Graz, 25 th
/ 26 th
November 2013
12 th of January 2014
Preface ..................................................................................................................................................... 2
Executive Summary and Main Recommendations .................................................................................. 3
1. Mission ................................................................................................................................................ 4
2. Funding, Facilities, Equipment and Staffing ........................................................................................ 4
3. Results ................................................................................................................................................. 4
Programme Line A: Pathomechanisms of Vascular Remodelling – Reverse Remodelling Strategies . 5
Programme Line B: Pharmacologic Tailoring and Assessment ........................................................... 5
Programme Line C: Non‐invasive Diagnostics of Pulmonary Hypertension ........................................ 6
Programme Line D: Clinical Data Base and Clinical Studies ................................................................ 7
4. Partners ............................................................................................................................................... 8
5. Organization Structure and Governance ............................................................................................. 8
6. Promotion of Young Researchers ........................................................................................................ 9
7. Outlook and Recommendations for the Future Development ........................................................... 9
Evaluation Report LBI LVR, Graz November 2013
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Evaluation Report LBI LVR, Graz November 2013
Preface
The Ludwig Boltzmann Gesellschaft (LBG) invited an international team of experts in order to evaluate the
Ludwig Boltzmann Institute for Lung Vascular Research (LBI LVR) in Graz at 25 th and 26 th of November 2013.
This evaluation is a regular procedure within the statutes of LBG after three years of setting up a Ludwig
Boltzmann Institute. Independent external experts are invited to evaluate the results of the past period and to give recommendations for the future development.
The LBG Head Office generated a comprehensive set of questions which served the evaluation panel as terms of reference. The evaluation results are based on the following facts and actions:

The LBG Head Office provided the evaluation panel with the following material one month be‐fore the on‐site‐visit: o The institute´s evaluation report o Annual reports 2010, 2011 and 2012 o Minutes of the meetings of the Scientific Advisory Board 2011, 2012, 2013 o Proposal for setting up the Institute (2009)

The evaluation panel visited the LBI LVR on 25 th and 26 th of November 2013. Together with the institute, the LBI Head Office had prepared an agenda allowing for contacts with relevant staff groups: o Directors o Key researchers and doctoral candidates o Employees charged with scientific service o Members of the Scientific Advisory Board o Representatives of partner organisations
The meetings of the review panel were chaired by Prof. Rubin. The panel had the opportunity to set its own priorities and to adapt the composition of the interviewed groups. The review panel declares that it had full access to the relevant informants and was free to ask any questions. The LBI head of‐fice accompanied and supported the panel in an excellent way without any influence on the evaluation process or result. The review panel wishes to express its appreciation for this cooperative approach.
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Evaluation Report LBI LVR, Graz November 2013
Executive Summary and Main Recommendations
The Ludwig Boltzmann Institute for Lung Vascular Research (LBI LVR) is dedicated to contribute to the better understanding of the pathomechanisms underlying different forms of pulmonary hypertension and to develop new reverse‐remodelling therapies to improve the outcome of this devastating disease.
In the first 3.5 years of its existence, the institute has completed a very impressive establishment, started obtaining international visibility and presented excellent results. All in all, the review panel assesses the institute’s performance as excellent with the potential to achieve an outstanding position in the future.
Therefore, the review panel emphatically recommends continuing its funding. It also strongly encourages the institute to continue its devoted engagement in research and translation of the results to the clinical situation. Thereby it should even more consequently take advantage of its intrinsic strengths that are, for instance, access to a unique patient cohort at risk for pulmonary hypertension, extraordinary facilities combining clinical and research environments, highly motivated and compe‐tent staff, excellent leadership, and strong competences in physiology and ion channel science, to mention just the most striking examples.
In order to strengthen the institute’s successful development, particular attention should be paid to the following recommendations (highlighted in boldface in the full text of the evaluation report):
1.
The size of the institute in terms of staff is ideal for intensive exchange and trustful cooperation, which is stimulating the scientific activities in an optimal way and allows for a flat hierarchy. In order to profit from these advantages also in the future, it is recommended to maintain the pre‐sent dimensions at least until a certain level of investigator maturation and sustainable produc‐tivity is achieved that allows for expansion.
