Progress report

I.C. Overview activities and expenditure

2013 Budget
Total Action Budget:			75000
Remaining Action Commitment: for future meetings budget is in italics
Meetings
Meeting Type	Date	Place							Cost	Total
Other COST relevant meeting	2013-06-21	London, UK								4257
Management Committee	2013-09-25	Leiden, NL								8671
Workshops /Conferences	2014-01-30	Madrid, SP								5383
Core Group Meeting	2014-03-26	London, UK								3640
Management Committee	2014-04-30	Stockholm, SW								17000
Core Group Meeting	2014-05-26	Leiden, NL								5000
STSM
Beneficiary	Date	Place							Cost	Total
Rutten, J.W.	2013-07-15	NL								2300
Reza, M.M.	2013-10-21	UK								1320
Koeks, Z.	2013-10-21	NL								1765
Dias,G.F.L.	2013-12-06	FR								1200
Ruiz, E.	2013-12-06	ES								1900
Malcher, J.	2014-04-12	FR								2145
Left in STSM pot										2370
Workshops	(linked to MC meetings, so costs are shown twice)
Title	Date		Place						Cost	Total
	From	To	From	To
Workshop on Delivery for COST Action	2013-09-25	2013-09-26	Leiden, NL							(8671)
Workshop on Brain delivery	2014- 01-30	2014-01-31	Madrid, SP							(5383)
Workshop on AON Chemistry and Toxicology	2014-04-09	2014-04-10	Stockholm, SW							(17000)
General Support Grants
Beneficiary	Date								Cost	Total
										0
Schools
Title	Date	Place							Cost	Total
										0
Dissemination
Title	Date	Place							Cost	Total
Website										4500
Others
Management fee										8500
						Action Total :				69951

II. Scientific Report
II.A. Innovative networking

This COST Action aims to advance the development of antisense-mediated exon skipping for rare diseases, using Duchenne muscular dystrophy as a prototype. Several challenges hamper its development to wide clinical application: 1) There is no standardized protocol for important biological outcome measures, such as dystrophin restoration. 2) The approach is mutation specific; development for patient subgroups is challenging as most mutations are rare. 3) Fragmentation: several European groups work on preclinical optimization. 4) There is therapeutic misconception amongst patients and unrealistic expectations.

Towards standardisation of dystrophin quantification the biochemical outcome measures working group has distributed control and patient muscle samples in a blinded fashion to different expert laboratories for a head-to-head comparison of different methods currently used to assess dystrophin levels. This revealed a good correlation between findings of different laboratories and also between different analysis methods. A report describing this effort and its outcome is currently being drafted for submission to a scientific journal. Three early stage researchers have done an STSM to learn the standard techniques for dystrophin quantification. A meeting to discuss the way forward and discuss remaining challenges (e.g. common control samples between groups) is planned for March 26.
The regulatory models working group has been involved in preparing for and organizing a meeting to discuss draft guidelines for DMD clinical trials that were published by the European Medicine Agency in March jointly with the TREAT-NMD Alliance and patient advocacy groups. This meeting involved all key stakeholders (researchers and clinicians from academia, industry representatives, patient representatives and regulatory representatives) and was organized to allow drafting a consolidated response to the draft guidelines during the public consultation period. This response can be found on the Action website (http://exonskipping.eu/wp-content/uploads/2014/03/TREAT-NMD_Response_to_the_EMA_consultation_EMA_CHMP_236981_2011.pdf).
A core group meeting involving members from the biochemical outcome measures and regulatory models working group has been planned for May 2014 to discuss challenges of conducting trials in small patient groups, focusing on biochemical and functional outcome measures and different types of market approval. A statement paper will be drafted after this meeting by the participants.
Common challenges to the exon skipping field have been discussed in 3 workshops, focusing on delivery, delivery to the central nervous system and chemistry and toxicology. These workshops were done under a confidentiality agreement and participants primarily presented unpublished work. Ample time was available for discussion and each workshop involved ~50% early stage researchers, who had opportunities to present their work and to interact with the PIs during the workshop and the social dinner. Confidential minutes from each workshop have been drafted and distributed to the participants.

During our first MC meeting it was agreed that for each meeting at least one early stage researcher should be involved with the scientific programme and/or local organisation of the meeting.

In total 6 early stage researchers have done an STSM. Meeting reports have been written by most researchers and are available on the Action website (http://exonskipping.eu/stsm/). The opportunity to work in a different laboratory and learn new techniques was appreciated by all early stage researchers.
Our network website has been launched (www.exonskipping.eu) and contains information of the network objectives, instructions on how to apply for an STSM, lists the network participants, and products of the network amongst others.

A one slide summary has been generated as well as a networking poster to allow participants to present on the Network during meetings they attend.

