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click the underlined words for informations on Phase B, 1999-2001
or abstracts of intermediate reports of, or divulgation texts each research group
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General remarks
A very large number of life-threatening or strongly debilitating disorders is caused by a genetic defect or insufficience. The underlying defect can be inherited, spontaneous or induced by traumatic agents, poisons, mutagens or viruses and can involve one or more important cellular functions that ultimately lead to cancer, immune deficiencies or degenerations, metabolic diseases or neurodegenerative diseases etc...
Somatic gene therapy aims at the direct correction of inborn or acquired genetic defects that alter the function of cells and tissues. To this purpose a vector construct encoding the therapeutic gene must be targeted to the affected cells of a tissue. One distinguishes two categories of therapeutic genes: (A) those that will supplement a missing or a lost function and (B) those that will antagonise a dominant function arisen by mutation or viral infection. Different kinds of gene delivery have been proposed and tested. They can be categorised as follows: a) in vivo topical delivery; b) in vivo systemic delivery; c) ex vivo delivery; d) delivery of the therapeutic compound via artificial organs ('organoids')
Several pioneering works have been started and reported within the last five years. In retrospect one can say that this initial phase has brought the proof of principle, although it has certainly outlined a series of technical problems that will certainly delay the broad-basis application of these therapeutic approaches. Therefore, numerous efforts must be still devoted to the solution of those issues.
The crucial problems can be summarized as follows:
a) Lack of an efficient and general DNA delivery system (and consequently the high interest on viral transducing systems)
b) Difficulties in establishing efficient targeted DNA delivery systems
c) Packaging constraints in viral vectors
d) Disadvantages of retroviral vectors (mutability, silencing, incapacity of infecting quiescent cells), Adenoviral vectors (cell preference, toxicity, immunogenicity, small packaging size for transgene), AAV vectors (random integration, silencing).
e) Difficulties in regulating the transferred gene (usually referred to as 'transgene')
f) Maintenance (positive selection) of transfected cells, escape from immune-reaction.
Some disorders (like metabolic diseases) require long term correction while for some others (like wound healing or acute rejection, etc.) it is sufficient to supplement a genetic functiion for few hours, days or weeks, to obtain a permanent and satisfactory therapeutic effect. TRherefore, the above-mentioned problems do not always concomitantly apply. No matter for which application, macro-molecules like entire genes or gene fragments are promoising to become the pharmaceutical agents of the next century. The secret behind their potential resides in the immense amount of information stzored in those complex molecules, compared to the limited chemical complexity of conventional drugs. Obviously, macromolecular pharmacogenetics will require the identificationof novel strategies for the efficacious delivery and the specific functioning of those therapeutic agents. So we can conclude by stating that gene therapy is nothing else but a discipline trying to find elegant solutions to a conceptually simple but practically complex problem.
The Swiss reality and the necessity of an impulse for GT research
The Swiss economical and academic realities have an outstanding record of reliability and quality, but remain a meager background for a massive impulse on innovative research. From one hand, the concept of venture capital is practically inexistent and this prevents the formation of the many small size companies that represent the humus of the applicative research in a rapidly expanding field. From the other hand, the Swiss academic world does contemplate only very few full time jobs for research and positions such as senior research scientist are rather exceptional.
In its initial form, the NRP37 project conceived the creation of one, perhaps two centers of excellence for somatic gene therapy in our country. The numerous problems that emerged from the pilot experiments in other countries and the inherent structural problems in our own country (see above) have suggested a perhaps a less spectacular dedication to more basic research, still with an extremely focused aim towards the clinical application. It was in this sense that the project was advertised in 1995. The advertisement attracted 56 project sketches, 32 of which were invited for a more detailed submission. The work of the expert's board (together with external referees) has led to a final screen of 20 projects. Few more projects have been re-examined and one more has been recently granted. The granted projects and their characteristics are briefly sketched in Table 1. The most important role of the project director, will be to ensure that the involved scientists maintain the original aims and to promptly alert those who are getting lost in the meanders of the fascination of basic science.
The project has been broadly divided into two phases: Phase A, three years in which the initially granted projects shall be followed and evaluated; Phase B in which the 'most suitable' projects may be continued and new projects shall be implemented. Two grants (44718 and 46196) have been financed for the full period of 60 months (see column M in table 1).
Some interesting aspects about phase A
A) Number of people involved: 19 principal investigators with 58 collaborating and 25 co-authors, makes an effective number of about 35 full-time senior investigators time. The salaries will engage 12 Graduate students, 15 postdocs and 4.5 technicians. This brings the number of directly involved people to around 60. It is conceivable that a certain number of junior, senior and technical positions that will directly participate in one form o another does not appear in this scheme since these persons are financed by other means. Finally we can calculate that the ensemble of the projects will involve around 80-100 people, 40 of which at the bench.
