 Introduction History and geographical location of the unit

The current UMR-S951 (Molecular Immunology andInnovative Biotherapies, 2009-2013) is structured as a single unit (team 1), representing one of the research groups of the R&D department at Genethon, with three main axes of research:

(I) elaborate treatment of primary immune deficiencies by gene therapy with the use of advanced vectors;

(II) study mechanisms of vector/cell interactions, in particular those that cause epigenetic changes in transduced cells;

(III) study immune responses induced by viral vectors in vivo.

The unit has grown from 18 staff members to 28 in 2013, 21 permanent staff and of these 12 permanent research staff, two postdocs and four PhD students.

The new UMR proposes an extensive translational research program, involving biological systems and pathophysiology, genetics and gene-based technology with the perspective to develop novel therapies for rare genetic diseases. Because of significant interactions that have been established during the past five years between researchers of team 1 and the incoming team 2 (Novel gene-based therapies for neuromuscular diseases: Mr Fulvio MALVILIO), both teams will be associated within a single unit for the purpose of further enhancing interactions and building future synergies. Each team will have several groups of researchers with specific projects.

The new UMR, tutored by Inserm, UEVE, EPHE and Genethon, will form the "Academic Research" group at Genethon and will be located at Genethon, 1bis Rue de l'Internationale -91000 EVRY.

The team joining this new UMR is currently at Genethon.

Management team

The new UMR will be headed by Dr. Anne GALY who also heads team 1. She will be assisted by Dr Fulvio MALVILIO (Chief Scientific Officer of Genethon and head of team 2). 2  Overall assessment of the unit

AERES nomenclature

The director of UMR-S951 has high international visibility, strong international collaborations and is leadpartner in international networks.

UMR-S951 has carried out successful preclinical research resulting in four international clinical trials and has been instrumental in drawing full benefit from original methods that have been developed, including patent filing. There is an active partnership with patients' groups. Although acting as a dynamic interface between academia and biotechnology industry, the level of academic output of the unit is average and is perfectible.

The UMR is characterized by a very good internal organization permitting the establishment of optimal interactions between all groups. Free core facilities at Genethon allow for very good accessibility to research platforms.

The UMR is well implicated in university teaching, makes strong efforts in training doctoral students and is strongly involved in the training programs of the Doctoral Schools of Université d'Evry and the EPHE.

UMR-S951 has developed an exciting five-year plan with high-risk elements. The strategy is based on excellent cell biology and translation of experimental results into clinical applications. There is, however, a need for some refocusing. Combining the future teams to form a new research unit will increase critical mass. Synergistic, mutually beneficial, interactions between these teams will permit the achievement of proposed projects.

Strengths and opportunities related to the context

 Strengths

The unit has strong international visibility and recognized expertise in the field of gene therapy, in particular in Wiskott Aldrich Syndrome gene therapy with gene-corrected stem cells, using lentiviral hematopoietic gene therapy, and more recent expertise in X-linked chronic granulomatous disease with engraftment of gene-modified hematopoietic stem cell and granulocyte correction.

The director is lead-partner in several international networks: ongoing international clinical trials and collaborations with groups in London, Boston, Milano, and Paris, as well as an EC network with eleven other European laboratories.

Genethon provides very good access to various core facilities.

Strong collaboration with Genethon allows for excellent valorisation of research towards clinical applications.

This Unit constitutes a dynamic interface between academia and biotechnology industry.

Quality of the SWOT analysis is excellent, realistic and self-critical.

Opportunities

There is ample opportunity to associate with other researchers at Genethon thus increasing critical mass. Establishment of team 2 will strengthen the UMR and generate an even stronger team in neuromuscular disorders.

Genethon is in a favorable phase for the development of excellence in academic activity and research.

There will be the opening of an academic environment close to Genethon with the establishment of a large campus at the Université Paris Saclay.

Weaknesses and threats related to the context

Scientific output in terms of publications (impact factors) is average.

Research focus is wide rather than deep.

The current UMR has suboptimal critical mass and an imbalance between the number of investigators/Staff Scientists and Postdocs/PhD students.

The unit faces the challenge to maintain an adequate balance between academic and applied activities.

The UMR lacks sufficient expertise in bioinformatics.

A complex organization makes it a challenge to direct a unit where several independent organizations are involved to support and finance the operation.

The UMR is physically separated from a strong University Hospital as well as a strong academic environment, which is definitively a weakness and possibly a threat for development of original research beyond state-of-the-art.

Strong competition in the field.

Recommendations

The project on increasing efficiency of lentiviral transduction focuses on viral entry, but does not fully take into consideration the cell biology aspects of stem cells to improve their survival, activation, maintenance or possible increase in self-renewal to improve gene transfer efficiency. The focus on cell biology should be improved instead of only focusing on the vector/viral issues. The director has a strong background in cell biology from her years as an immunologist and could contribute.

There are many projects within the UMR that are somewhat disperse. The question is whether all these projects can be internationally competitive at the highest level. The program should be focused more to generate international competitiveness. The most important projects are the immunodeficiency projects and improvement of lentiviral gene transfer. The immune response to viral DNA seems out of focus of the main program and it is unclear whether the immune sanctuaries and epigenetics part can be competitive.

The unit has many permanent employees and relatively few postdocs and PhD students. It may lead to a more dynamic, original and creative environment if a higher number of outstanding postdocs with transient employment of 3-4 years come to generate innovation and leave once their project is finished.

 Detailed assessments Assessment of scientific quality and outputs

The UMR has a high-risk approach with methodological breakthroughs. There is an excellent focus of UMR 951 on translational research and the development of novel tools to achieve safe and efficient gene therapy in primary immune deficiencies. In particular, its preclinical research on Wiskott Aldrich Syndrome (WAS) has explored an original approach. Experimental data obtained from models of WAS gene therapy and lentiviral technology have been successfully translated into ongoing international Phase I/II clinical trials of gene therapy for WAS in France, Great Britain and the United States. The development of strategies of lentiviral-based gene therapy by the unit is highly promising, as WAS lentiviral vectors -unlike LTR-driven Murine leukemia viral vectors, the use of which has led to a high frequency of leukaemia -do not have transforming activity. At present, seven patients have been treated using the lentiviral-based gene therapy developed at Genethon with encouraging results. Results from a parallel trial involving treatment of three WERE patients with TIGET in Milano, Italy, with the same vector have been published recently with the UMR's director as collaborator in this study. Results from these studies have been published. More recently, expertise in the clinical grade manufacturing of a lentiviral vector to be used for the treatment of Xlinked chronic granulomatous disease has been acknowledged, as part of an EC network with 10 others European laboratories. However, no results have been published as yet.

Mechanisms that induce humoral immune-responses against viral components of recombinant adeno-associated viral vectors (rAVV) have been investigated using various murine models with targeted mutations in genes involved in innate immune responses. This work has been published.

The UMR has developed a family of cationic amphipathic peptides referred to as Vectofusins® that are active on several lentiviral subtypes and that enhance the frequency of transduced hematopoietic stem cells. One of these peptides in particular, Vectofusin-1®, a promising additive that could significantly ameliorate hematopoietic stem cell gene therapy, has been published, trademarked, and patented.

The UMR is exploring different epigenetic contexts (histone modifications) that will affect retroviral vectors in their choice of integration sites. It has also taken up the very important issue of determining the impact of gene transfer protocols on the epigenetic status of the host cells. This has allowed them to document changes in DNA methylation induced by the cytokines used for pre-activation of the cells, but also by the lentiviral vector itself. These approaches will be very precious to design safer protocols and vectors. To increase efficiency of gene transfer, the UMR finally shows much interest for the fluctuating expression of both endogenous genes and transgenes. This project, at the interface between epigenetics, vectorology, and systems biology is carried out in collaboration with cellular biology and bioinformatics labs in the context of an ANR-program.

The immunology project, involving immune sanctuaries in the field of neuroimmunology has yielded no publications yet within the setting of the UMR-S951

During the period 2008-2013, 46 original peer-reviewed articles with one team member as first and/or last coauthor have been published. Although the very good experimental results have been published in solid specialized scientific journals (Gene Ther, Mol Ther, PloS One, Hematologica and Mol Ther Nucleic Acids), output in terms of impact factor needs to be improved.

The experts committee judges the cited scientific output "very good".

Assessment of the unit's academic reputation and appeal

Members of the unit have been part of organizing committees for national and international congresses in the field of gene therapy, gene expression, and neuroimmunology and are regularly invited to international conferences, as speakers or chairpersons, as well as invited seminars and lectures. The UMR's director is on the editorial board of the journal Human Gene Therapy and on the Gene Therapy committee of the International Society for Cell Therapy. She participates in and coordinates international research programs and is lead partner in international networks.

