Section des Unités de recherche

Report from the visiting committee Research unit :

Institut de la Vision – UMR_S 592

University Pierre et Marie Curie

April 2008

Section des Unités de recherche

Report from the visiting committee Research unit : Institut de la Vision – UMR_S 592

University Pierre et Marie Curie

April 2008

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Report from the visiting committee

The research unit :

Name of the research unit : Institut de la Vision

Requested label : UMR_S INSERM

N° in case of renewal : 592

Head of the research unit : M. José SAHEL

University or school :

Université Pierre et Marie Curie – Paris 6

Other institutions and research organization:

INSERM

Date(s) of the visit :

17 - 18 mars 2008

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Members of the visiting committee

Chairman of the commitee : M. Yvan ARSENIJEVIC, Lausanne, Suisse

Other committee members : M. Alberto AURICCHIO, Naples

M. Carlos BELMONTE, Alicante

M. Frederic CHIAMBARETTA, Clermont Ferrand

M. John FORRESTER, Aberdeen

M. Christian HAMEL, Montpellier

M. Kenneth MOYA, Paris

M. Francis MUNIER, Lausanne

M. Jean-Paul ROMANET, Grenoble

M. Adam SILLITO, Londres

M. Bernard WEBER,Regensburg

CNU, CoNRS, CSS INSERM, représentant INRA, INRIA, IRD…) representatives : M. Pierre GASTAUD, Nice, représentant du CNU

M. Henry KENNEDY, Lyon, représentant des CSS de l’INSERM

Observers

AERES scientific representative: M. Bernard DASTUGUE

University or school representative: Mme Jocelyne CABOCHE, Université Paris 6

Research organization representative (s) : Mme Danièle MURCIANO, INSERM

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Report from the visiting committee

1 Short presentation of the research unit The Unit includes:

• 22 full time researchers

• 17 researchers with teaching and clinical duties (hopitalo-universitaires)

• 56 engineers and technicians

• 21 PhD students

• 25 post-doctoral fellows

• 4 PH

• 2 Invited Professors (UMPC)

- Number of PhD since January 2004 : 31

- Number of lab members with a HDR : 23

- Number of publishing lab members (among full time researchers) : 22 out of 22

- Number of publishing lab members (among researchers with teaching/clinical duties) : 17 out of 21

2 Preparation and execution of the visit On Monday, March 17th, the President of the committee and the deleguate of AERES first met with the director

of the Unit in his office during half an hour and then with the committee members to underline the important points to evaluate during this mission. This meeting was followed, in the presence of all the members of the Unit, by a long presentation (1h40) of the different Unit activities. One hour of questions finalized this first exchange. A dinner was taken together with all the experts and team leaders. On the next day, starting at 8:00 AM, each team project was presented with a schedule of 10 minutes for the presentation and 10 minutes for questions. The President of the committee decided to extend the period of questions to ensure that the relevance of each project could be well understood by each expert. This led to an extensive delay in the agenda resulting in a very short lunch time and an important curtailment of the visit of the Institut de la Vision. In between, the committee discussed half an hour with the technicians and the students in two separate groups. Finally, the committee debated on the different evaluations for 2 hours in order to reach a consensus. Whereas a rapid consensus was found for the evaluation of the Institute as a whole, the comments of each team (11 in total) required more explanations because not all experts had read all the projects. At the end of this consultation, the president gave a general analysis on the evaluation of the Institute and the departments in the presence of the Director of the Institue and his team. To conclude, the Director of the Unit gave his comments.

3 Overall appreciation of the activity of the research unit, of its links with local, national and international partners

Vision is our most precious sense. It provides our 'window' onto the world and its loss is almost inconceivable. Yet visual impairment is a significant and growing problem in our society with enormous socio-economic consequences. Although the ability to see is central to nearly all we take for granted in life, there is surprisingly little public awareness of the problems of vision and the growing incidence of sight threatening diseases in the population. These have enormous implications for the quality of life of individuals affected and economic implications for our

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society. Thus the creation of the Vision Institute in Paris is a timely development to target a coordinated translational research facility to a problem that affects the French Nation and Europe as a whole.

The « Institut de la vision » is a new and unique institute in France rallying high competences in the field of ophthalmology principally investigating the retina. The main purpose of this institute is to develop high levels of knowledge concerning diseases affecting the retina in order to develop new therapeutics for diseases untreatable to date, and affecting millions of individuals in the Western World. The specialties involved in this project comprise experts in molecular biology, cell biology, development, genetics, proteomics, genomics, neurophysiology, neuropsychophysiology, bio-informatics, physics in imaging system, and ophthalmology. Moreover, the network established with other specialists in the academic field (to use gene therapy) or with the industry (to valorise inventions and produce pharmacological products) renders this institute, in term of ophthalmology, remarkable and unique in the continental Europe to develop therapy from the bench to the bedside. This aspect is reinforced by the fact that the CHNO des XV-XX contains a CIC oriented towards retinal disease showing the pertinence of the projects developed in the Institut de la Vision to be in line with the hospital goals. Moreover the director of the Unit is also director of the RTRS “Voir et Entendre”. The presence of the CHNO is also a unique opportunity in France (and even in Europe) to have a so large pool of patients (with a wide range of eye diseases) who can be involved in different research projects and in clinical trials.

The fantastic development of this unit was due to the influence of the director who is a strong leader able to federate people around him and gather money from almost every possible public and private agency in France and in Europe. This fund raising capacity is a guarantee for the stability and future development of the institution.

This dynamism led to the creation of the start-up Fovea which received an investment of 50 million euros. In the proximity of the institute, a new building was erected to receive biotechs in order to establish a synergy between the fundamental and translational sciences as well as with the clinic.

Although heterogeneous in their strengths, the teams are very complementary by their projects and techniques developed in their department. Already several collaborations are ongoing between the researchers and the arrival of new persons as well as teams will enhance this synergy. The core disciplines further fundamental research at the highest standard in their area and bring this excellence to bear on the various clinical programs to which they contribute. It enables the leading clinical researchers to collaborate with established leaders in the fields of expertise they need. Each department contains at least one team highly recognized internationally and teams with persons of high potential. Such mix will enhance the strength of the emerging teams. At present, the unit has reached a critical mass that will ensure major innovative contributions to the field and will be very attractive for students, postdocs, and young scientists. To date, around 30 students are completing their PhD. Nonetheless, the appurtenance to the Unit is not a warranty to stay indefinitely. Indeed, each team needs to generate their proper funding to ensure the development of its projects. A certain help can be provided for the team during a while, if a problem occurs in the fund raising, but the team will have to assume the consequences of not having the quality to ensure its research project. Such rules will select productive teams.