2.
On the base of a detailed and coherent planning, the institute should eventually shift its focus towards clinical applications of its basic research findings. To this end, the programmes should be overhauled with regard to their potential to increase the translational nature of research.
3.
Having established a broad and solid base, the LBI should now focus, to a greater extent, on carefully selected questions allowing for building on the institute’s specific strengths. Especially trans‐lating the knowledge on ion channel biology into clinical practice appears a promising approach. Another very interesting and promising object of future investigations might be the field of “om‐ics”.
4.
It is recommended to identify new cooperation partners that might be other LBIs, academic institutions, companies or health care providers, in order to further increase the institute’s interna‐tional visibility and to prepare for the second phase of LBG funding.
5.
To meet the high quality of the institute’s scientific findings, it is recommended to take the time necessary for maturing the results in order to facilitate their publication in internationally visible, high impact journals. The review panel expects that this would lead to a further rise in the quality of the publications.
6.
The interconnections between the different programme lines should be intensified in order to even more efficiently use the institute’s resources and to increase the advantages given by the favourable conditions of combined basic and clinical research.
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Evaluation Report LBI LVR, Graz November 2013
1. Mission
The LBI LVR is dedicated to investigate the fields of pulmonary vascular biology, vascular diagnostics, and reverse‐remodelling therapy by combining experimental know‐how, innovative imaging technology and clinical background for high‐yield research in an integrated approach, in order to develop new diagnostic tools and therapies for pulmonary vascular diseases.
This mission is considered to be sound and scientifically sustainable. The evaluation panel considers pulmonary hypertension to be a severe disease featuring a high mortality and characterized by a markedly decreased exercise tolerance and right‐sided heart failure. Its diagnosis is still very chal‐lenging, especially at an early stage, which yet remains very important to improve the patient’s con‐dition. Current therapies improve symptoms and outcome but are not curative. Hence, the institute’s efforts to develop novel therapies targeting newly identified pathogenic mechanisms are of highest scientific and clinical relevance.
2. Funding, Facilities, Equipment and Staffing
Funding
The institute’s funding is appropriate for the tasks to be accomplished and allows for adequate working space, acquisition of equipment and facilities, and staff employment. It is welcomed that the institute’s management has cared for preparing comprehensive applications for third party funding.
Facilities and Equipment
In terms of facilities and equipment, the institute disposes of extraordinary conditions: The review panel was particularly impressed by the sophisticated infrastructure – including a comprehensive human tissue bank, cutting edge facilities and state of the art instrumentation – that has been in‐stalled and further developed since the establishment of the centre.
Staffing
Staff at LBI LVR are highly qualified and strongly motivated. There is a very good atmosphere, trustful cooperation and a positive team spirit encouraging good ideas and creativity. At present, the proportion of clinical staff is reasonable. As they are providing the access to human tissue samples, they have a key function for the whole investigation. Since an increase of the research’s clinical relevance is expected, it should be examined whether the clinical staff can be augmented if necessary.
3. Results
All in all, in 3.5 years, LBI LVR has achieved more than expected compared to the planning and expec‐tations drafted in the proposal. This is considered an excellent result. Based on very sophisticated mouse models and human tissue analyses, the institute has been able to identify new pathogenic targets and to initiate the translation of these findings to the clinical situation.
Since its establishment, the institute has presented outstanding scientific insights and generated a very good publication record. The institute’s open access policy is appreciated. To meet the high quality of the institute’s scientific findings, it is recommended to take the time necessary for matur‐ing the results in order to facilitate their publication in internationally visible, high impact journals. The review panel
expects that this would lead to a further rise in the quality of the publications.