Members of the UMR participate in scientific evaluation committees and the director is president of the CSS8 permanent scientific evaluation commission of the Inserm.

UMR-S951 has been highly successful in the establishment of international networks and participation in EC-FP6 (n=1) and EC-FP7 (n=3) grants resulting in high number of international collaborations. The UMR has been successful in raising funds from national, institutional, and private funds.

Based on these observations, the experts committee judges the academic reputation and appeal of the UMR "excellent".

Assessment of the unit's interaction with the social, economic and cultural environment An important asset of the research program of the UMR is its strong involvement in translational research with a clear aim at bringing results generated from basic research to clinical applications. Work carried out by the team has an important impact on therapeutic approaches with respect to gene transfer. Two patents, pertaining to the development of peptides with viral infection-enhancing properties and production of enveloped viruses, have been deposited.

All members of UMR-951 are actively involved in the dissemination of scientific knowledge to the general public, via organized visits to Genethon, open days for various patient's associations and AFM/Telethon events. Overall contribution of the unit to interactions with social, cultural and economic environment is estimated at close to 10% of time.

These observations indicate an "outstanding" level of the UMR's interaction with its social and economic environment.

Assessment of the unit's organisation and life

UMR-S951 has an excellent internal organization facilitating the interaction between the different groups as well as with members of team 2 who will join the new UMR. Institutional budget allocations are shared to purchase common supplies and to support interns and students if needed specifically. The UMR's director manages the funds and the budget requests following consultation with each of the partners and the team members. All team members expressed satisfaction about the organization of the UMR. There is a very good integration of the different groups in the overall project. This is furthermore facilitated by the very good access to core-facilities and research platforms at Genethon. It is to be noted, however, that the units lacks good access to /does not possess expertise in bioinformatics which hampers efforts to manage, analyze, and process biological data. The current website of Genethon does not allow for sufficient visibility of the various groups within the unit. This shortcoming should be corrected.

Based on these observations, the experts committee felt that the UMR's organization and life is "excellent".

Assessment of the unit's involvement in training through research

The UMR is affiliated with the Université d'Evry Val d'Essonne (UEVE, Doctoral School related to Biology entitled "des Génomes aux organismes"; ED423), the "École Pratique des Hautes Études" (EPHE: Doctoral School n°472), a leading institution of higher education and research, providing highly specialized training in basic and applied research, and the Doctoral School n° 273 "Biologie et biotechnologie" (B2T) of the Université Paris Diderot -Paris 7.

According to the respective representatives of both institutions, the Doctoral School of the Université d'Evry allows PhD students to be supervised by the scientists from the Inserm UMR, provided that the latter have acquired the accreditation to supervise research (HDR). This is also the case for the EPHE; however, as the EPHE is a rather small, pluridisciplinary school, there are only a limited number (five to six) PhD-scholarships for biology available each year. Moreover, the UEVE has a changing policy each year and communicates rather late in the academic year whether they allow only one or two students per PI-HDR to apply, which can lead to an organizational problem for the PIs. In spite of the efforts put in by both Doctoral Schools, the actual situation only provides a minimal number of PhD students per year, which is clearly not enough to reach a critical mass of doctoral students in the UMR.

Two main actions have been identified to try and remedy this situation that should be, or are currently being, explored: 1) Obtaining PhD salaries through competition for grants by the different PIs in the unit (e.g. an Advanced ERC grant has been obtained by team 2 allowing to hire more PhD students) and 2) As Genethon, being a private entity, cannot finance directly PhD students, to explore the possibility how this institution can augment the critical mass of PhD scholarships for the two Doctoral Schools. This was also mentioned as an action being currently explored by the president and the scientific director of Genethon. Clearly, an ambitious postdoctoral program will give the UMR much more international visibility and will lead to a more dynamic, original, and creative environment. The UMR has received a total of 39 interns -rotation between one and six months -for L3, L3 pro, M1 and M2 students, whereas two PhDs in the fields of molecular biology and epigenetics, respectively, were produced with four PhD students currently working in the fields of immunology and molecular biology.

Altogether, the experts committee felt the UMR has a "good" involvement in teaching through research.

Assessment of the strategy and the five-year plan

Both team leaders present an exciting five-year plan of translational research with high-risk elements. The addition of a second team to UMR-S951 brings along a strong and internationally recognized expertise in molecular biology, genetics, muscular dystrophies, and neuro-muscular disease. This extension of the original UMR will increase its critical mass and will help to develop cutting edge concepts and technologies to improve translational research, which remains the hallmark of the new UMR.

The future UMR will consist of seven adequately balanced groups (organized into two teams) of roughly equal size with satisfactory mentoring potential and excellent technical support within a high quality research environment provided by Genethon. Based on excellent results obtained by team 1 and team 2 with respect to gene-based therapies of immuno-deficiencies and (neuro)muscular disease, respectively, the strategy to profit from the synergy of both teams is an excellent choice and will ensure the further development and feasibility of the strategies and projects put forward in the project. This regrouping will also increase the academic appeal of the new UMR; it is however important to implement a strong postdoctoral program that will not only attract highly qualified post-docs, but that will also contribute to a dynamic scientific environment.

The main core of the program of team 1 is the preclinical and clinical work that involves transduction of hematopoietic stem cells, as well as immunology studies in gene transfer settings that use DNA vectors (AAV), which represents good to excellent work. Although it might be possible to reduce this part of the project in order to focus more on the lentiviral work in hematopoietic stem cells, an advantage of continuing the immune-AAV work is the collaboration with team 2 where AAV vectors are used thereby maintaining its scientific level.

The approaches of the group working on stochastic fluctuations in gene expression are original, but the group needs a high profile publication in the area to demonstrate that it is competitive. The complementary work on the impact of gene transfer technology on host cell epigenetics must be acknowledged as very useful for the scientific community. Structurally, this group, that by its composition has much contact with the university, would benefit from a more proactive student policy.

The other immunology project, involving immune sanctuaries in the field of neuroimmunology, as well as the epigenetics studies are much less impressive than the main core of the program. team 1 is unlikely to remain competitive in the long run if it maintains its broad focus on three categories of rather dissimilar projects.

Given these observations and considerations, the experts committee judges the strategy and five-year plan "excellent".  Detailed assessments

Assessment of scientific quality and outputs

Based on a strong collaboration with Genethon, this team has developed a high-risk approach with methodological breakthroughs. There is an excellent focus on translational research, in particular the development of novel vectors to safely and efficiently deliver gene therapy to patients with primary immunodeficiencies. There is internationally recognized expertise in Wiskott Aldrich Syndrome (WAS) hematopoietic stem cell (HSC)-corrected gene therapy using a lentiviral vector system that has been developed by this team. Experimental work carried out by the team has underscored the absence of transforming properties of the vector in immortalisation assays, in contrast to earlier MLV-based vectors that were found to induce a high frequency of occurrence of leukaemia in treated WAS patients. Indeed, as of yet, the use of this vector in several international clinical trials in collaboration with teams in Paris, London, Boston and Italy has yielded promising results showing stable engraftment of WASP-expressing cells and clinical improvement and no selection of viral integration near oncogenes. These results have been published with the team's director as co-author, in the journal Science.

More recently, expertise in X-linked chronic granulomatous disease (X-CGD) with engraftment of gene-modified HSC and granulocyte correction has been acknowledged. The group leader coordinates an EU network with eleven other European laboratories and is involved in the development of an externally generated lentiviral vector, which includes non-clinical regulatory studies and manufacturing/development of the vector to GMP standards.

It shows strength that the most outstanding groups in clinical gene therapy of inherited blood disorders are collaborating with the team and it needs to be emphasized that essential original scientific contributions are performed at Genethon that cannot be performed efficiently by the leaders of these clinical studies.

Excellent work in this team has resulted in the development a family of cationic amphipathic peptides referred to as Vectofusins® that are active on several lentiviral subtypes and that enhance the frequency of transduced hematopoietic stem cells. One of these peptides in particular, Vectofusin-1®, a promising additive that could significantly ameliorate hematopoietic stem cell gene therapy, has been published, trademarked, and patented.

The team has also worked on understanding epigenetic modifications induced by gene transfer in HSC, i.e. changes in the DNA methylation profile upon lentiviral transduction and preactivation with cytokines. This has allowed them to document changes in DNA methylation induced by the cytokines used for pre-activation of the cells, but also by the lentiviral vector itself. These approaches will be very precious to design safer protocols and vectors. To increase efficiency of gene transfer, the team finally shows much interest for the fluctuating expression of both endogenous genes and transgenes. However, this project being at the interface between epigenetics, vectorology, and systems biology requires bioinformatics, which is not in their field of expertise and is therefore carried out in collaboration with a bioinformatics lab in the context of an ANR-project.