The achievements of the Director are remarkable and all members of the committee felt he should be complimented on this. His work has led to the creation of a very significant eye research facility with a diversity of multi-disciplinary teams with a very strong sense of common mission and a group commitment to translational eye research to the benefit of the patient. However the substantive expansion of the number of teams will present new challenges to the task of sustaining the sense of common mission and determining the research focus of components in the perspective of the mission of the whole. For example the rapid emergence of many topics in certain departments (eg genetics team 4 and visual processing team 10) may dilute the manpower and finally the impact of these researches. There will be a need to establish a more formal management structure and a research strategy group (to include QVCHNO) to help the Director sustain the progress achieved. The fact that the Unit is already managing two projects of the European commission suggests that the Unit has the capacity to undergo such change rapidly.

Several projects aim to use stem cells to develop therapy, but no team has an expert in this field. All the projects would benefit from the presence of a biologist with a good track record in stem cells. Such recommendation could also be applicable for gene therapy. Indeed, several projects have very good collaborations with experts in gene therapy, but the use of a vector would be really optimized with an in house expert in this field. To understand exactly what a vector is, requires some competences that are not obvious and all the projects could profit from the presence of an expert in this field. The committee feels that the institute would gain in prestige if it can enlarge its field of research to include visual cortex studies. In his response to this comment, the director mentions that the institute will collaborate with the new centre in Neuroscience of Paris to link retinal studies with the cortex. The committee hopes that a good collaboration will be established between these two institutes located at a reasonable distance.

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It appears that the Institut de la Vision is an excellent centre as a whole and will provide major outputs for research, student training, patient diagnostic and care, as well as for the local economic development, the recommendations provided here being a guideline to ensure the best success possible.

4 Specific appreciation team by team and/or project by project

Department of Development :

The composition of this department will ensure the coverage important themes concerning the retina as well as the visual system development and should generate major contributions to these fields. The mix of an internationally recognized team with other members bearing a strong potential in their research development, will provide an important synergy between the groups. The result will be a solid basic knowledge necessary to understand the biology of the visual system as well as the related pathologies and to develop appropriate therapeutic approaches. In consequence, the competence and the viability of the Department can be considered as excellent.

Team 1 : The Department of Development is composed of 3 teams. Team 1 is the major team both in terms of numbers of researchers and scientific Excellency. Past research made groundbreaking discoveries in axon guidance. The team proposes extensive projects in sensory system development including projects on cell migration and the role of guidance molecules on myelination. The team leader is outstanding and he and other members have published many papers in strong to top journals (26 in 4 years, such as Nat Neurosci, Nat Cell Biol, Cell, Nature, Neuron). The team has a strong track record of attracting funding but more effort could be made to increase the number of PhDs defended from this work. The team members are well integrated into the project and have fruitfully worked together in the past. The project is largely basic research and important current developments are being made to link the research program to clinical issues. The project has the potential to have a major impact on the field of developmental neuroscience. Nonetheless, the investigator is encouraged to better integrate this program with the overall mission of the Vision Institute. The team has a high International profile and participates in a number of national and international networks. It constitutes the backbone of the Department of Development and has established or plans to establish valuable collaboration with other teams in the Institute and has the potential to be the driving force for excellence.

Team 2 : The project proposed by this team is the continuation of previous work aimed at unravelling mechanisms controlling photoreceptor differentiation. The project is original by its use of a factor that blocks photoreceptor differentiation (CNTF), and has already identified some candidate genes controlling this event (this research is currently supported by grants). The team has published solid papers in the field of retinal cell differentiation, but the frequency of publication is rather low in view of the Aeres criteria. The team has at present two PhD students which is adapted to the size of the team. Concerning the relevance of the project, the experiments planned are in accordance with the aims of the Institute and will also increase the knowledge in the field of interest and help to understand the mechanisms controlling development. The project appears coherent and feasible, ensuring the generation of pertinent results. Moreover several techniques developed by the team are of importance for the other teams of the Unit (retina explant, in vivo electroporation, RCAS virus). The team leader has great expertise in molecular and cell biology. The project is in part ambitious and appears in some points to diverge from the main goal which is to generate photoreceptors, but will ensure interesting publications. The project concerning stem cells is not supported by preliminary experiments and remains speculative concerning its feasibility. Nonetheless, the team has shown a good improvement in the generation of results these last months and has publications in review. The integration of this team in the Department of Development will enhance the expertise of the department, and this team will benefit from the structure that may help to supervise the progress of the project and stimulate the production of excellent level publications.*

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Team 3 : Team 3 has a highly original research project. The past work of the team leader has been prominent in establishing the biology of multiligand endocytosis in the adult and more recently during development. The team has completed the ground work to now undertake an extremely original and highly promising research on the role of Cublin and megalin on forebrain and visual system development showing how these receptors control the action of morphogens (such as Bmp4, Shh, and FGF8). The future exploration of these results will lead to important advances in our understanding of CNS development.The originality of the research is greatly strengthened by the coherence and continuity of the research interests of the PI and the senior researcher of the team as well as by the preliminary and ongoing results. The expertise of the team has been strengthened by the addition of a researcher who has a well-established track record in forebrain development and this will ensure an important extension of the research aims of the team. The director of the team has shown a steady increase in the importance of her publications. From the continuity of her work on these molecules the team leader has established a strong reputation in the field. All 3 researchers in the team have an even publication record. Nonetheless, the absence of publications in high impact journals is to be regretted. Given the size of the team, the number of PhD theses (3) in the last 4 years is appropriate and these students have been well placed in publications. The number of publications in 4 years (23) is really correct given the size of the team. The team has taken full advantage of the potential of the Institute of Vision in clinical research, to explore the significance of their fundamental findings in a clinical context. There is evidence that Megalin is implicated in Donnai-Barrow malformations. The team’s collaboration with the Department of Neuropediatrics in the hospital and the Genetics department will allow the team to explore the involvement of cubulin dysfunction in these conditions. The team has a proven record in the techniques that they need to master. Their future research project is well thought out. They will benefit form the excellent research environment provided by team No 1. The excellent relationships between the 3 teams making up the department of Development, as reflected by multiple interactions between teams and especially team 1 as well as organizations of Dept meeting, will ensure a high degree the required critical internal scientific self-examination that is necessary. Likewise, the proximity of the clinical expertise will provide the appropriate environment for the team to successfully undertake the appropriate translational research.

Department of Genetics :

This department contains two teams with several members of very high quality. The strength of their competences includes gene/protein identification to clinical application. In consequence, the Department appears to respond precisely to the goals of the Institute by providing major contributions to basic science as well as to the development of therapeutic approaches. The structure of the proposed project will continuously provide innovative strategies reinforcing the visibility of the Institute and increasing the chances of developing appropriate tools to alleviate or cure some forms of retinal degeneration processes. This excellent regrouping of technologies and competences will surely have a societal and economic impact.