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Evaluation Report LBI LVR, Graz November 2013
Programme Line A: Pathomechanisms of Vascular Remodelling – Reverse Remodelling Strategies
The major goal of programme line A is to delineate the mechanisms that lead to pulmonary vascular remodelling. The institute considers this being especially important because of the recent shift in treatment paradigm from vasodilatory to anti‐remodelling and even “reverse‐remodelling” thera‐peutic strategies for pulmonary hypertension. It states an urgent need for novel therapies addressing the full range of mechanisms intrinsic to pulmonary hypertension pathology in order to allow for the identification of both significant new therapeutic targets and new disease biomarkers that could en‐able specific diagnosis and therapy monitoring. Hence, the primary objectives of the programme line include the establishment of human pulmonary hypertension tissue bank, the characterisation of novel signalling pathways, contributing to the development of pulmonary hypertension, and the identification of novel molecular targets for therapeutic interventions.
In the short time since the establishment of the centre, remarkable results have been achieved and proved the strong capability of the team. In particular, the identification and description of pathome‐chanisms, pathways and new biomarkers relevant for protection and diagnosis are considered to be major strengths of this programme line. By validating newly discovered signalling pathways in animal models and human tissue, significant progress has been achieved. In particular, the finding that me‐prin‐β plays a significant role in the pathobiology of pulmonary hypertension provided a nice exam‐ple of pursuing approaches discovery in human samples, with reverse translation to the mouse and back to man. It is welcomed that these findings will be further pursued by the pharmaceutical con‐sortium partner, Bayer.
Another important strength of the programme line is its unique expertise in ion channel biology which is particularly relevant for genetic research. Here, the researchers capitalize on their assets and profit from the investment of time and resources in the development of complex mouse models. It is welcomed that, after having started on a broad base of interests, the team has dropped some objects of lower interest and is now focussing on few highly promising pathways. Now, the team is challenged by the task of validating its hypotheses and indentifying underlying connections.
So far, the publication outcome of programme line A is assessed very good, but should be improved in the future by fully exhausting the great potential of the scientific methods and results. In particu‐lar, it is recommended to further mature the findings in order to publish more comprehensive and profound results in internationally visible journals with high impact.
Overall, programme line A is considered to be LBI LVR’s strongest pillar providing an excellent per‐formance and bearing the potential for even outstanding results in the next few years.
Programme Line B: Pharmacologic Tailoring and Assessment
This programme line focuses on the development of novel therapeutic options for the treatment of pulmonary hypertension using nanocarriers as delivery systems. Moreover it aims at the establish‐ment and application of complex animal models. Primary objectives of the programme line include the design, development and biophysical characterisation of liposomes / micelles as nanocarriers for pulmonary application, the optimisation of liposomal formulations for specific drugs and substances for reverse remodelling in terms of encapsulation efficiency and controlled release profiles, the adap‐tation and optimisation of drug loaded liposomes / micelles for advanced inhalation devices, the es‐
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Evaluation Report LBI LVR, Graz November 2013 tablishment of reliable in vitro model systems for stability and release assessment, the characterisa‐tion of aerosols and its stability and release profiles in vitro, the development of reliable inhalation devices combined with nanoparticle delivery systems for animal models of pulmonary hypertension and for pulmonary hypertension patients, and the establishment of complex animal models of pul‐monary hypertension with clinically relevant end points.
Currently, in Europe the only approved inhalable medication for treatment of pulmonary hyperten‐sion is the prostacyclin analogue, iloprost (Ventavis, Bayer Healthcare). However, due to its short bio‐logical half‐life, long and frequent inhalation manoeuvres are required. Even though the review panel recognises the good intention of trying to optimize the pharmacological dynamics of iloprost by modifying the delivery of the molecules, in order to enhance the duration of the drug intensity and minimizing negative side effects, the results of programme line B have been disappointing so far. The publication outcome is not significant, and the focus of the investigation is too narrow. The whole investigation is rather an experiment than a comprehensive programme line. A marketable product that could have been a result of programme line B’s efforts has not been realized so far. Conse‐quently, it seems that the relevant consortium partner
Nebu‐Tec GmbH is no longer interested in and committed to this programme line.
Nevertheless, from a methodological viewpoint, the experiments are very interesting and can be used in the context of other topics. As the institute disposes of considerable resources allowing for application of the models, methods and technologies, the LBI management is encouraged to develop new and more promising questions in order to use them more efficiently. Research on the right ven‐tricular dysfunction, for instance, would be a more relevant objective. Focussing on cardio‐pulmo‐nary physiology would also facilitate the identification of clinically relevant aspects that are highly relevant for the investigations of programme line A.