Gene transfer in immune sanctuaries for the treatment of ocular diseases is a new development proposed by team 1 with the arrival of a newly recruited university professor in 2011. Production for this group from 2008-2013 is correct, but the periodic level/quality is perfectible. Citations are weak and international visibility low. Based on the mentioned observations, the experts committee judges the scientific production of the team "very good".

Assessment of the team's academic reputation and appeal

Members of team 1 have been part of organizing committees for national and international congresses in the field of gene therapy, gene expression, and neuroimmunology and are regularly invited to international conferences, as speakers or chairpersons, as well as invited seminars and lectures. The team's director is on the editorial board of the journal Human Gene Therapy and on the Gene therapy committee of the International Society for Cell Therapy. She also participates in and coordinates international research programs and is lead partner in international networks.

Members of the team participate in scientific evaluation committees and the director is president of the CSS8 permanent scientific evaluation commission of the Inserm.

Team 1 has been highly successful in the establishment of international networks and participation in EC-FP6 (n=1) and EC-FP7 (n=3) grants resulting in high number of international collaborations, as well as in fund raising via national, institutional, and private funds.

Based on these observations, the experts committee judges the academic reputation and appeal of the team "excellent".

Assessment of the team's interaction with the social, economic and cultural environment

An important asset of the research program of team 1 is its strong involvement in translational research with a clear aim at bringing results generated from basic research to clinical applications. Work carried out by the team has an important impact on therapeutic approaches with respect to gene transfer. Two patents, pertaining to the development of peptides with viral infection-enhancing properties and production of enveloped viruses, have been deposited.

All members of the team are actively involved in the dissemination of scientific knowledge to the general public, via organized visits to Genethon, open days for various patient's associations and AFM/Telethon events. Overall contribution of the unit to interactions with social, cultural and economic environment is estimated at close to 10 % of time.

Based on these observations, the experts committee judges the level of the team's interaction with its social and economic environment "outstanding".

Assessment of the team's organisation and life

This team has an excellent internal organization facilitating the interaction between the different groups. Institutional budget allocations are shared to purchase common supplies and to support interns and students if needed specifically. The team's director manages the funds and the budget requests following consultation with each of the partners and the team members. All members of the team expressed satisfaction about its organization. There is a very good integration of the different groups in the overall project. This is furthermore facilitated by the very good access to core-facilities and research platforms at Genethon. It is to be noted, however, that the team lacks good access to /does not possess expertise in bioinformatics which hampers efforts to manage, analyze and process biological data. The current website of Genethon does not allow for sufficient visibility of the various groups within the team. This shortcoming should be corrected.

Based on these observations, the experts committee feels that the team's organization and life is "excellent".

Assessment of the team's involvement in training through research

Team 1 is affiliated with the Université d'Evry Val d'Essonne (UEVE, Doctoral School related to Biology entitled "des Génomes aux organismes"; ED 423), the "École Pratique des Hautes Études" (EPHE: Doctoral School n°472), a leading institution of higher education and research, providing highly specialized training in basic and applied research, and the Doctoral School n° 273 "Biologie et biotechnologie (B2T) of the Université Paris Diderot -Paris 7.

According to the respective representatives of both institutions, the Doctoral School of the Université d'Evry allows PhD students to be supervised by the scientists from the Inserm team, provided that the latter have acquired the accreditation to supervise research (HDR). This is also the case for the EPHE; however, as the EPHE is a rather small, pluridisciplinary, school, there is only a limited number (five to six) of PhD scholarships for biology available each year. Moreover, the UEVE has a changing policy each year and communicates rather late in the academic year whether they allow one or two students per PI-HDR to apply, which can lead to an organizational problem for the PIs. In spite of the efforts put in by both Doctoral Schools, the actual situation only provides a minimal number of PhD students per year, which is clearly not enough to reach a critical mass of doctoral students in the team.

Two main actions have been identified to try and remedy this situation that should be, or are currently being, explored:

1) obtaining PhD salaries through competition for grants by the different PIs in the team (e.g. an Advanced ERC grant has been obtained by team 2 allowing to hire more PhD students);

2) as Genethon, being a private entity, cannot finance directly PhD students, studying how this institution can augment the critical mass of PhD scholarships for the two Doctoral Schools. This was also mentioned as an action being currently explored by the president and the scientific director of Genethon. Clearly, an ambitious postdoctoral program will give the team much more international visibility and will lead to a more dynamic, original, and creative environment. Team 1 has received a total of 39 interns -rotation between one and six months -for L3, L3 pro, M1 and M2 students, whereas two PhDs in the fields of molecular biology and epigenetics, respectively, were trained with four PhD students currently working in the fields of immunology and molecular biology.

Altogether, the experts committee felt the team has a "good" involvement in teaching through research.

Assessment of the strategy and the five-year plan

The team presents an exciting five-year plan of translational research with high-risk elements. The main core of the program is the preclinical and clinical work that involves transduction of hematopoietic stem cells and ultimately leads to clinical benefit for patients with inherited blood disorders and which is highly successful. The second part of the program of the director's group represents immunology studies in gene transfer settings that use DNA vectors (AAV) which represents good to excellent work. It could be advised to reduce this part of the project in order to focus more on the lentiviral work in hematopoietic stem cells. On the other hand, one advantage of continuing the immune-AAV work is the possible collaboration with team 2 where AAV vectors are used.

The other immunology project, involving immune sanctuaries in the field of neuroimmunology, as well as the epigenetics studies are much less impressive as the main core of the program and this project remains insufficiently elaborated. A robust model of systemic immune tolerance (anterior-chamber associated immune deviation: ACAID) is mentioned in the achievements of the team, but the development of a robust experimental model of ACAID is proposed in the team's project. This issue needs to be clarified. Team 1 should make an effort to focus among the different projects proposed and it is not sure whether the development of this direction will be a valuable addition.

Development of the project on chromatin dynamics at the genomic integration site and its impact on the stability of transgene expression will require special attention by the team's members. The same comment is valid for the assessment of the means dedicated to and the feasibility of the project regarding the "non-invasive manipulation of the chromatin structure" to increase the efficiency of LV integration into the host genome. The approaches used to investigate stochastic fluctuations in gene expression are original, but the group needs a high profile publication in the area to demonstrate that it is competitive. The complementary work on the impact of gene transfer technology on host cell epigenetics must be acknowledged as very useful for the community. This group is small but relatively productive and with good networking. Structurally, this group, which by its composition has much contact with the university, would benefit from a more proactive student policy.

Overall, the five-year plan involves three categories of rather dissimilar projects and team 1 is unlikely to be competitive in the long run with each of these projects by continuing its broad focus.

In view of these observations and considerations, the experts committee judges the overall strategy and five-year plan "excellent".

Conclusion  Strengths and opportunities:

Strengths:

-very strong translational research focus; -leadership and high visibility in gene therapy field through international networks;

-access to various core facilities provided by Genethon.

Opportunities:

-to produce therapeutics that help patients suffering from primary immune deficiencies; -to generate valuable synergies with team 2 in the field of bioinformatics and cell biology. -other vector production units (current and future); -to lose visibility by becoming part of Genethon's R&D.

 Recommendations:

Use scientific standing in the field and the synergies with team 2 to deepen research focus.

Attract more PhD students and Post-docs. Assessment of scientific quality and outputs

Team 2 is a recently formed structure consisting of three groups, all being internationally renowned experts in gene therapy of neuromuscular diseases. All three PIs have obtained significant results and their research is at the forefront of innovation in terms of gene therapy. This is demonstrated by the publications of the three PIs in more than 30 articles as first/second or last/before last author. The vast majority of the studies are published in journals with an impact factor over 5 and some publications even raised a high impact, such as Blood, J Clin Invest, Sci Transl Med, Circulation and Proc Natl Acad Sci USA. Moreover the three PIs participate in other numerous studies attested by their co-authorship, reflecting their active level of collaborative work. Their impact in the field is also attested by the reviews the three PIs have published in top review journals such as EMBO J., Nature, Current series and Trends series.

The experts committee considers this an "excellent" scientific output.

Assessment of the unit's academic reputation and appeal

The team leader is a world-known expert in gene therapy and molecular biology and member of various international committees and organizations.

The activity of the three PIs in the animation of research is very high. They regularly participate in congresses and meetings as invited speakers and/or chairmen/women, give many seminars in laboratories and institutes in France and abroad. They serve on executive boards and have editing activities in scientific journals as well.