Team 4 : The proposed project is an integrated approach for the study of retinal diseases incorporating genetics to functional biology and exploring novel modes of genetic therapy. The program proposed by the team will undoubtedly makes significant contribution to the knowledge in the field of ophthalmic genetics, since there are very good resources (large series of patients and families, appropriate in vitro models, good phenotyping strategy). Moreover, the presence of the CHNO is also a unique opportunity in France (and even in Europe) to have a large pool of patients (with a large diversity of diseases) who can be involved in gene mutation identification and in clinical trials. The balance between fundamental and applied research is excellent (3 AJHG, 1 PNAS, 1 HMG) with team members doing phenotyping analysis, others linkage studies, and some others post genomic and pathophysiological studies. Because, each individual researcher of the group has made important progress in one’s field, and that the strategy chosen was straightforward, there is clearly some potential for the discovery of new genes starting from this material. Such discoveries will help to establish better diagnostics and will generate new pathophysiological studies. The director of the team is highly renowned on the international scene although he only has a limited number of invited conferences. Other team members are younger and will benefit of the environment of this group to enhance their background. Overall there is a great potential for establishing a program at the forefront of the field and given this importance the development of some aspects of the program need careful consideration. These included the issues of animal models for the research, the basis for choosing candidate genes for AMD research and generating a coordination of the current diverse studies in areas such as AMD and Congenital Stationary Night Blindness. Additional support may be necessary to compensate for the fact that the team leader, although very distinguished is only part time. This team has made in the past highly significant advances in the field of ophthalmic genetics and the quality and number of publications is high. However, the long term viability of the team is weakened due to very different

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projects distributed between each team scientist. It is recommended that the team members evolve towards a more focused project to really reach an added value of putting together their complementary competences.

Team 5 : The approach was based on the concept raised by the 2 former team members that cone survival in retinitis pigmentosa may depend on the presence of rod diffusible factors. Subsequently, they demonstrated that this was indeed true and they isolated a rod-derived cone survival factor for which they obtained a highly rated price of the US foundation for fighting blindness. Their recent experiments demonstrated the effectiveness of the RdCVF factor and they have now discovered another, more potent factor. The research conducted is an example of very rational strategy of research. The director of the team has become a highly renowned researcher on the international scene. The 3 other team senior members are also highly recognized in different and complementary fields. The distribution of the production is quite well balanced with some members having good clinical publications and some other very good basic papers. The quality of the publications is very good with some highly ranked papers (the highest rates being 1 Nature Genetics, 3 Hum Mol Genet in first or last author), many papers of good scientific quality in molecular biology, neuroscience, bioinformatics and ophthalmological research. Overall quality is very original and excellent : The productivity is also excellent with many PhD theses conducted or are currently conducted by team members (19 PhD theses for 3 of them) and a high number of original publications is very good (131 papers for 4 authors). One member of the team has an excellent productivity. There are three patents and the group has obtained several tenths of grants from academic international institutions, private foundations and industry. The group has created a start-up to develop preclinical studies. There is a very strong potential for increasing the knowledge in the mechanisms of photoreceptor degeneration and survival, genes involved in these diseases and protecting molecules. This research will impact on the future treatments of patients with inherited retinal diseases and will probably lead to new therapeutic solutions. The impact in term of strategies is high and will probably continue. The work done by this team is one of the best example of functional cloning in the life sciences, and they also have been excellent in using yeast strategy to search for transcription factor as well as with bioinformatic analysis. The team has in charge a bioinformatic platform in Strasbourg and has set a specific platform to automatically count photoreceptors in retina. In its design, the past and current research done by this team represents mostly basic science and pre-clinical investigations. However, the team has anticipated the clinical applications and therefore oriented its investigations in order to offer to clinicians a very appropriate therapeutic solution. The team is organizing its research strategy with many engineers and technicians, which is valid for ascertaining good pre clinical results. In addition, the use of many collaborators in France and abroad is also a good choice since best expertise is a guarantee of useful results. Nevertheless, it would be of interest for the team to hire 1 or 2 researchers specialized in biochemistry, physiology, as well as in gene therapy to develop the various aspects of the project (receptor, photoreceptor physiology, and delivery to the appropriate cellular target). This is an excellent team which has done a remarkable contribution in the understanding of the protection strategy in neurodegeneration. The discovery of RdCVF not only may be of high interest in the field of ophthalmology, but also for the degeneration of the central nervous system (Parkinson, Alzheimer).

Department of Visual Processing :

It was recognised that this Department played a crucial role in the new Institute and formed essential collaborative links with the other sections. The research is scientifically excellent and makes a unique contribution to the translation of the Institute’s work to the benefit of the patient. The new team (Team 10) brings an extra and essential dimension of expertise to the Institute and if focussed will add greatly to the work of the whole. In addition the panel felt that a further dimension of work introducing fundamental research into the central visual system and visual cortex was very important and urged the Director to consider this. This would benefit both the Institute and provide a superb environment for such a team to develop their research. It was also felt that the psychophysicists at present working in the clinics should be more integrated into the Department and that the area of visual psychophysics should be developed systematically together with the other areas of the Department, but within the overall objectives of the Institute as a whole.

Team 7 : The program builds on the strong track record of Team 7 in the areas of photoreceptor degeneration and the role of GABAergic neurotransmission in the interactions between horizontal cells and cones. A strong contribution also comes from the group’s work in the development and analysis of animal models of retinal degenerative diseases and the introduction of behavioural, imaging and electrophysiological tests adapted to probe the disease mechanism in these models. This has been paralleled by the development of cellular models and retinal

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explants to enable another level of the dissection of disease mechanism and the early screening of neuroprotective strategies. There are three things that define the strengths and contribution of this group; they contribute to the advancement of our understanding of the function of the retinal mechanisms subserving early vision, they are making significant advances in the application of this knowledge to the development of new therapeutic strategies in the treatment and prevention of eye disease and they are developing new techniques for studying normal and abnormal function in the retina. In the case of the latter they provide an enabling function for the work of the Vision Institute as a whole and this together with the focus of the group’s core research and its links to the other research programs gives great added value. Overall the productivity is excellent. There are great strengths in core scientific publications and in publications focussing on ophthalmic issues and the translation of research into improved clinical care of patients. With respect to translation the work on Vigabatrin is a case in point as are the plans for the retinal prosthesis and the identification of neuroprotective models for retinal ganglion cells and receptors. The relevance of the work of this group is beyond as underlined by the comments above. This applies both in the sense of the groups own work and in the broader perspective of the service and contribution it makes to the Institute as a whole and the needs for both collaboration and service functions. The long term viability is excellent and the only possible issue is that more funds will be needed to expand this crucial component of the Vision Institute as the research of the Institute as a whole develops. An excellent and well focussed group, making a vital research contribution, and playing a vital enabling role in the overall mission of the Vision Institute.