From a methodological viewpoint, and also taking into account the sophisticated mouse models, programme line B is considered providing a very good performance. Nevertheless, the optimisation of liposomal formulations should no longer be pursued, because it is unlikely to be successful.
Programme Line C: Non‐invasive Diagnostics of Pulmonary Hypertension
As it is especially difficult to identify the early changes in the development of pulmonary hyperten‐sion, the aim of programme line C is to provide quantitative, non‐invasive and reproducible tech‐niques with minimal user intervention for the early diagnosis of this disease. The investigations are based on the hypothesis that the quantitative assessment of the pulmonary perfusion and vascula‐ture by means of chest CT imaging can yield relevant, reliable and easily accessible information about the presence and severity of pulmonary hypertension. The results are compared with the results of gold‐standard examinations as provided by the clinical programme line.
Primary objectives of this programme line include providing a reliable non‐invasive assessment of regional pulmonary perfusion using chest CT in patients at risk for pulmonary hypertension, provid‐ing assessment of cardiac output and distinguishing Pulmonary Arterial Hypertension (PAH) from non‐PAH pulmonary hypertension.
As the early detection of dysfunction (even before pulmonary hypertension is manifest) is considered to be crucial for improving the chances of alleviating the disease’s effects, the aim of developing non‐
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Evaluation Report LBI LVR, Graz November 2013 invasive diagnostic tools is highly relevant. Once they have been validated, these techniques could become part of routine diagnostic procedures.
In order to identify signs of vessel loss prior to the manifestation of pulmonary hypertension, it is recommended to systematically include patients at high risk for pulmonary hypertension. The institute’s scleroderma cohort (involved in activities of programme line D), for instance, could be inte‐grated into the investigations. Also, the team should increase its collaboration with programme line A and check whether the findings relating to relevant biomarkers can be more consequently incorpo‐rated into the research design.
Overall, programme line C is considered providing a very good performance bearing the potential for even excellent results in the next few years, as far as validation of the assumptions has been achieved.
Programme Line D: Clinical Data Base and Clinical Studies
The major task of programme line D is connecting the institute’s basic research results with clinical science.
In close cooperation with the Division of Pulmonology at Graz Medical University, clinical datasets of patients suffering from pulmonary hypertension who have undergone a complete diag‐nostic work‐up are systematically collected and analysed. In addition, the clinical data of well characterized groups of patients at risk for pulmonary hypertension are interpreted. Moreover, in an ongo‐ing cooperative project with the lung transplantation programme at the Medical University of Vienna, a tissue biobank consisting of ca. 100 lung tissue specimens from explanted diseased lungs in‐cluding 13 IPAH lungs and from healthy donor lungs has been established. This is an important cor‐nerstone for identification of new pathophysiological mechanisms and targets for translational re‐search.
Primary objectives of programme line D include the recruitment of pulmonary hypertension patients, the promotion of non‐invasive diagnostic and follow‐up tools and the improvement of early recogni‐tion and adequate early management of pulmonary hypertension. An important focus in this respect has been the physiology and pathophysiology of the pulmonary circulation at rest and during exer‐cise.
With regard to the short period of the institute’s establishment, the results of programme line D are very impressive. A considerable number of patients have been included in very thorough investiga‐tions and a careful characterisation of their disease. The publication outcome is considered very good and having already a high international visibility. The importance of programme line D’s activities for programme lines
A and C is evident. Nevertheless, the cohort of patients with manifest pulmonary hypertension remains modest in size. In order to achieve more efficient results, it is recommended to develop a cohort enrichment strategy with particular consideration of scleroderma patients and to increase internal collaboration especially with programme line C. Such cohorts would provide the basis for novel discovery of biomarkers and genetic susceptibility factors, potentially as part of larger collaborations.
Overall, programme line D is considered providing an excellent performance bearing the potential for even outstanding results in the next few years.