The funding of the research has been coming from several sources, of which several FP7 programmes, support from private foundations, and an ERC for the team-leader can be cited. The team's head is Chief Scientific Officer of Genethon.

Based on the observations, the experts committee felt that this team has an "outstanding" academic reputation.

Assessment of the unit's interaction with the social, economic and cultural environment

The three PIs have patented their research in five patents for the 2008-2013 period.

As part of Genethon, which is very active in this field, they participate in the promotion of translational research and applications of their research and also to science dissemination towards the society.

This team therefore has "excellent" interactions with the socio-economic environment.

Assessment of the unit's organisation and life

There is a very good internal organization facilitating interactions between the distinct groups of team 2. The team will include twelve persons, among them six permanent researchers and six permanent technical staff, which is a very good ratio. It includes two qualified research supervisors ("HDR").

Although there is no doubt that the three PIs will benefit from their close proximity and that of team 1, it is important for the three groups to put together their respective research in one main goal and develop synergistic interactions with each other.

All team members expressed satisfaction about the organization of the team.

The experts committee felt that this team's organization is "excellent".

Assessment of the unit's involvement in training through research

The team has trained eleven PhD students for the period 2009-2013. However, too few post-docs are currently working in team 2, which is likely due to the recent arrival of two of the three groups on the site of Genethon. It is of note and to be commended that the team strongly promotes technicians to graduate.

The PIs are involved in international and national training and teaching programs.

Training through research by this team is therefore "excellent".

Assessment of the strategy and the five-year plan

The three groups will develop their research in the direct line of their previous results, which are excellent and ensure the feasibility of the project. They will develop and investigate cutting edge concepts and technologies to improve gene-base therapies of neuromuscular diseases, in particular limb-girdle muscular dystrophies, sarcoglycanopathies, and myotubular myopathy. The joining of the groups of team 2 with those of team 1, within the R&D structure of Genethon, will provide the necessary critical mass permitting to optimally exploit these therapeutic strategies for the treatment of such diseases. Results from this endeavour in both basic and applied research, as being carried out in the past, will continue to be beneficial for translational research projects of the UMR as a whole.

Based on these considerations, the experts committee judges the strategy and scientific project of this team "excellent".

Conclusion  Strengths and opportunities:

Strengths:

-strong group of PIs who are scientifically very productive; -impressive preclinical work based on solid genetics, cell biology and animal models; -access to various core facilities provided by Genethon.

Opportunities:

-to form a highly competitive research unit that focuses on muscular dystrophies, backed and supported by Genethon;

-to generate valuable synergies with team 1 with respect to translation of experimental data into the clinic.

 Weaknesses and threats:

Part of the proposed research is highly risky.

The team is physically separated from a strong university Hospital.

 Recommendations:

PIs should rapidly connect with the academic environment, e.g. UEVE, to hire undergraduate and graduate students. They should also rapidly hire post-docs, which could be achieved in part through ERC support.

Because of long-standing experience of the three PIs to work independently, the experts committee recommends to put all efforts into building a strong unit with synergistic dynamics that will be beneficial to both teams.

To team up with a national of international gene-editing specialist, to jump-start the projects involving designer nuclease-mediated genome engineering. La production scientifique de l'équipe 1 a été jugée un peu en deçà, mais toutefois très bonne. Effectivement, dans un contexte de recherche translationnelle, la réalisation d'études précliniques ne favorise pas les publications dans des journaux généralistes de haut impact facteur. La réalisation de brevets, notamment par le Pr. Fisson, est aussi à mettre en perspective avec la qualité de la production scientifique. L'équipe 1 a toutefois publié des travaux scientifiques compétitifs sur les cellules satellites musculaires en « back to back » et éditorialisés, avec 3 autres groupes dans la même issue de «Development » un journal dans le top tier. Ces travaux n'ont pas été mis en avant lors de la visite du comité par souci de clarté mais s'inscrivent bien dans les intérets de l'équipe 1 pour comprendre la biologie des cellules souches somatiques adultes. L'équipe a également réalisé des collaborations qui ont été publiées dans des journaux de fort ou très fort impact.

L'évaluation de la formation par la recherche est jugée « bonne », mais nous tenons à apporter quelques éléments susceptibles d'améliorer cette appréciation. Rappelons que les enseignants chercheurs de l'équipe 1 assurent une forte charge d'enseignement, ce qui a bien été constaté par le comité. Il faut aussi donner crédit aux responsabilités administratives académiques. Le Pr.

  At present, UMR-S951 has three university professors (UEVE 2, EPHE 1), three assistant professors (UEVE 2, EPHE 1) and one Research Assistant (UEVE) who are involved in teaching in Molecular and Developmental Biology, Genetics, Epigenetics, Immunology, Cell and Gene Therapy and Biotechnology. The UMR's director is faculty of the Translational Research Training in Haematology, a joint training program of the American and European Societies for Haematology.

4

   Team-by-team analysis Team 1:Blood and immune systems: a target for treatment and host-vector interactions Name of team leader: Ms Anne GALY

  At present, team 1 has three university professors (UEVE 2, EPHE 1), three assistant professors (UEVE 2, EPHE 1) and one research assistant (UEVE) who are involved in teaching in Molecular and Developmental Biology, Genetics, Epigenetics, Immunology, Cell and gene therapy and Biotechnology. Teaching duties are considerable. The team's director is faculty of the Translational Research Training in Haematology, a joint training program of the American and European Societies for Haematology.



  Weaknesses and threats:Weaknesses:-scientific output in terms of publications (impact factors) is average; -research focus wide rather than deep; -imbalance between number of Pis / Staff Scientists and Postdocs / PhD students.Threats:

N3:N6

  Permanent EPST or EPIC researchers and similar positions 4 Other permanent staff (without research duties) 5 N4: Other professors (PREM, ECC, etc.) N5: Other EPST or EPIC researchers (DREM, Postdoctoral students, visitors, etc.) 5 spent at least 12 months in the unit Number of Research Supervisor Qualifications (HDR) taken Qualified research supervisors (with an HDR) or similar positions 2  Detailed assessments

  Fisson est le directeur du département de biologie de l'université d'Evry, et à ce titre coordonne les activités d'enseignement de 43 personnes (professeurs, maitres de conférences, contractuels, ingénieurs et techniciens) à l'Université. Il a initié et organise à Evry depuis 2012 un congrès annuel "Evry Bio" avec communications orales et posters, permettant des rencontres entre étudiants, académiques et industriels. L'appréciation du comité semble se baser surtout sur le faible nombre de doctorants mais ce point doit être commenté. Bien que seulement 2 doctorants apparaissent dans les tableaux « résultats au 30 Juin 2013 », 2 autres théses ont été soutenues Unité Mixte de Recherche U951, Généthon, Inserm, UEVE, EPHE « Immunologie Moléculaire et Biothérapies Innovantes » Direction Anne Galy PhD, galy@genethon.fr 2 sur 2 depuis cette date, et 2 nouvelles théses sont actuellement en cours dans l'équipe. Par ailleurs, nous souhaitons mentionner l'encadrement de 5 thèses supplémentaires qui ont été co dirigées par les Pr. Fisson et Pr. Paldi durant la période d'évaluation (*). Ces activités n'avaient pas été mentionnées dans la section des doctorants du dossier, car elles ont été réalisées en dehors du laboratoire. Toutefois ces co encadrements font bien partie des activités professorales et ont donné lieu à des publications communes qui ont bien été comptabilisées. Nous pensons donc que le bilan d'enseignement serait plutôt « très bon » que « bon ». En espérant que ces commentaires pourront contribuer à renforcer notre évaluation, nous n'avons pas d'autres remarques sur le rapport qui est par ailleurs très objectif et remercions le comité de ses commentaires et suggestions pertinentes. Avec nos respectueuses salutations, Anne Galy, DR1 Inserm Directrice UMR_S951 (*) Shoaib AL ZADJALI : PhD defended in November 2011 ; Co directed by Andras Paldi Claire GALAND : PhD defended in November 2011 ; Co directed by Sylvain Fisson Anim PATHARE : PhD defended in October 2012 ; Co directed by Andras Paldi Rym BEN ABDELWAHED : PhD defended in September 2013 ; Co directed by Sylvain Fisson Jérémie COSETTE : PhD defended planed in June 2014 ; Co directed by Sylvain Fisson

Unit workforce Number as at 30/06/2013 Number as at 01/01/2015

	Unit workforce
	N1: Permanent professors and similar positions	7	7
	N2: Permanent researchers from Institutions and similar positions	4	6
	N3: Other permanent staff (without research duties)	10	14
	N4: Other professors (Emeritus Professor, on-contract Professor, etc.)	1
	N5: Other researchers from Institutions (Emeritus Research Director, Postdoctoral students, visitors, etc.)	2	7
	N6: Other contractual staff (without research duties)
	TOTAL N1 to N6	24	34
	Unit workforce	Number as at 30/06/2013	Number as at 01/01/2015
	Doctoral students	3
	Theses defended	2
	Postdoctoral students having spent at least 12 months in the unit*	1
	Number of Research Supervisor Qualifications (HDR) taken	1
	SVE1 LS7 (biomedical technology)
	Qualified research supervisors (with an HDR) or similar positions	5	6

  Acquire bioinformatics expertise. 6  Supervising bodie's general comments Unité Mixte de Recherche U951, Généthon, Inserm, UEVE, EPHE « Immunologie Moléculaire et Biothérapies Innovantes » Direction Anne Galy PhD, galy@genethon.fr A la lecture du rapport d'évaluation de notre structure par l'Aeres, nous souhaitons tout d'abord remercier le comité d'évaluation pour la qualité de son analyse et pour la clarté de son rapport. Nous sommes heureux d'avoir été évalués « excellent » ou « remarquable » sur les aspects de visibilité scientifique, d'attractivité, d'organisation, sur nos interactions avec l'environnement ou sur notre projet futur.

