtually, and progress towards reaching the initial objectives of this 253rd international ENMC workshop have been made. Participants found it a successful experience which allowed experts in clinical and basic research, and patients and associative representatives to review updated data, interact in real-time and identify priorities and face future perspectives.
All these virtual meetings have been an excellent opportunity to update and deepen our knowledge of natural history of laminopathies, promoting the international research and collaborative studies to better characterize and follow our patients, while we all really hope to meet again in person on June 24-26th 2022.

Date: June 24-26, 2022, fourth hybrid meeting

After two successive postponements due to the COVID-19 SARS2 worldwide pandemic, the 253rd ENMC international workshop on Striated Muscle Laminopathies scheduled initially in March 2020 had been eventually held on June 24-26 2022 in Hoofddorp, The Netherlands.
Between March 2020 and June 2022, the Striated Muscle Laminopathies (SML) Consortium has been very active with numerous activities in order to progress in the preparative work necessary to reach the initial aims of the workshop which are 1) to share available data on natural history in adult and pediatric SMLs among experts and 2) to create working groups focused on the identification of clinical outcome measures and biochemical, molecular and imaging biomarkers useful for natural history studies and future clinical trials. Three virtual conferences were held in 30-31 October 2020, 19-20 February 2021 and 12 December 2021; surveys circulated as well as a series of short virtual sessions every two months along 2021 were organized in small working groups, see previous lay summaries of December 2021 & October 2020).
Thus, the Striated Muscle Laminopathies Consortium was extremely happy to eventually meet in June 2022 on a hybrid mode, gathering 31 participants, 21 in person and 10 connected remotely, from Europe and America, including healthcare providers and researchers from Argentina, France, Germany, Italy, the Netherlands, Spain, UK and USA, as well as patients and representatives from four advocacy associations (Cure-CMD, Muscular Dystrophy UK (MD-UK), Associazione Italiana Distrofia Muscolare di Emery Dreifuss (AIMED) and LMNACardiac.org. We had also two invited guest participants from industry, i.e. Sanofi and Nuevocore.
The workshop was opened by Dr Kate Adcock, member of the ENMC Executive Committee who welcome all participants and introduce the ENMC commitments and objectives. Then G Bonne (Paris, France) and Lorenzo Maggi (Milan, Italy) gave an overview of previous achievements since March 2020 as well as the main objectives of the workshop.
The workshop was organized in 8 sessions focused on:
1) Current status of research and how to fill the gaps of our understanding using various preclinical models
2) Patients ‘perspectives and needs,
3) Clinical recommendation and standard of care for the cardiac involvement and stroke
4) Clinical recommendation and standard of care for the skeletal muscle involvement
5) Current status and future of patient registries
6) Translational research with a focus on non-clinical and imaging biomarkers as well as identification of meaningful outcomes measures and e-CRF
7) Ongoing development of new therapies
8) Clinical trial readiness in striated muscle laminopathies

The workshop allowed substantial and productive discussions and ended with propositions for both further developments of preclinical research including deeper understanding of pathological mechanisms at play and development of therapeutic approaches as well as starting prospective natural history studies, all being necessary for complete clinical trial readiness for striated muscle laminopathies.

According to the patient voices and needs, it was agreed to:
1) Prepare Care Guidelines with support from the European Reference Network Euro-NMD for cardiac involvement in patients with skeletal muscle laminopathies.
2) Produce Consensus for management of non-cardiac features of striated muscle laminopathies for both adult and pediatric patients
3) Produce lay recommendations/guidelines to be produced towards the families
4) Set up, with the help of representatives from the advocacy associations, a shared international plateform gathering updated information with easy access for every patients and families.
5) Upgrade the French patient registry named OPALE towards an European/International patient Registry

In order to progress further towards clinical readiness, it was agreed to
1) Prospectively collect clinical and imaging data as well as biological materiel (i.e. blood serum) along the routine follow-up of patients
2) Retrospectively review available clinical data to clarify disease natural history, with specific focus on deep phenotyping, contractures, stroke, respiratory, spinal and gastrointestinal involvement.
3) Share between clinical centers eCRF and standard protocols to explore imaging data and to collect and store blood serum
4) Organize grant(s) proposal taking in account complementarity expertise of the different research teams to further develop preclinical research including identification and validation of biomarkers and development of therapeutic approaches
5) Write reviews of the current status of pathomechanisms knowledge of SML.

Finally coming together after a two year delay, the preparative work done in the meantime and finally the workshop itself have provided excellent opportunities to update and deepen our knowledge of natural history of laminopathies, promoting the international research and collaborative studies to better characterize, follow and care for SML patients.