• 
  Innovative knowledge resulting from COST networking through the Action. (Specific examples of Results vs. Objectives)
  
• 
  Significant scientific breakthroughs as part of the COST Action. (Specific examples)
  
• 
  Tangible medium term socio-economic impacts achieved or expected. (Specific examples)
  

The network is not yet one year old and is at the moment still growing and getting started. Nevertheless, several members of the regulatory working group have been asked by EMA to serve as external experts. Furthermore, in the US the Parent Project Muscular Dystrophy (PPMD) has organized a meeting with the Food and Drug Administration (FDA) (Duchenne Policy Forum, 12/12/2013, Washington DC, US) that was based on the COST meeting to discuss the EMA DMD guidelines. Following this meeting FDA has asked PPMD to coordinate the drafting of FDA guidelines for DMD clinical trials. The following members of the regulatory models working group have been recruited to contribute to this effort: Dr Aartsma-Rus, Dr Bushby, Dr Vroom and Dr Goemans. These guidelines are expected to expedite clinical development of therapies for DMD (including exon skipping).

• 
  Spin off of new EC RTD Framework Programme proposals/projects.
  

Plans to apply for Horizon2020 grants are in place and the ‘personalizing health and care for rare diseases’ (PHC14) fits perfectly with the exon skipping approach, since it is an innovative approach with therapeutic potential for rare diseases. It is anticipated that the Action Chair and one of the MC members will be co-applicants and that multiple members will be involved in this application.
Furthermore, the following international grant has been applied for:

Advances in oligonucleotide-mediated exon skipping for DMD and related disorders by Profs Muntoni and Straub (UK), Voit (France) and Verschuuren (the Netherlands); Association Francaise contres les myopathies. Requested budget €1,325,794 (outcome pending)

• 
  Spin off of new National Programme proposals/projects.
  

1. 
   In vivo and in vitro studies of affected cellular pathways and genetic therapies in neurometabolic diseases. PI : Lourdes R. Desviat, National grant application 2013 with the Ministry of Economy and Competitiveness. Outcome pending.
   
2. 
   Peptide-conjugated oligonucleotides for splice switching therapy of Spinal Muscular Atrophy. PIs: Matthew Wood, Francesco Muntoni and Mike Gate. MRC Development pathway funding scheme. Outcome pending
   
3. 
   Evaluation of peptide antisense oligonucleotides as gene therapy for myotonic dystrophy. PIs: Matthew Wood, Jack Puymirat and Mike Gait. Association Francaise contres les myopathies. Outcome pending
   
4. 
   Antisense-mediated modulation of splicing for neuromuscular disorders. PI: Annemieke Aartsma-Rus. Prinses Beatrix Spierfonds. Outcome pending
   
5. 
   Development of a U1 snRNA-adapted gene therapeutic strategy to correct 5’ splicing defects in Lysosomal storage disorders. Liliana Matos and Sandra Alves. Portuguese Society of Metabolic Diseases/Genzyme (€5000)
   

II.B. Inter-disciplinary networking

• 
  Additional knowledge obtained from working with other disciplines within the COST framework. (Specific examples)
  
• 
  Evaluation of whether the level of inter-disciplinarity is sufficient to potentially provide scientific impacts. (Specific examples)
  
• 
  Evaluation of whether the level of inter-disciplinarity is sufficient to potentially provide socio-economic impacts. (Specific examples)
  

Different stakeholders are involved in this COST Action, i.e. patient representatives, clinicians involved in the exon skipping trials, researchers, people working for Industry and for the regulatory agencies to provide different perspectives towards working to the objectives.
A link is in place to COST Action BM1304, focusing on MRI analysis, which can provide an additional outcome measure for clinical trials. In the future, joint workshops or meetings may be organized when there is a need for this.
Should there be a need for additional expertise to achieve the objectives, we will exploit the multi-disciplinarity of COST. Currently all required expertise appears to be in place.

II.C. New networking

• 
  Additional new members joining the Action during its life.
  

At the time of the application, 5 countries were involved in this Action (the Netherlands, Sweden, France, UK and Italy). At the kick off meeting in April 2013, 9 countries had signed up (Germany, Israel, Norway and Spain in addition to the countries applying for the Action). During the first year, 4 more countries have joined (Belgium, Denmark, Malta and Portugal).

• 
  Total number of individual participants involved in the Action work. (Give % of female and of early stage researchers)
  

Total number of participants: 79

Percentage of females: 63%

Percentage of early stage researchers: 48%

• 
  Involvement of Early Stage Researchers in the Action, in particular with respect to STSMs, networking activities, and Training Schools. In addition, justification should be provided if less than 4 STSMs were carried out during the year.
  