	Evry, 12 Mars 2014
	Anne GALY
	Directrice de l'unité Inserm U951 Généthon, Inserm, UEVE, EPHE
	+33 1 69 47 29 93
	galy@genethon.fr
	Objet : S2PUR150007905 -Observations générales
	Approches génétique intégrées et nouvelles thérapies pour les maladies rares Integrare
	E2015 EV 0911975C S2PUR150007905 005045 RT.pdf
	1 sur 2


Theses defended 14 5

Postdoctoral students having spent at least 12 months in the unit* 5 6

Number of Research Supervisor Qualifications (HDR) taken 5 8

Qualified research supervisors (with an HDR) or similar positions 6 8

2  Assessment of the unit Strengths and opportunities related to the context I-STEM has acquired a unique expertise on human pluripotent stem cells (hPSCs) and their clinical applications. The strategy to develop in parallel cell-based therapy approaches for a diversity of disease such as Huntington's disease and skin ulcer and also drug-screening projects on rare diseases is unique at the international level. This strategy is obviously ambitious but the track record of each principal investigator is reassuring and the expert committee thinks that they will deliver successful projects. Importantly, basic studies on diseases mechanisms are also a major interest and will guarantee the long-term sustainability of this unit. Overall, I-STEM is a unique structure developing translational projects competitive at the highest level and this unit represents a driving force for the stem cell field in France and abroad.

Weaknesses and threats related to the context

One issue could be a certain lack of focus. Indeed, the unit is targeting a broad number of diseases with a diversity of approaches (cell-based therapy and drug screening). Therefore, it could be challenging to be successful in everything single area. Similarly, the balance between basic studies and pure translational projects could be difficult to maintain which might ultimately decrease the capacity of this group to be innovative.

I-STEM's visibility at the international level remains limited despite impressive achievements and this could be problematic for future developments that require international collaborations.

I-STEM should be more ambitious and more systematic concerning genome editing and genome wide analyses.

These technologies represent important tools and I-STEM will need to invest resources in this area to remain competitive at the highest level.

Recommendations

The recruitment of international post-docs / group leaders will help to increase the international recognition of I-STEM. In addition, it could bring a different vision to specific projects.

Training of scientists clinicians should be a priority for the unit. Integration of PhD students with a clinical background could be very useful to develop the stem cells applications in the clinics.

The international visibility could be increased. The work generated by I-STEM is remarkable and will benefit from more exposure at an international level.

3  Detailed assessments Assessment of scientific quality and outputs I-STEM has an impressive track record in the stem cell field. Each team has published in high impact journals (Nature Biotechnology; Cell Stem Cell; Lancet; J Clin Invest.) and has shown a high level of creativity. Furthermore, translational projects such as the clinical trial for the metformin represent a major achievement. Few institutes in the world have the capacity and expertise to achieve such projects.

The knowledge and the expertise on translational work and disease modelling are also impressive especially on such a diversity of diseases. Once again, very few institutes are able to manage so many projects successfully.

Publication track record is excellent especially considering the translational focus of the institute. Each team has published in high impact journals.

Importantly, basic studies of diseases mechanisms remain a major focus. Accordingly, several teams have published studies describing novel mechanisms of diseases. This aspect is essential and will continue to bring important publications.

Assessment of the unit's academic reputation and appeal

I-STEM is involved in a diversity of European consortia and is having a leading role in several projects. The reputation of I-STEM is excellent and well recognized.

Mr Marc PESCHANSKI is a worldwide recognized expert and a leader of the stem cell field who is regularly invited to speak in the most important international meetings. He is also involved in several major international initiatives in which he has an active role concerning translational aspects of hPSCs. The other group leaders are more junior and thus are less visible at the international level. Nevertheless, their reputation is growing as shown by their invitation to International meetings and to write reviews in specialized journals. So, there is no doubt that their impact will continue to grow and that they will become international leaders of their respective field.

I-STEM has achieved major objectives especially for drug discovery and cell-based therapy. However, these accomplishments could be more publicized. Indeed, few groups are aware of the projects currently developed by the unit. The metformin clinical trial and the cell based therapy project on skin ulcer are major achievements and should be promoted at the international level. Managing patients' expectation is a challenge, but should not block the unit to interact with other groups.

Assessment of the unit's interaction with the social, economic and cultural environment I-STEM is strongly associated with AFM and thus has regular contacts with patient associations. It is involved in the Telethon and other fund raising activities.

The unit has also developed networks of collaborations with diverse hospitals and clinicians. This aspect is essential to achieve the translational objectives of the unit.

Several group leaders are involved in EU consortia, which provide an important network of collaborators while providing the opportunity for I-STEM to share its unique expertise.

Contacts with industry represent a major activity. Several projects have developed in close collaboration with pharmaceutical companies. Furthermore, I-STEM has created a spin-off company, which will have a major role in the commercialization of the intellectual property generated by the unit. Indeed, this unit has generated 5 patents.

I-STEM has an essential role locally and at the international level. It provides training regarding hPSCs derivation and differentiation. It also co-develops project with external partners (academic / industrial). Furthermore, the infrastructure and resources available to each group are unique in size and quality. Thus, I-STEM has an important leadership in France.

Assessment of the unit's organization and life

The governance of the unit is well established and functions well despite the complexity added by the close interaction with CECS (Centre d'Etude pour les Cellules Souches) under AFM leadership.

The organization of the unit is coherent and democratic. The group leaders meet every week and take decisions collectively. Nevertheless, there is a new leadership and the transition between Ms Cécile MARTINAT and Mr Marc PESCHANSKI is working well. Mr Marc PESCHANSKI will maintain his involvement by providing mentorship to Ms Cécile MARTINAT as the new head of unit. This interaction is very reassuring given his wealth of experience and will ensure the long-term vision for the unit.

The rest of I-STEM is also involved in the decision-making process through weekly lab meetings, presentations and journal club. Feedback to management are generally well received and result in improvements. Strategic decisions are well explained and the overall objectives of the unit is known and understood by all personnel.

Distribution of resources and funding is centrally managed through a collegial system where each group leader can propose new ideas/projects. International seminar speakers could bring added benefit to the unit, which will benefit to be more open to external interactions. Recruitment of foreign post-doctoral fellows and group leaders would also be helpful.

Assessment of the unit's involvement in training through research

I-STEM has a high number of PhD students most of which are registered at Evry University. The corresponding doctoral school is currently being re-organized with Saclay University. There are 12 PhD students for 8 HDR. The ratio is low compared to other units, but normal for groups mainly focusing on applied research. Regional support also provides additional PhD positions.

Evry University supports only a few lecturers and thus the impact of I-STEM on teaching remains limited. However, the unit has access to a diversity of grants, sabbatical for lecturers/readers. Importantly, recruitment of new lecturers/readers has been suspended for the coming year and thus the situation is unlikely to change significantly in the near future.

Importantly, there is no faculty of medicine and no CHU in Evry. Local hospitals can accommodate medical students.

PhD students are generally successful. The average time for PhD is 42 months. PhD often results in several publications. Most of the students find a job very quickly after their PhD. 15 have a job. 9 in companies and 6 in post-doctoral positions. Overall, I-STEM seems to provide very good training to PhD students.

Assessment of the strategy and the five-year plan

The strategic plan for the next five years is a continuation of the work achieved by the unit in the past five years. The focus will remain to develop new therapies for rare diseases and to better understand their pathophysiology using hPSCs.