B) Distribution of finances: from the total around 7 Mio Sfr, only 1 Mio will be devoted to consumables. A smaller part will be reserved for apparatuses (230 kFr) and for other expenses (110 kFr). Thus the majority of the financing is for salaries. It is interesting that the senior jobs outnumber the junior positions. This may outline the effort to maintain the experimental line on a very focused path, rather than dispersing forces in training exercises. Considering that the average granting time is around 3 years, and that the number of bench-working persons is around 30, the financed amount for consumables will be around 10'000 Fr per person per year. This is at the low-limit for molecular biology labs and indicates that other resources will have to be mobilised to ensure the proper functioning of the various projects (see also point C).
C) Geographical distribution: the geographical distribution of the assigned projects is rather unique since it is one of the rare events that favours the French-speaking part of the country (F) versus the German speaking part (D). The total financing is of 3.7 Mio for (F) versus 2.6 Mio for (D). It may be interesting also to remark that the vast majority of consumables (827 kFr) has been requested by groups of the category (F). This could indicate that the support from 'external' resources is stronger in the German speaking part of the country.
Themes addressed by the Phase A participants to the NRP37.
Table 1, categories of projects and aims
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1. total of fellowships |
3 |
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2. Total of research proposals granted for phase A |
20 |
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3. Ethical / psychological / legal aspects |
2 |
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4. Experimental projects |
18 |
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5. Use / generation of transgenic animal models |
16 |
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6. Control of Cancer and/or Hyperproliferation |
8 |
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7. New/ Improved vector design |
6 |
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8. New / improved DNA-delivery design |
4 |
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9. Control of transgene regulation |
3 |
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10. Control of Metabolic / degenerative diseases |
2 |
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11. Control of Immune deficiencies |
1 |
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12. Not targeted to a specific disease |
7 |
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13. Disease-targeted with results extrapolatable to other diseases |
6 |
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14. Aimed to in vivo gene delivery |
5 |
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15. Aimed to ex-vivo gene delivery |
9 |
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16. Aimed to topical gene delivery |
4 |
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17. Aimed to use of heterologous transplants |
2 |
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18. Clinical phase I trials during first 3 years |
3 |
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19. Clinical phase II trials during first 3 yrs |
1? |
From this table it is evident that the majority of research effort belongs still to the developmental phase (see the many entries under: improvement of transfection / infection protocols, vectors, gene regulation etc). Noteworthy, a number of research proposals does not deal with a particular disease and only few of those addressing a specific foresee clinical trials during the next three years. From the targeted disease models, it is clear that the control of hyperproliferative disorders is raising the main interest whereas the metabolic and immunodeficiency diseases are less represented. This corresponds well to the average interest in other countries. This picture may chance in Phase B. The project of a 'core facility' did not take off, in spite of the many hopes and discussions. I attribute this stagnation to a lack of precise orientation and exact priorities in this field. It may be one of the task of the director and of the expert's panel to find out more about this aspect. Two young researchers have been granted a fellowship to proceed in postdoctoral training in the field. It may be that these young investigators will submit a research proposal for phase B. Finally, an important aspect, is that a large proportion of the research proposal specifically mention the prospected use or generation of transgenic animal models. This aspect is particularly important, considering the debate of 1997/98 around the 'Genschutzinitiative'.
Prospected tasks for the program director
The list below, arises from study of the 'Vademecum to the NRP', from the examination of documents relating to previous NRPs and from the several discussions with the NRP37 secretary, Dr. Kästli. The list does not need to be exhaustive and it may give excessive or insufficient emphasis on some specific points. However, there are the tasks that I anticipate to assume:
Task 1 Constant contact with experts panel, the president (Prof. Weissmann) and the main referee (Prof. Baggiolini). Knowledge of their decisions, provide consultation in those decisions whenever required, enforcement of those decisions. Continuous contacts with the general secretariat (Dr. Kästli) who will be the center of distribution of informations. Prompt notification of critical situations.
Task 2 Knowledge of current and submitted projects and of their respective PIs and collaborators.
Task 3 Site visits at beginning of the granting period, repeated where necessary, identification of problems. Visit of newly granted teams (phase B or intermediate applicants).
Task 4 Enforcement of networking proposed by experts panel, support and encouragement of inter-team communication
Task 5 Promotion and supervising organisation of regular meetings/briefings
Task 6 Assist in the development of phase B, wherever required. Supervise phase B as phase A.
Task 7 Develop and maintain an updated understanding on current knowledge, who's-who, and discoveries in the field of somatic gene therapy.
Task 8 Establishment of yearly reports in scientific and divulgative terms. Preparation of final report.
Task 9 Contacts with the 'Pressestelle' of the Nationalfonds and contacts with external information-requesting channels (possibly via Pressestelle). Be ready for contacts with opinion-making (media) and decision-making channels (political instances). Be ready to activate contacts with industry, clinical milieus, universities (specially in view of the valorisation).
Task 10 Guarantee the normal proceeding of his current administrative, teaching and research activities (Entlastung).
Details about the prospected implementation mode of those tasks are given in the director's grant proposal, a copy of relevant passages can be obtained by enquiring.
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