Team 10 : This is a very ambitious group with wide ranging interests focused on human cognitive mechanisms subserving vision and spatial integration in normal subjects and those with central or peripheral pathological damage to their sensory systems. They have an extensive track record in these areas with a strong clinical focus to their publications and bring some highly novel ideas to their work. They introduce expertise in the clinical assessment of the cognitive aspects of visual function, FMRI and TMS techniques. They will apply this knowledge to an evaluation of the plasticity and reorganization of cortical visual areas after central and peripheral lesions with a particular focus on visual rehabilitation. The productivity is very clinically focussed, with a solid output, and there is a good record in training PhD and masters students. The introduction of this team brings a new range of techniques and approaches to the Vision Institute. These will enable more effective assessment of the outcomes of other programs in the Institute such as the implementation of the use of the retinal prosthesis, lead to better strategies for visual rehabilitation and more effective ways of following the outcomes of the various strategies for therapeutic intervention in glaucoma and AMD. The group also opens the door to research into clinically relevant areas of the central mechanisms of vision and this has to be a key component of the portfolio of a Vision Institute. Nonetheless, there is a need for structured guidance of the group’s focus to ensure that some areas of the more esoteric objectives are shifted to practical and realistically achievable programs. A group introducing a new range of expertise that is an essential component of the work of the Institute as a whole, a clear record of achievement, but a need to refocus some objectives to achieve its full potential in the role of the Institute.

Department of Physiopathology (Therapy) :

The projects of each team in the Department of Therapy contribute to the scientific goals of the Institut de la Vision. The projects of these teams are the continuation of previous works concerning the mechanisms controlling inflammation and apoptosis in the ocular surface and in the anterior segment of the eye, the mechanisms increasing the success of cell transplantation in limbal stem cell deficiency as well as in corneal endothelium diseases, the development of a gene therapy strategy for retinal dystrophies caused by mitochondrial dysfunction, the construction of novel models of retinal vascular diseases and the study of the function of dystrophin in the vascular development. Such biological projects are completed by the development of imaging systems and mathematic models to better identify the markers of certain diseases. It appears that this department has a strong potential for therapy development with broad applications generating new tools for all the members of the Institute as well as for the community in Ophthalmology.

Team 6 : The team 6 comprises several excellent research workers investigating a range of fields mostly concentrating on retinal diseases. A major focus of the future plans is age related macular degeneration and the role of lipofuscin. In addition the group are developing novel imaging techniques which combine adaptive optics approaches with more conventional imaging using scanning laser ophthalmoscopy and high resolution optical coherence tomography. Finally they are developing novel techniques in predicting the outcome of clinical studies in particular drug trials using mathematical modelling techniques. This group are making significant inroads into a range of ophthalmological diseases using cutting edge technology. The output is excellent (good international ophthalmology journals, top in immunology, 1 NEJM) and the future plans are strong. The senior members bring important

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complementary contributions in electrophysiology, immunology, imaging techniques (in both the human and rodent), vascular remodelling, diabetic retinopathy, genetic studies and molecular techniques. The leader of the team (and of the Institute) is the major driving force behind the research programme. In addition to his considerable scientific prowess he has remarkable interactive and networking skills which permit him to achieve what he has: an extremely productive researcher with ambition and vision for the future. His main difficulty is that he might be overstretched in what he is trying to achieve. The panel recommends that some researchers could be drawn closer to the focus of the research. This excellent team brings a wide range of novel techniques with an aspect of mathematic modelling focusing on aged-related macular degeneration and diseases related to angiogenesis. Such strategy is a strong added value for the Institution as whole. Clearer directives to optimize the existing manpower are suitable.

Team 8 : The research program of Team 8 is focused on understanding of the role of some inflammatory molecules in the pathogenesis of glaucoma as well as on the evaluation of the potential role of mesenchymal stem cell (MSC) therapy for glaucoma. The team leader made previous important contribution by showing that conservatives in eye drop medications may generate an immune reaction leading to the worsening of glaucoma and other diseases. The present project extrapolates that an origin of glaucoma could be immune-related, but no preliminary data are provided. These are theoretically relevant goals but the research plan to attain them seems inadequate. In the first part (role of CCR and their ligands) the program focuses on expression studies in in vitro and ex vivo systems which most likely won’t demonstrate the role of any of these pathways in the glaucoma pathogenesis. Such hypothesis should require genetic proofs such as crossing animal models of glaucoma with knockout or transgenic animals for the molecules considered and/or the use of specific pharmacological inhibitors in the appropriate disease model. In the cell therapy section of the project, the studies proposed to understand the role of MMP3 in MSCs engraftment appears incomplete. Although attractive to potentially reduce an inflammation, the transplantation of MSCs necessitates addressing the question of the biological function of the transplanted cells. The team leader is a productive ophthalmologist with a good track record of publications (many but not high impact) in immunology of the anterior structures of the eye. The team allowed the training of several PhD students. The team leader shows his strong capacity to convince several Pharma to avoid conservatives in their product to prevent side effect of the medication. This involvement shows his strong commitment to translate the discovery of the team into clinical application. The topics proposed here could be relevant and in principle fit well into the therapy department, but urgently needs to provide concrete evidence of relevance before a large investment is made in this area. It appears that the hypothesis merits to be challenged and corresponds to the first part of the proposed project, but it is at high risk. These series of experiments may serve to reveal whether immune components are linked to some forms of glaucoma, and should be validated by genetic models to provide a long-term viability of the project.

Team 9 : The project proposed by this team is the development of a technical platform for human cell culture to treat corneal diseases. The team has already certified this platform and transplanted two patients with limbal cell cultures. The project proposes to continue to use limbal stem cell cultures and to develop endothelial cell cultures as well. The methodology is poorly described and it is in consequence difficult to comprehend a potential innovative approach, except for the proposition to use stroma slices to start endothelial cell cultures. Nonetheless, such platform is important for the clinic, but no novelties are proposed to ameliorate the process of limbal cell culture or to verify whether the culture system has integrated the cornea or has mobilized remaining quiescent endogenous stem cells. It appears that the team necessitates the presence of an expert in stem cell biology to render this project viable on the long term, from an academic point of view. The team published several papers in journals of ophthalmology, but the team leader has a limited number of publications as first or last author. The establishment of a platform for human cell transplantation is of high relevance for the clinic and to provide translation between the Institut de la Vision and the clinic. Nonetheless, progress and excellence can be reached only if biological and medical questions are identified and solved, which is missing in the present project. The integration of this team in the Department of Therapy is logical, gives an important perspective to the clinic, and shows very well the will to apply new technologies to the clinic.