There is no plan to develop new tools but to build on existing resources and knowledge. For example, there is no major plan to develop new methods of differentiation, but rather to take full advantage of the existing methods. So, the major focus will remain on neuronal/ectodermal cell types.

There is no plan to develop entirely novel projects on cell based therapy or target new major diseases for drug screening. The objective is to achieve the current programs especially the most recent one while remaining open to new opportunities. New programs could be developed if basic studies lead to important discoveries for translational work. hiPSCs are taking a predominant role in disease modelling/drug screening projects and hESCs, especially derived from pre-implantation genetic diagnosis (PGD) embryos, will become less important. Nevertheless, hESCs will remain the priority for cell-based therapy.

Several key challenges have been identified with the program around drug-screening especially small molecules optimization. Acquiring the necessary expertise is not envisaged. However, the creation of the new team focusing on stem cell platform for pharmacology is aiming to address this issue. Drug combinations and drug repurposing are two key aspects while open access to drug-screening results could also help to disseminate important information. I-STEM is also starting to integrate new tools including genome wide analyses using Next Generation Sequencing (NGS) and genomic editing using CRIPSR technology. Both approaches could deserve a more ambitious vision. 10 4  Team-by-team analysis Qualified research supervisors (with an HDR) or similar positions 2 3

 Detailed assessments

Assessment of scientific quality and outputs

Team 1 focuses on monogenetic forms of Huntington Diseases (HD) and retinal diseases (RP). This group utilizes hPSCs to better understand mechanisms of diseases and to develop novel therapies. The program is divided in three major areas cell therapy for RP and HD, disease modeling and quality control of genome and transcriptome.

The track record of this group is impressive. The team leader published regularly in high impact journals (Stem Cells 2013, J Clin Invest. 2012, Proc Natl Acad Sci U S A. 2008, Nature Biotechnology 2008) and is a well recognised expert in the neuroscience field.

This group has developed numerous protocols of differentiation, which enable the production of telencephalic neurons (FoxG1 + cells) and then striated neurons cells Lateral Ganglionic Eminences (LGE). These protocols are well accepted in the field. They enable the production of functional cells and thus represent a significant advance. This work is recognized at the international level.

The Retinal Pigmented Epithelial (RPE) cell differentiation protocol is more recent and thus less validated. However, significant progresses have been made in a short period of time and in a very competitive environment. The focus on scaffold also represents a strong competitive advantage.

The work on animal models and the development of selection gene to make cell therapy safer represents an innovative work even if the application of such approach in the clinical might be challenging.

The program aiming to model HD in vitro is well advanced and has already resulted in major discovery including new genes, which could be involved in the disease onset. The disease modeling will be associated with drug screening programs, which aim to develop more phenotypic assays, molecular assays, and phenotype and molecular screenings, to validate drugs or gene therapy in vitro. This part of the program is ambitious but this team has all the expertise and skill to be successful.

Disease modeling of RP is less advanced but the focus on monogenetic form separates this program from competitors.

The new program focusing on Genome and transcriptome integrity does not really fit with the general strategy of this group. This team might struggle to have an impact without additional support and strategic directions. However, the aim of this project is commendable. Indeed, accumulation of genomic anomalies in hPSCs and differentiated derivatives represent a major challenge. A broader strategy regarding Genome wide analyses would be useful.

Assessment of the unit's academic reputation and appeal

The work generated by this group is well recognized worldwide as confirmed by around 16 invitations to international meetings. He has been involved in organizations of 3 international meetings.

This team is involved in several important EU consortia (FP6 and FP7). This aspect clearly demonstrates the importance of the work generated by this group at the international level. He got 2 ANR grants.

The team leader is recognized as a top expert in the HD and stem cell fields. Accordingly, he has published regularly in high impact journals.

The team brings together to different components of I-STEM including cell based therapy, drug screening and now next generation sequencing (NGS).

Assessment of the unit's interaction with the social, economic and cultural environment

Team leader and colleagues are strongly engaged with patients' organizations.

The group has generated 7 reviews for experts but also for general public.

Translational work is significant. Several contacts with industry have been developed and one patent has been filed.

Assessment of the unit's organization and life

Team 1 is subdivided in 3 programs (HD, RP and NGS). This scope of these different programs is broad and might be difficult to coordinate. The coordination of this activity remains unclear and the development of each program could be better achieved independently. The program on RP represents a team by itself and could benefit from more independence.

Nevertheless, the general organisation of the team follows conventional rules and seems to work well.

Assessment of the unit's involvement in training through research

The team hosts PhD students who seem to be well supervised. Their knowledge is well established and their technical training adequate.

Previous PhD students have been successful in securing post-doctoral positions and have generally found a job rapidly at the end of their thesis.

The team takes part of the general organization of I-STEM and joins the regular meetings.

Assessment of the strategy and the five-year plan

The three main research programs are 1) Cell therapy programs for HD and RP; 2) Disease modeling and drug screening for HD; 3) To develop next generation sequencing (NGS) applications for addressing questions raised by programs 1) and 2).

The five years plan for the HD subgroup is ambitious but achievable. The focus on HD is important and will generate interesting data. Cell based therapy could be a major development. However, the basic studies need to be supported since they will enable the development of better strategies for drug screening.

Developing cell based therapy and drug screening approaches for RP in parallel could be challenging. The program on RP is likely to be the most difficult to fully achieve. The competition is important and innovative strategy might be difficult to develop. The interactions with international consortia will be essential.

The program around NGS is essential since this tool will be necessary to quality control cells but also for studying molecular mechanisms of diseases. So, this part could be reinforced to enable broader number of applications. In house bio-informatics support could become necessary. Further expertise on RNA-Seq/ChIP-Seq could help to initiate new projects. Thus, a broader vision including epigenetic analyses could be essential for this new program.

Conclusion

Team 1 is a strong research group, which has been successful and is an important leader in the field. This team has demonstrated its capacity to secure funding with national and international grants. This is also a productive lab with a solid track record (n=11) and several interactions with industry. The committee was very supportive and found this group to be recommended at the excellent level.

 Strengths and opportunities:

The expertise of the team and its international visibility.

 Weaknesses and threats:

The relative complexity of the team might limit the impact of some studies.

 Recommendations:

The subdivision in three sub groups might not be optimal. There is not obvious linked between HD, RPE and NGS program. The RP sub team could become independent and could be better placed in an environment with strong focus on eye disease such the Institut de la Vision. The strategy around NGS needs to be reinforced and clearly defined. The absence of in house bio-informatics support is a concern. Assessment of scientific quality and outputs

Team 2 has worked the past 5 years on Myotonic Dystrophy type I (DM1) using PGD-derived hESCs. The team 2 has used protocols to differentiate these cells into different cell types affected by the diseases including Mesenchymal Stem Cells (MSCs) and NPCs. Using this approach, splice defect affecting the Insulin receptor was identified. Furthermore, whole genome analyses have identified additional genes possibly involved in the disease. This work was combined with drug screening which uncovered that metformin could rescue splice defects. Based on this result a clinical trial has been initiated on 40 patients. This is a unique example where disease modeling in vitro had had a direct impact on clinical development. This is an impressive achievement, which validates a major part of the strategy developed by I-STEM. This project will have an important impact on the Stem cell field worldwide. Furthermore, it demonstrates that the approach developed by this team can have a direct translational impact.

More recent work includes the development of new protocols of differentiation to generate motorneurons (MN) with different function. These protocols allow the generation of near homogenous population of different MN subtypes. This approach represents a progress when compared to previous methods, which were not efficient and only work with a limited number of cell lines. Similar efforts are currently conducted for cardiac differentiation. The next step is to apply this diversity of protocol on neuromuscular diseases including SMA. A Si-RNA screen will then be employed to find new targets provoking the disease.

Importantly the main goal of this group is to understand the basic mechanisms of disease even if drug screening remains a major focus. Cell based therapy is unlikely to have an impact for Neurodegenerative diseases. The science generated by this team is impressive and will continue to develop in the next few years.

The team leader published in high impact journals (Cell Stem Cells 2011; J Cell Sci. 2013; Human Mol Genet. 2013) as senior author and as co-author (Stem Cells 2013; Cell Reports 2012).

Assessment of the unit's academic reputation and appeal

The work generated by this group on DM1 is exceptional and the resulting clinical trial will have a broad impact.

The team has changed of leadership in 2010 when Ms Geneviève PIÉTU left I-STEM to retire upon retirement of the previous head. Thus, Ms Cécile MARTINAT is relatively junior but has already started to build her international visibility by participating to international meetings. She has also published in high impact factor journals as last author (Hum Mol Genet. 2013, Curr Gene Ther. 2013, J Cell Sci. 2013, Cell Stem Cell. 2011). So, the expert committee agrees to say that her network of collaborators and interactions with international consortia will increase in the next few years.