6 STSMs were conducted so far during this year, all by early stage researchers.

Early stage researchers were part of the scientific and logistic programme committees for organizing Networking Workshops and as such they were involved in the generation of the agenda, providing participants with logistic information and arranging the networking dinners. During each workshop from each institute one PI and one early stage researcher is entitled for reimbursement, thus facilitating the participation of early stage researchers to the workshops. The workshop host is allowed to invite up to 10 early stage researchers to the workshop as an incentive to host the workshops and provide extra opportunities for early stage researcher to build a network and present and discuss their work (these locally invited early stage researchers have not been included in the statistics for the previous question).

• 
  Involvement of researchers from outside of COST Countries. (Number of participants from non-COST Countries approved by the CSO. Give % of such participants from countries with reciprocal agreements. Specify their contribution)
  

Prof Eric Hoffman from Children’s National Medical Center (Washington, USA) is the only participant from a non-COST country. He discovered dystrophin and is a world expert on dystrophin analysis. He is involved in the biochemical outcome measures working group and provides expertise on dystrophin quantification. He uses his own funding to attend meetings.

• 
  Advancement and promotion of scientific knowledge through publications and other outreach activities. (Number of publications and other outreach activities that resulted from COST networking through the Action. Complete list should be given in an annex)
  

Network participants contributed to a special focus issue of the Nucleic Acids Therapeutics journal on exon skipping and the editorial introduced COST and the Network to the readers (http://online.liebertpub.com/doi/pdfplus/10.1089/nat.2014.1500).
The COST Action has been presented and announced at numerous scientific and patient meetings (see Annex for a complete list).

• 
  Activities and projects with COST network colleagues.
  

Joint research projects are ongoing between different participants (see list), and joint grant applications have been applied for.
Ongoing collaborations:

1. 
   Dr El Andaloussi, Edvard Simth (Sweden) and Dr Gait (UK) collaborate on
   

• 
  splice-switching in X-linked agammaglobulinemia
  
• 
  lipopeptide delivery of PMO for DMD treatment
  

2. 
   Dr Aartsma-Rus (Netherlands) and Dr Wood (UK) collaborate on miRNA analysis in serum of DMD mouse models
   
3. 
   Dr Aartsma-Rus (Netherlands) and Dr Bushby, Straub and Lochmuller (UK) collaborate on biomarker discovery in NMD patient serum
   
4. 
   Dr Aartsma-Rus (Netherlands) and Dr Khoo (UK) collaborate on exon skipping as a potential therapy for hypercholesterolemia
   
5. 
   Dr Aartsma-Rus (Netherlands) and Dr Krause (Germany) collaborate on exon skipping in the DMD pig model
   
6. 
   Collaboration in the Liliana Matos PhD project “Splicing Therapeutics for Lysosomal Diseases”. Drs Alves and Matos (Portugal) with Dr Desviat (Spain)
   
7. 
   Natural history studies for DMD with profs Muntoni, Straub (UK), Voit (France) and Verschuuren (the Netherlands)
   

• 
  The capacity of the Action members to raise research funds.
  

Sufficient funds are currently available to conduct the exon skipping research in the groups of the participants from national and international grants, e.g. participants are involved in FD7 projects such as NEUROMICS, SKIP-DMD, SCOPE-DMD, Bio-Image. The Network actively looks to obtain further funding.
II.D. Self evaluation
Indicate in no more than 1 page what, in the opinion of the MC, were the main successes, drawbacks (if any) and the key difficulties encountered (if any).
The MC appreciates the following opportunities COST offers:

• 
  Networking opportunities for both established scientists and early stage researchers
  
• 
  The flexibility of the system that allows to organize workshops on selected topics in a timely fashion
  
• 
  The open system where new members can join the Action
  
• 
  The opportunity for STSMs with a very flexible system
  

Main successes so far:

• 
  3 workshops on key challenges that were very valuable to all participants
  
• 
  6 STSMs that were highly valued by the early stage researchers
  
• 
  Launching of the website (www.exonskipping.eu)
  
• 
  Arranging with Nucleic Acids Therapeutics to have a focus issue on exon skipping to highlight this approach and introduce the network
  
• 
  The meeting to discuss the EMA DMD guidelines of clinical trials, leading to a consolidated response, a similar meeting in the US with the FDA and the FDA requesting for guidelines to be drafted for the US
  

Drawbacks

• 
  The difficulty of reimbursement in a timely fashion (this is mainly due to different rules applying to COST and the Grant Holder and some participants being extremely tardy with filling out their reimbursement forms)
  
• 
  The fact that for some countries it is much more difficult to join the Action than for others (e.g. colleagues from Switserland have been trying for months but there is an absurd amount of paperwork involved in this)
  
• 
  The fact that when the Action grows over the course of the year, the budget for workshops is no longer sufficient at the end of the year (because the number of participants increased)
  

III. Previous scientific report(s)
Not applicable.