Team 11 : This team aims to unravel the role of mutated mRNAs affecting mitochondria physiology and leading to eye diseases. Such knowledge may also have a broad impact on diseases affecting other organs. This research program is focused on the following aspects of mitochondrial diseases involving the eye : understanding the molecular bases, generation of animal models by somatic or germline gene transfer and treatment by gene therapy. The strength of this project is the focus on a single group of ocular diseases with common pathophysiological aspects and the strong promising preliminary results on gene therapy presented. This is the soundest project proposed in the

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Physiopathology Department. The originality encompasses not only the ophthalmologic field, but many other systems. It is important to underline that the team identified sequences addressing nuclear mRNAs to mitochondria surface allowing local protein synthesis. Such knowledge allows for developing appropriate therapy. The group published in very good papers, but not with a high frequency. Nonetheless, the potential of this project is very high due the strong preliminary data revealing some mechanism controlling mitochondria mRNA synthesis. One weakness is that the project may be too ambitious for a group of 6-7 people where the only senior investigator is the PI. The PI may additionally want to consider AAV-mediated gene transfer as preferential gene delivery tool for future experiments if the final goal of this part of the project is human gene therapy. From the translational point of view the group will certainly benefit from joining the Vision Institute where they will find expert geneticists and ophthalmologists to complement their basic science expertise. In summary, the project is of high potential and considering the environment of the Institute may provide major breakthrough in the understanding of mitochondria related diseases.

5 Appreciation of resources and of the life of the research unit — Management :

The achievements of the Director are remarkable and all members of the committee felt he should be complimented on this. His work has led to the creation of a very significant eye research facility with a diversity of multi-disciplinary teams with a very strong sense of common mission and a group commitment to translational eye research to the benefit of the patient. However the substantive expansion of the number of teams will present new challenges to the task of sustaining the sense of common mission and determining the research focus of components in the perspective of the mission of the whole. For example the rapid emergence of many topics in certain departments (eg genetics team 4 and visual processing team 10) may dilute the manpower and finally the impact of these researches. There will be a need to establish a more formal management structure and a research strategy group (to include QVCHNO) to help the Director sustain the progress achieved. The fact that the Unit is already managing two projects of the European commission suggests that the Unit has the capacity to undergo such change rapidly.

— Human ressources:

The number of the unit members and the diversity of the the different competences renders this unit very coherent with a high potential of major contribution. Because of the rapid expansion of the Unit, the secretary needs supplementary manpower to be able to manage correctly the administrative tasks.

6 Recommendations and advice — Strong points :

The CHNO is a unique opportunity in France (and even in Europe) to have a so large pool of patients who can be involved in different research projects and in clinical trials.So there is a strong synergy between the fundamental and translationnal sciences as well as the clinic. The teams are very complementary by their projects and technicds developed in their department. The achievements of the Director are remarkable and all members of the committee felt he should be complimented on this. The major conclusion is that the Insituteis an excellent centre as a whole and will provide major outpus for research,student training,patient diagnostic and care as welle as for the economic development.

— Recommendations :

Several projects aiming to use stem cells would benefit from the presence of a biologist with a good record in this field.Analogous recommendation could be done for gene therapy and expertise in the use of vector. There will be a need to establish a more formal management structure and a research strategy group to help the Director sustain the progress achieved and enlarge the center to new scientific challenges and the turnover of teams.

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Pr José Alain Sahel

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F-75012 PARIS

Tél. : (33) 01 5346 25 04

Fax: (33) 01 5346 25 05

Reply to the AERES report UMR S 592 Inserm-UPMC

General comment

We thank the committee for their very positive assessment and for theirguidance. They clearly recognized the novelty and importance of creating andsupporting the Vision Institute. Overall we find the report faithful and veryuseful and only wish to correct some errors and omissions, pro vide updatesand attempt to compensate for the main problem with the assessment process :i.e. the lack of appropriate time for an in depth review.

- First of ail, we felt that the very late communication of documents (writtenand downloaded to the Inserm EVA site 5 months earlier) to committee

members gave the impression that the visit was not weil prepared, which wasclearly not the case. Such information had been made available for monthswithout being communicated to the experts. The director was asked, a fewweeks and even sometimes a few days before the visit, to send the documents(hundreds of pages) directly to the experts, which was embarrassing on bothsides and led to some misinterpretations.

- More important/y, overall the visit lasted less than a full day as the generalpresentation started on the 1ihat 7 pm and the committee started to conveneat 4 pm on the 1Slh. While the time allowed for individual team presentationswas limited to 10-12 minutes, the duration of the period of questions extendedfar beyond the original planning. This certainly offered the opportunity toaddress sorne questions from the committee but this also resulted inconsiderable delay at the expense of the presentation of transversal projects(especially on stem cells and glaucoma), and of the visit of the Institute.Several presentations were given and discussed hours behind schedule after anendless morning. We had struggled for the previous several weeks in order tobe able to show this novel place, conceived and conducted with the researchersin order to promote an integrated strategy. A 5 minutes race through thebuilding was the only opportunity for some committee members to observe theresult of years of commitment from many members of our Institute, which wasvery frustrating!

Yet the committee was able to grasp some of the spirit of this new centre. Theadvice on the governance is certainly worth being followed although severalfacts on this topic are overlooked in the report. This is particularly obviousregarding the existence and importance of emerging teams. While so muchemphasis is put on management and governance issues in the report, thecommittee does not even mention one of the key successes of our scientificstrategy, namely the attraction of promising young scientists from abroad asexemplified by the existence of the Avenir team of Jean Livet, who develops atotally novel approach (the brainbow technology, Nature, Nov 07) despite hispresentation during the visit (see below). It did not either recognize that theGenetics team 4 includes three novel teams identified by an InternationalScientific committee set with Inserm and UPMC andfunded by the RTRS "Voiret Entendre" and Fondation Bettencourt-Schueller. Several comments on the

structure of group 4 simply reflect the lack of awareness that emerging teamscould not be presented independently in the written documents (due toadministrative rules beyond our control). The role of the internationalcommittee, the importance of the scientific strategy that led to the attractionand selection of new groups (including also two Chaires d'Excellence by ANR)has apparently not struck the writers of the report. Thus, we feel that thecommittee has underestimated the strategy that attracted several internationaland national groups of high calibre, with extremely scarce funding, as a resultof a genuine scientific strategy.