The focus on disease mechanisms to identify new target for drug screening is very relevant and has already been successful with metformin.

Assessment of the unit's interaction with the social, economic and cultural environment

The team has generated one important patent, which could attract interest from industrial partners.

Team leader and colleagues are strongly engaged with patients' organizations including DM1 patients. The clinical trial is done in close collaboration within the DM1 consortium.

The group has generated publications in "Medicine et Science" for the general public and has participated to a national radio program on Bioethics.

Assessment of the unit's organization and life

Team 2 has a coherent organization with strong focus on a limited number of diseases, which is the strength of this team. The change of leadership has occurred very smoothly and the new leader has managed the transition perfectly well. This is a healthy group with a strong potential for future development.

Assessment of the unit's involvement in training through research

The team hosts 5 PhD students who are well supervised. Their knowledge is well established and their technical training is adequate. Several members of the team teach at the local university.

Previous PhD students have been successful in securing post-doctoral positions and have generally found a job rapidly at the end of their thesis.

The team takes part of the general organization of I-STEM and joins the regular meetings.

Assessment of the strategy and the five-year plan

The five years plan for this team is well organized with precise objectives around disease mechanisms. Four main research programs will be developed: Systematic high throughput assay for production of neuronal subtypes; Disease modeling and drug screening for DM1; Disease modeling and drung screening for SMA; Largescale functional screening targeting alternate splice defects associated to DM1 and SMA. The team leader wants to apply the approach developed on DM1 on other type of neuromuscular diseases such as SMA, focusing first on the mechanisms and then on identifying new targets for drug development. These goals are ambitious but achievable. The recent development of directed protocol of differentiation to generate MN and Cardiac cells is an important achievement since it will enable further studies on a diversity of cell types. Furthermore, these protocols could be compatible with drug screening platform and enable more specific screen. Overall, this team has already acquired all the tools necessary for their future projects.

Conclusion

Team 2 is a relatively new group, which has already made an important participation in the stem cell field and has achieved major goals including the development of a clinical trial. Future projects are important and will lead to interesting results.

 Strengths and opportunities:

The focus on disease mechanisms combined with drug screening.

Expertise in differentiation.

 Weaknesses and threats:

The relative lack of experience of the team leader. However, mentorship support is available.

 Recommendations:

The mentorship of Mr Marc Peschanski is important. Nevertheless, additional interactions could be useful for the group leader to extend her network or collaborators and to develop a fresh vision. This group needs to maintain its focus on basic studies. This will be essential for future projects and for future publications.

The committee was very impressed by this group and marks it at the outstanding level. They also uncovered novel mechanisms involving miRNA in epithelial skin cell differentiation.

This program of research has now move toward cell based therapy. A clinical trial is currently in preparation with a focus on sickle cell disease epidermis ulcer. Animal work has already been performed and GMP protocol is now available. The clinical trial should start in 2015. This is a major development with a unique interest at the international level. This group is leading this kind of application and this clinical trial will have a major impact in the stem cell field and beyond.

In parallel, this team is also developing an ambitious program of disease modeling and drug screening. They focus on a diversity of diseases including Neurofibromatosis type 1 and Epidermolysis bullosa simplex. This program of research is impressive and will generate important results. Only few groups in the world can achieve such screen on a diversity of cells. However, the interest to uncover basic mechanisms of disease is less obvious and might limit future developments.

Of note, an important part of their objectives will rely on the development of a protocol for generating Schwann cells from hPSCs. This objective is important and will be ground breaking if successful.

Assessment of the unit's academic reputation and appeal

The team has published several manuscripts in high impact journals such as Lancet, PNAS and Developmental Biology. However, the presentation of this work in international meetings has been limited. The team leader should be more frequently exposed to international evaluations and interactions.

The work generated by this group is important and will have an international impact especially the cellbased therapy clinical trial. However, this team would benefit to have more interactions and collaborations at the international level. Their achievement should be more broadly recognized.

Only a handful of clinical trials with hESCs are so advanced. This team is doing what a lot of laboratories/institute are only planning to achieve. This important experience could also be shared more broadly.

The work of basic mechanisms will also benefit from further exposition and collaborations. There are only a few groups working on skin development and diseases with hPSC and thus the achievement of this team should raise a lot of interest.

Assessment of the unit's interaction with the social, economic and cultural environment

The team has established several contacts and collaborations with industrial partners including pharmaceutical companies. This team has filed 3 patents and this intellectual property represents an important asset for I-STEM.

The team leader is involved in several consortia for the clinical trial. Patient organizations are also involved.

Assessment of the unit's organization and life

Team 3 has a coherent organization with a strong focus on diseases affecting the skin and related organs. This team is fully integrated in I-STEM organization and its activity is essential for the success of the unit. The organization of the group is sound and seems to work well.

Assessment of the unit's involvement in training through research

The team hosts 4 PhD students who are well supervised. Their knowledge is well established and their technical training adequate.

Previous PhD students have been successful in securing post doc positions and have generally found a job rapidly at the end of their thesis.

The team takes part of the general organization of I-STEM and joins the regular meetings.

Assessment of the strategy and the five-year plan

The main objectives for the next five years are 1) Regenerative medicine of the epidermis using human embryonic stem cells derivates for skin ulceration complication sickle cell disease; 2) Disease modeling and drug screening of cellular markers of simplex epidermolysis; 3) Disease modeling on the neurofibromatosis type I. The five years plan is extremely ambitious but the underlying strategy is sound. The clinical trial will consume a lot of resources and times. This is expected and necessary. There is high level of uncertainty with this type of clinical trial which might be achievable or not and which might be successful or not. This is an inherent risk with clinical development but a backup plan or alternative strategy could be useful. Similarly, the disease modeling / drug screening program is rightly ambitious. However, it could be challenging to achieve all these objectives and some diseases/screening might have to be prioritized. The plan to study basic mechanisms of diseases is less clear and could be reinforced if time and resources are available. Importantly, this team is well organized and has been successful in the past. So, the expert committee thinks that this group will produce important results.

Conclusion

Team 3 is a strong group, which has already made an important impact in the stem cell field and has achieved major goals including the development of a clinical trial. Future projects are interesting and will lead to important results. The track record of this team is impressive. This group has made significant progress toward the use of hPSCs in cell-based therapy for skin ulcer. This is a unique focus and renders this group competitive at the international level.

 Strengths and opportunities:

Cell therapy expertise. Focus on skin.

 Weaknesses and threats:

The lack of exposure of the team leader to international evaluation.

 Recommendations:

The program on disease modeling/drug screening is impressive but could be further supported by more detailed studies on basic mechanisms. The objectives of this group in this area are less clear and could be more ambitious.

Additional interactions with external collaborators especially at the international level will be important to validate the strategy around cell based therapy but also for future development.

The committee was very impressed by this group and marked it at the excellent level.

 Detailed assessments

This team is new and will start following the renewal of the unit. Therefore, only the five-year plan is assessed.

Assessment of scientific quality and outputs NA.

Assessment of the unit's academic reputation and appeal NA.

Assessment of the unit's interaction with the social, economic and cultural environment NA.

Assessment of the unit's organisation and life

NA.

Assessment of the unit's involvement in training through research NA.

Assessment of the strategy and the five-year plan

The main objective of this team is to address the issues associated with primary drug screening. Indeed, identification of molecule at an early stage of development is useful but lead optimization is a major challenge requiring specific expertise and resources. This team aims to address this challenge by taking advantage of existing molecule, analyzing combinatorial effects, and repurposing existing drugs. This strategy is important to address an important limitation of drug screening and to ensure rapid drug discovery for rare diseases, which are not always of interest for industry.

Proof of principal has already been achieved with Metformin for DM1 but also for statin and Farnesyl inhibitor for Progeria. The plan is to extend this strategy using basic knowledge already available, developed by the other teams of the unit or by this team itself on specific disorders such as Wolfram syndrome.

Conclusion

The creation of this team is answering an important gap in the strategy of I-STEM and will be essential to achieve the translational objectives of this unit. Therefore this initiative is welcome and will bring an added value to the general organization of I-STEM.

 Strengths and opportunities:

Drug repurposing.

Existing expertise.

 Weaknesses and threats:

Lack of focus and cohesion.

 Recommendations:

Scientific coordination with the other groups of the unit needs to be more defined. Overlap could create some confusion and decrease the impact of the other teams.