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Evaluation Report LBI LVR, Graz November 2013
The interconnections between the different programme lines should be intensified in order to even more efficiently use the institute’s resources and to increase the advantages given by the fa‐vourable conditions of combined basic and clinical research.
4. Partners
Members of the LBI LVR consortium are Bayer Pharma AG, Nebu‐Tec GmbH and Graz Medical University.
The review panel had the occasion only to meet representatives of Bayer Pharma AG and Graz Medical
University who are very much committed and have confirmed their interest in continu‐ing the synergetic and fruitful cooperation. Nebu‐Tec GmbH, however, the primary sponsor of pro‐gramme line B, which is anticipated to be discontinued, was unavailable.
It is recommended to identify new cooperation partners that might be other LBIs, academic institu‐tions, companies or health care providers, in order to increase further the institute’s international visibility and
to prepare for the second phase of LBG funding (2017 to 2023), when the contribution of the Ludwig
Boltzmann Gesellschaft will decrease from 60 % to 40 %.
5. Organization Structure and Governance
Institutional Framework
The Ludwig Boltzmann Gesellschaft is congratulated for having installed, since 2005, such an intelligently conceptualized research institution like the new generation of LBIs. Characteristic and constructive features are the competitive procedure of installation, the establishment of a mandatory but flexible partner consortium, the limitation of the funding period to 14 years at maximum with mid‐term evaluations and the obligation to acquire 40 % (in the first phase) and 60 % (in the second phase) of the funding by consortium partners or external donors. These characteristics enhance the quality, competitiveness and potential of sustainability of the whole endeavour.
Organization Structure and Governance of LBI LVR
The institute’s organization chart is helpful to carry out the tasks. Moreover, its scientific leadership is excellent. The scientific director is not only an excellent and visionary scientist but also a very good science manager with strong competences in conceptualizing research programmes and projects, as well as in social leadership. With her distinguished commitment, the institute is about to develop into an internationally recognized centre.
The size of the institute in terms of staff is ideal for intensive exchange and trustful cooperation, which is stimulating the scientific activities in an optimal way and allows for a flat hierarchy. In or‐der to profit from these advantages also in the future, it is recommended to maintain the present dimensions at least until a certain level of investigator maturation and sustainable productivity is achieved that allows for
expansion.
Quality Management
As proved by the results, the institute’s internal quality management system is very good. Moreover, the
Scientific Advisory Board (SAB) is composed of outstanding and very experienced senior re‐
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Evaluation Report LBI LVR, Graz November 2013 searchers who have demonstrated an enormous commitment and carried out a thorough assess‐ment of the institute’s progress. It is welcomed that the institute’s leadership has been very respon‐sive to SAB’s advice.
6. Promotion of Young Researchers
The institute is an extraordinary stimulating learning environment for young scientists. It is wel‐comed that the partnership with the university allows for an optimal training and supervision of the doctoral candidates. As a result, the doctoral candidates are highly motivated and very productive.
7. Outlook and Recommendations for the Future Development
The institute is considered having built, in the first 3.5 years, a very solid base that, in the future, will allow for outstanding research result and an increase of international visibility. Constitutive elements of this base are an excellent infrastructure, mainly provided by Graz Medical University, sound insti‐tutional support by the Ludwig Boltzmann Gesellschaft, complementary consortium partners, the scientific qualification and quality of the young investigators and the experience and leadership com‐petences of the senior investigators.
Prospects of the institute’s further development in the second half of the first funding phase include a comprehensive package of innovative and very promising topics of investigation. In general, the review panel is expecting that translational aspects will become more and more relevant in the com‐ing years. This would be a consistent follow‐up.
In order to promote the institute’s further development, the review panel suggests observing the following recommendations:

On the base of a detailed and coherent planning, the institute should eventually shift its focus towards clinical applications of its basic research findings. To this end, the programmes should be
overhauled with regard to their potential to increase the translational nature of research.

Having established a broad and solid base, the LBI should now focus, to a greater extent, on carefully selected questions allowing for building on the institute’s specific strengths. A very
in‐teresting and promising object of future investigations might be the field of “omics”.
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