Moreover, we simply emphasize that the department structure, the regularmeetings of teams leaders, the function of the lab council, the role of thescientific committee in the assessment of the overail strategy and in theselection of teams, are already implemented. Our laboratory has grown from asingle person 15 years ago to the current Institute(about 130 persons), whilemanaging major European projects and networks. Decisions have always beenreached by consensus and we would like to keep that spirit, exclusivelydrawing from scientific priorities. The management team includes persons incharge of EU programs, grant applications, human resources, contracts,quality insurance, and partnerships with industry through the Carnot Institute.Almost none of these functions hold permanent position. We therefore believethat the management structure and strategy group already exist and have beenefficient at both the local and European level. A proper management alsoimplies means for efficient and rapid action. Such type of support in the currentproject driven general funding scheme with extremely low recurrent resources,simply does not exist. Only the common will to share and exploit togetherconsolidated common platforms and costs leaves some room for a limitedstrategy. Such approach already enabled us to support early, high riskprogram by limited bridging funds until larger grants and proper recognitionoccurred.

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Only IWo groups working on the visual cortex belong today to the Institute(teams 3 and 10). Another group ([rom CNRS) was selected by the scientificcommittee and shou/d join us once technical issues (working on small rodentsvers us cats) are fully solved (which is happening) and administrative issueswith CNRS are finalized. Yet, we decided and explained to the committee that,given the limited size of the Vision Institute, the vicinity of the ICM (Institut duCerveau et de la Moelle, due to open soon), the existence of Neurospin and ofexcellent vision science groups in Orsay, we are structuring a frame forcooperation and complementarities with these entities, rather than attemptingto duplicate everything in a single place in central Paris, which in our view isunrealistic and would occur at the expense of topics that are more relevant tothe location of the Institute inside the hospital. The new MRI3 Tesla facility ofCHNO and the new imaging team on site will faci/itate functional studies, incooperation with the other centres.

We agree that a vector specialist would be useful. Vectors are designed on siteand prepared in collaborating expert centres (public or private, e.g. Nantes).As stated in team 5 comments, one of our post-do cs from Ireland trained inPete Humphries lab and is now preparing a new post-doc in Jean Bennett 's lab(a world leader in the field). We hope that the creation of positions will enablethis type of recruitment.

As to the comments on stem ceIls, we restate that the stem cell project could not

be presented, per lack of time (as was the case for the ganglion cellstransversal program). One of the groups has worked deeply into molecularmechanisms regulating progenitor difJerentiation. This long-haul program hasnot yet produced ail what was expected, but the same held true, IWoyears ago,for programs that are now complimented by the experts. We believe that thetype of careful, stepwise research conducted will bear its fruits, timepermitting. Such expertise and our pre-clinical and clinical capabilities havealready paved the way for large scale collaborative programs with strong stemcell biology groups (e.g. EVI-Genoret, IStem). We are ready to welcome aworld class ocular stem cell specialist if the funding becomes avai/able (somesenior teams selected by the international committee in 2007 could not comefor lack of attractive packages).

We think that this report provides the instant image of a new structure, that theexperts, within the limits of the exercise, took hold of the dimension of thisenterprise and provide useful guidance for us and even more the fundingbodies. Proper recruitments for the management, for the platforms, for severalteams that have no permanent staff, allocation of recurrent significant base linefunding, would enable our scientific strategy to become obvious and ourprojects to blossom. A strong public research environment offers the conditionsfor independent scientific endeavours and for partnerships (with charities or

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private companies) where both sides can drive towards an efficienttransiationai research.

Team 1We first want to thank the committee for their kind evaluation of the work

perfomed in our group. We just would like to remind the Aeres that thestructure of our team had evolved since the application was submitted lastOctober, as Dr Jean Livet has been running independently an Avenir team(using the « brainbow » technology to study neuronal circuits) since January2008 (this was clearly presented during the visit). Therefore, the Department ofDevelopment regroups 4 teams and not 3. It is unfortunate that the visitingcommittee did not provide a written evaluation ofthis new group.

Team Avenir

ln the evaluation report of the Institut de la Vision (ldV), the AEREScommittee did not include any comments regarding my Inserm Avenir teamand project (nor about any of the young researcher teams presently emerging atthe institute). My Inserm Avenir grant only started in January 2008, and myteam was only recently added to the chart of the Institute. As a consequence, itwas not listed as such in the IdV activity report given to the AERES committee,although my research project was described. However my team was mentionedin the documents distributed to the committee during the March 17-18 visit,and 1 also presented it in front of the committee. 1 find the attitude of the IDVextremely positive, as it encourages the creation of emerging younginvestigator teams which develop their projects autonomously. 1 feel quitecertain that the AERES committee has a similar view and hope that theiromission can be corrected before final publication of the evaluation report. lnthat prospect, 1 would be happy to provide any information requested by thecommittee.

Team 2

We have noticed the different comments pointed out by the AERES committee(coherence, feasibility, expertise, skills ... ) particularly those required toimprove the quality and the pertinence of the project (frequency of publicationand feasibility of the "stem cells" project). Our research is focused on themolecular mechanisms involved in photoreceptor differentiation, with the finalaim to participate at the development of new therapeutic approaches based onretinal cell regeneration. We have chosen a relatively long fundamentalapproach rather than an immediate therapeutic approach using stem cells. Ourstrategy, combining transcriptomic screens and different gene transferapplications needed a long range effort. This type of approach could explain thelow frequency of publication these last four years in view of Aeres criteria.Nonetheless, two papers have been published the last two years, resulting fromthe set up of gene transfer by electroporation and the long analysis of oursubtractive screens (Roger et al. Dev. Biol. and Mol. Vis.) and two others are

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under CUITentsubmission and in writing. We would like to mention that fourcollaborative papers (2004 and 2008) have been published. Finally, the middlesize of our group (six peoples with three permanent researchers, but with onlytwo technicians and generally one PhD student) could also explain this relativelow frequency of publication.

As mentioned by the Aeres, our expertise in retinal development is importantfor other teams in the Institute. We have already initiated collaborations withtwo groups working on axonal guidance, particularly A. Chedotal (Teaml atthe Vision Institute), to characterize the retinal developmental defaults ofdifferent knock-out mice.

Regarding the "stem cells" project, we agree that the approach using non­retinal derived cells is not supported by preliminary experiments of our group.However, this project is in accordance with the evolving strategy of our groupinside the "Vision Institute", taking advantage of our expertise in photoreceptordifferentiation and has to be considered as a starting translational researchprogram including both on site and external partners recognized as specialistson stem cells (human ES cells and cord blood stem cells). Using eachmember's expertise, we aim at minimizing the risk of this "speculativeapproach". This translational project has unfortunately not been evoked duringthe Aeres visit owing to the very short time of the evaluation.

Team 3We can only agree with the comment of the committee concerning theoriginality of our research. Starting up projects like ours is always difficult andthis is indeed what we experienced in our previous environment. We have nowgood hope to see our results published in high impact journal.We hope and in fact feel confident that the "Institut de la Vision", and inparticular the department of development, will provide us with a stimulatingenvironment which will allow us to establish fruitful scientific collaborations

as weIl common operational platforms.