The activity of this team is also very broad without clear therapeutic focus. So, overall this team will have an important role but coordination is necessary to ensure that this team is working synergistically with the existing teams. The committee agrees that this creation of this new team is necessary and will be essential for the future success of I-STEM. Therefore this team and the corresponding project has been noted excellent. We are very thankful to all the members of the AERES committee for their positive report. We'd like to clarify two points that have been raised by this committee:

 Conduct of the visit

1) Concerning the development of Next Generation Sequencing applications within the unit the committee stated that "this part could be reinforced to enable broader number of applications. In house bio-informatics support could become necessary. Further expertise on RNA-Seq/ChIP-Seq could help to initiate new projects. The absence of in house bio-informatics support is a concern."

As explained during the audition when this point was raised, we completely share the views of the committee regarding the development of NGS at I-Stem. The implementation of this technology in the lab has been initiated within Team n°1. Initially we have decided to focus NGS applications on the development of quality control assay(s) to certify the genomic integrity of stem cells bank and medicinal product destined to research and clinical applications.

We agree with the committee that beyond RNA-seq and Exome-seq applications currently developed, additional NGS expertise (e.g Chip-seq) could help initiate new projects. This is why Team n°3 and n°4 have already developed strong collaborations both with the national center of sequencing (CNG, Evry) and with the group of Dr. Auboeuf (INSERM 1052, Lyon) whose team is dedicated to bio-informatics analysis.

The initial investment regarding NGS in the U861 has consisted in the purchase of the high performance sequencer (IONproton) itself and the dedication (full time) of a research engineer from the Inserm (IR1, Dr Nathalie Lefort). In 2014, the strong dedication of the U861 to the development of NGS applications will consist in the hiring of two full time engineers (Ms. Jarriche and Ms Guigue) put in charge of RNA/DNA sequences production and bioinformatic analyses, respectively. In this context, Ms Guigue will work part time in Dr. Auboeuf lab to complete her training in bioinformatics.

2) The second point that we would like to clarify concerns the following comment regarding Pr. Monville in Team n°1 by the AERES committee: "The RPE sub team could become independent and could be better placed in an environment with strong focus on eye disease such the Institut de la Vision.". This program of research is already independent and is fully under the direction of Pr. Monville. She has and will continue to direct these programs and to work in close collaboration with Dr Goureau lab in the Institute de la Vision.

Yours Sincerely, Cécile Martinat

  Other permanent staff (without research duties) N4: Other professors (PREM, ECC, etc.) N5: Other EPST or EPIC researchers (DREM, Postdoctoral students, visitors

N3:

  Permanent professors and similar positions N2: Permanent EPST or EPIC researchers and similar positions 2 2 Other permanent staff (without research duties) N4: Other professors (PREM, ECC, etc.) N5: Other EPST or EPIC researchers (DREM, Postdoctoral students, visitors

N3:

  Permanent EPST or EPIC researchers and similar positions 1 1 Other permanent staff (without research duties) N4: Other professors (PREM, ECC, etc.) N5: Other EPST or EPIC researchers (DREM, Postdoctoral students, visitorsdeveloped innovative protocols to generate keratinocytes and melanocytes from hESCs and hIPSCs. These protocols have been published in high impact journals (Proc Natl Acad Sci U S A. 2011, Lancet 2009) and are used by other groups worldwide.

  management team. Audience: Committee members, AERES delegate 15h00-17h45: Closed-door meeting. Audience: Committee members, AERES delegate 6  Supervising bodies' general comments 5 rue Henri Desbruères 91030 Evry Tél : 01 69 90 85 20 -Fax : 01 69 90 85 21 INSERM UEVE UMR 861 I-Stem Evry, April 8 th 2014

Qualified research supervisors (with an HDR) or similar positions


Evaluation report

This report is the result of the evaluation by the experts committee,the composition of which is specified below. The assessments contained herein are the expression of an independent and collegial deliberation of the committee. 2  Overall assessment of the unit

Unit name:

GenHotel is a small research unit that develops good genetics research thanks to original cohorts of patients affected with Rheumatoid Arthritis. Based on the Evry campus, it offers a special service to any researcher asking for it: it can organize the testing of any kind of genetics project using its facilities and its cohorts.

Strengths and opportunities related to the context:

The availability of cohorts of patients with Rheumatoid Arthritis. They include hundreds of:

-trio families (a patient and his two parents); -affected sibling pairs; -multicase families (four patients or more in one family).

The local environment is very strong in genetics, with the presence of Genopole.

Weaknesses and threats related to the context:

This very small team lacks manpower and has a tendency to dispersion.

It lacks a strong clinical link with a rheumatologist to help direct the projects.

Recommendations

The experts committee suggests to recruit postdocs and to rebuild the link with the local rheumatology department.

 Detailed assessments Assessment of scientific quality and outputs

This laboratory studies the genetics of RA, has collected samples from RA families and DNA samples from multi-case RA families and trio families (one patient and his/her two parents). Its projects are:

1/ characterizing the transcriptome in pre RA; 2/ characterizing rare variants in RA by whole exome sequencing and analysis of copy number variation.

This small team has published 34 articles in the past 5 years, half of them originate from the lab and are piloted by lab's members, half of them are published in the top ranked Rheumatology journals. For instance, the lab has published three articles in collaboration with a Pavia immunologist on the influence of RA susceptibility genes on autoantibodies in RA in 2012 and 2013. Conversely, studies of the transcriptome in the PBMCs of RA patients have been directed from the lab (PLOS One, 2009).

Assessment of the unit's academic reputation and appeal

This work has national, but not international impact.

Assessment of the unit's interaction with the social, economic and cultural environment

There is good interaction with patient's associations; the principle of Genhotel (i.e. hosting scientists to perform genetics projects using the GenHotel Facilities and cohorts) is also a good way to attract collaborations.

However, there is little interaction with economical environment.

Assessment of the unit's organisation and life

The unit's life is marked by a friendly atmosphere and good interaction between students and staff. Interaction with rheumatologists is lacking.

Assessment of the unit's involvement in training through research

PhD-students, which are from the Doctoral School "Sciences and engineering" (ED n°423), are well supervised. They meet with their supervisor once a week. Lab meetings are held every other week. The PhD students sign their articles as first authors. The current students all have published or are writing a first author paper. They travel abroad to present their data.

Assessment of the strategy and the five-year plan

This laboratory has expertise in the genetics of RA and has collected its own samples from RA families. They include DNA samples from multi-case RA families (more than four patients per family) and trio families (one patient and his/her two parents). It develops two strong projects on the genetics of RA:

1/ characterizing the transcriptome in pre RA (This project is developed in collaboration with laboratories in Clermont-Ferrand and in Geneva); 2/ characterizing rare variants in RA by whole exome sequencing and analysis of copy number variation.

Whole exome sequencing will be performed in multicase RA families whereas copy number variation analysis will be performed in trio families.

Both projects are solid and their strength stems from the unique collection of families (trio and multicase) collected by this lab over the years.

3 N4:

 3 , Université Sorbonne Paris Cité (representative of CNU) Ms Wendy THOMSON, University of Manchester, United Kingdom Scientific delegate representing the AERES: Mr Joost vAN MEERWIJK Representatives of the unit's supervising institutions and bodies: Ms Florence GONNET (Doctoral School UEVE n°423) Mr Philippe HOUDY, Université d'Évry-Val-d'Essonne Mr Pierre TAMBOURIN, Genopole 1  Introduction History and geographical location of the unit The Genhotel Evry laboratory was created by Mr François CORNELIS in 1999 on the Genopole campus in Évry. It is a research unit of the Université d'Évry-Val-d'Essonne. Management team This is a one-team laboratory lead by Ms Elisabeth TEIXEIRA, a professor at the Université d'Évry-Val-d'Essonne. It includes three teaching researchers, three hospital practitioners, and two PhD students. Permanent researchers from Institutions and similar positions N3: Other permanent staff (without research duties) 3 Other professors (Emeritus Professor, on-contract Professor, etc.) N5: Other researchers from Institutions (Emeritus Research Director, Postdoctoral students, visitors, etc.) students having spent at least 12 months in the unit* Number of Research Supervisor Qualifications (HDR) taken Qualified research supervisors (with an HDR) or similar positions 2 2

On behalf of AERES, pursuant to the Decree of 3 november 2006 1 , -Mr. Didier HOUSSIN, president -Mr. Pierre GLAUDES, head of the evaluation of research units department On behalf of the expert committee, -Mr. Jean ROUDIER, chair of the committee 1 The AERES President "signs [...], the evaluation reports, [...] countersigned for each department by the director concerned" (Article 9, paragraph 3 of the Decree n ° 2006-1334 of 3 November 2006, as amended).

 Supervising bodie's general comments