Team 4

Members of Team 4 are grateful to the Committee Members of the "Agenced'Evaluation de la Recherche et de l'Enseignement Supérieur" for theirvaluable comments and suggestions. We are glad that we convinced theCommittee Members that our suggested project will undoubtedly makesignificant contributions to the knowledge in the field of ophthalmic genetics.While we certainly do not criticize the se insights, we feel that we need toexplain sorne points raised by the Committee.

Members of Team 4 just started to work together a few months back, and thusthe projects appeared perhaps too divergent. ln addition, novel aspects wereadded to the Team research program that was not present in the report sent to

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Members of the Committee last October. Team 4 includes three emerginggroups that were selected by the international selection committee and aredestined to become independent teams of the genetic department.

One goal of our group is to identify mutations in known or yet to be discoveredgenes involved in inherited eye diseases in patients seen at the CHNO Quinze­Vingts. These findings combined with exhaustive genotype-phenotypecorrelations deliver the basis for the preparation of patients for a clinical trial, ifa gene therapy of the respective gene is available (in close collaboration withTeam 5). The investigated gene defects are CSNB (Isabelle Audo, ChristinaZeitz) and AMD (Eric Souied), but also other inherited eye diseases like rod­cone dystrophies, nystagmus and glaucoma. Depending on the outcome ofnovel genes identified, more people should be recruited will focus on thespecific gene function and pathogenic mechanism. Moreover, Team 4 alreadyconcentrates expertises in several fields indissociable from understandingpathogenic mechanisms. Indeed, researchers specialized in RPE cell biologyand phagocytosis of outer segments of photoreceptors (Emeline Nandrot),splicing factors (Kinga Bujakowska), and cell biology and cell polarity (JordanDoumanov, Veselina Doumanova) integrated the Team since January 2008.They will work on understanding the role of RPE cells in different retinalpathologies and how defects in ubiquitous splicing factors lead to blindingdiseases.

Within a few months, over 130 autosomal recessive rod-cone dystrophypatients have been pre-screened for known mutations on a microarray (ASPER,Tartu, Estonia). The identified mutations will be now validated by directsequencing. ln addition, our cohort of autosomal dominant rod-cone dystrophypatients is investigated in known genes by direct sequencing. As a result, noveland known PRPF31 and RHO mutations have been identified, and co­segregation analyses on other family members are underway.

Committee Members also recognized that the Team Director (ShomiBhattacharya) is highly renowned, but only present half-time. Although thisholds true, the young group leaders (Emeline Nandrot and Christina Zeitz) arein daily contact with him while he is away from the Institut de la Vision,whenever needed. ln addition, besides their own starting financial support fromthe Fondation (RTRS) "Voir et Entendre" and Schuller-Bettencourt, they arealso financially supported by the director's grant (Chaire d'Excellence ANR) tobuild up their laboratories. Furthermore, this situation helps them takeresponsibilities and grow as independent group leaders.

Team 5

We thank the committee for their very positive assessment. Concerningbiochemistry, we have had two postdoctoral researchers specialized inbiochemistry over the last 5 years in the team, but because these profiles are

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highly sought by the industry and its attractive salaries, they both left the teamto the industry. Nevertheless, we are currently looking for the same profile withaIl possible sources of founds (ANR, CTRS, ... ) and have already obtained aExchange Visit Travel Orants with from the Karolinska Institute from theEuropean Science Foundation.Conceming gene therapy, a post -doctoral researcher from the team has a PhDthesis from the Trinity College of Dublin, working with Peter Humphries, aspecialist of gene therapy. ln addition, she is going to perform a second post­doc, working on RdCVF in the lab of our collaborator Jean Bennett at theUniversity of Pennsylvania. She will certainly be the right pers on after that, andwe hope to be able to recruit her upon retum.

Team 6

We thank the committee for their very positive appraisal. As stated in thepresentation documents, our team is novel both in its thematic and its

composition, comprising researchers with very different backgrounds thatdecided together to face the challenge of model design for pre-clinical research.Our current priority is to make converge the se experiences to reach our goal,that is, building new tools, markers and biomathematical models fortranslational research, with possible impacts, however, on more fundamentalresearch. The first of these tools, a high-resolution in vivo retinal imagingsystem, is now implemented with the Observatoire de Paris. We doacknowledge that developing mathematical modelling requires that wereinforce our manpower. Thus, Pierre-Yves Boelle will progressively increasethe time spent in our lab, reaching ultimately half time, and we will hire asecond, full-time mathematician. We already are establishing a partnership withthe Ecole Centrale de Paris, the Commissariat à l'Energie Atomique and theInstitut Supérieur d'Electronique de Paris for building projects onbiomathematical modeling of retinal vessels and neurons (e.g. CIFRE thesis).Thus, over the past few months, even before the opening of the Institute, thecohesiveness of our group has led to a consolidation of topics andcorresponding resources. Recruitments are planned, depending on availablefunding for this novel team.

Team 7

We thank the committee for the very positive assessment of the work andprojects. The committee was very sharp in underlying the importantcontribution to other teams, mainly through the platform for animalexperimentation. The need for adequate staff and funding for this team isobvious, highly qualified post-docs have already been hired in this team and wehope that national agencies (INSERM, CNRS) will follow theserecommendations by offering them permanent positions.

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Team 8This team belongs to the Department of Therapy since its main focus is thedevelopment of new approaches for the treatment of glaucoma. It is a strongtranslational team because it gives the opportunity to obtain from the teamleader (eye surgeon) human samples oftrabeculum -the structure of the anteriorsegment of the eye which is primary deteriorated in glaucoma-, as well asvarious liquids of the eye in order to study, in humans, the possible implicationof inflammatory molecules such as chemokines. The second aspect of theproject in relation to the chemotactic effects of chemokines is the cellulartherapy using mesenchymateous stem cells (MSCs) to restore trabecularfunction. ln contrast to what the AERES panel said, il' s a quite new team sinceit brings together the internationally recognized expertise of the team leader onimmune-related glaucoma together with three major scientists working intoxicology, metalloproteases/stem cells and chemokines.

ln contrast to the comments, the strategy to study the involvement ofchemokines in this dramatic pathology has been already very successful, inparticular in an attempt to demonstrate the implication of chemokines in brainneurotransmission as shown by the production of one of the new member of theteam internationally recognized on its pioneer work on chemokines in brain(Eur J Neuroscience, J Comp Neurol, PNAS, Nature Rev Neuroscience ... ).

Due to the too short time of the team presentation (10 min) during the AERESvisit, the panel members -which were experts on the retina but not on theanterior segment of the eye- did not probably have time to consider thepreliminary data obtained since October 2007 when the written application wasprovided to AERES; 1) The presence of chemokine receptors (CCR4 andCCR5) in ocular surface disorders (Baudouin et al. J Clin Allergy and Immunol116: 614-619,2005; Trinh et al. Am J Ophtalmol 144: 580-585,2007); 2) Theincreased expression of various cytokines in glaucoma (Baudouin et al.Ophtalmology 111:2186-2192,2004); 3) The presence ofCXCR4 (receptor forCXCLI2/SDF1) and ofCXCR3 (receptor for CXCL9, CXCLI0 and CXCLll)on our model of human trabecular cellline HTM3; 4) the increase in CXCL12and CXCR4 immunoreactivity in the presence of TNFalpha, a cytokine knownto produce retinal ganglion cell death.

Due to the high redundancy of chemokines to bind to the same receptor and theredundancy of the chemokine receptor themselves (see Rostène et al, NatureRev Neuroscience 8: 895-904, 2007), starting to address the question of therole of chemokines in this pathology by genetic mice models, as suggested,would be irrelevant. Furthermore, the anatomical structure of the trabeculum as

well the mechanisms of aquous humor secretion in mice is dramaticallydifferent from what is known in humans. It is much more relevant to tirst

demonstrate which chemokine is present or overexpressed in the eye of8

glaucomatous patients and then study their expression and protective orapoptotic properties on trabecular functions and retinal ganglion cells usingvarious techniques developed in the manuscript. Finally because the chemokinesystem is strictly species-specific (Rostène et al Nature Rev Neuroscience,2007), it was also clearly explained why the use of selective non peptideantagonists already available in human or chemokine agonists may be aninnovative strategy for the long term treatment of glaucoma. The expertise onMSCs and metalloproteases (Gabison et al Am J Pathol 166: 209-219,2005)will be first used as suggested to test the biological function of the transplantedcells and the effect of chemokines such as CXCLI2/SDFl on the tissue

attraction and homing process as already shown in various models for thischemokine.

The team 8 has just recently obtained a grant from University Pierre et MarieCurie to carry out the project, and an ANR project is scheduled to be proposednext year with two other teams of the Institute.ln summary the innovative (very few publications until now) translationalproject presented, the expertise of new members joining the team, should berecognized as an important asset for the Department of Therapy of the VisionInstitute.

Team 9Our team was previously a small and isolated university team and all effortswere made to develop a culture technique which could be approved by theFrench regulatory authorities. This implies that the level of safety reached bythe culture technique is high. To our knowledge our clinical trial is the firstFrench trial using cultured cells in eye diseases to be authorized by AFSSaPS.

Our objective is to develop scientific topics related to cell therapy in comealdiseases. From the written project to the presentation during the committeevisit we have scheduled to develop innovative approaches:

the interaction between comeal keratocytes (which act as feeders in our

culture system) and comeal epithelial cells will be investigated in order toisolate keratocyte-derived soluble factors which increase epithelial cellgrowth;the potential of differentiation of limbal epithelial cells will be investigatedto better understand the exact state of the cells (stem cells or progenitors);factors influencing the differentiation of cultured limbal stem cells will beinvestigated in order to promote growth of undifferentiated progenitors;characterization of the limbal epithelial cells will be studied. We stilliackmarkers which could specifically identify the limbal stem cells or

progenitors.

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We agree that we need close cooperation with experts in the field of stem cellbiology. Joining the research centre is an opportunity for us to develop suchcooperation.

To answer the question raised by the committee on the mechanism of thetherapeutic effect (integration of the cultured cells to the recipient comea ormobilization of remaining quiescent endogenous stem cells) DNA analysis ofrecipient comeal epithelial cells obtained several years after transplantation willbe used. However, answering this question implies that the therapeutic effect(which is of major importance for patients) has been obtained, which will beassessed by the ongoing studies. Furthermore if the expected effect is reached itseems unlikely that the cells could be from recipient origin as during surgerythe recipient comeal and limbal epithelium is completely removed togetherwith the subepithelial fibrosis.

Finally, as mentioned in the report, innovative approaches will be developed totreat comeal endothelial diseases.

Team 10We are grateful to the AERES Committee Members for their valuablecomments and suggestions. Our project is ambitious in studying the specificeffects of reorganization and plasticity of the visual system through cognitiveand non-invasive neuroimaging techniques but we believe that such atransdisciplinary approach is mandatory to follow functionally relevant plasticchanges in the human visual cortex. We have demonstrated our expertise in thefield of visual cognition in normals as weIl as in neurovisual rehabilitation inbrain-damaged patients. ln particular, we are the first team to demonstrate thatthe visual field can be restored in hemianopic patients by training unconscious,implicit residual capacities that are still present in the blind visual field(Chokron et al, Restorative Neurology and Neuroscience, 2008, in press). Froma more basic point of view, we will continue to compare the behaviouralconsequences of a lesion of the visual system as a function of its anatomicallocation and to measure the plastic changes consecutive to a lesion of the opticnerve, the optic tract or of the visual cortex in terms of cerebral activity usingfMRI recordings during visual recognition tasks. ln addition, in collaborationwith the departments of Visual processing and of Therapy, we will keep ondeveloping new rehabilitation techniques for visual and neurovisual deficitswith a specific interest in modelling the signal that should be delivered to thevisual cortex for retinal prosthesis. We regret the absence of coordinationbetween CNRS and INSERM at the AERES evaluation stage and hope thatthese two organisms will help us in being an integrate part of the vast VisionInstitute project, as wished by aIl teams.

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Team 11

We thank the committee for their positive assessment on Team Il researclproject and their trust in the promising data that could lead to the developmenof a gene therapy for treating optic neuropathies due to mitochondriadysfunction. The PI and a PhD student joined the 1aboratory in early 2004; Ontyear 1ater and until December 2005 it was composed of only 3 people (the PI, (PhD student and a post-doc feIlow). ln spite of this small size the stron~background of the Plon mitochondrial biogenesis led to the generation an<consolidation of a credible project on mitochondrial function and retinadegeneration, a field poorly explored in the ophthalmologic area probably ducto difficulties and pitfalls unavoidable. The committee raised two concerns an<we do essentially agree on both points:

1. The project is ambitious and the smaIl size of the team could sorne how hia handicap to succeed it. Dr. Corral-Debrinski applied for three fundinJsources. She hopes that at least one of them will be accepted and therefore shiwill become able to hire a new post-doc fellow and an engineer (lE) by the eneof 2008. She is also looking for an INSERM or CNRS scientist that could joiJthe team.

2. Publications are now produced by this group in good impact journals (e.gRNA, Rejuvenation research, ) This year the team has a paper accepted in BB~Mol. Cel! Res, and just received a very favorable review from the America:Journal of Human Genetics on the paper describing the newly designed modeof Leber' s optic neuropathy and of its rescue.

/~,co/

José-Alain Sahel