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Sandro Rusconi, Scientific Director NFP37 Report 10.12.02, NF Forschungsrat, Bern

UNIFR Rusconi 2002. Sandro Rusconi, Scientific Director NFP37 Report 10.12.02, NF Forschungsrat, Bern. 1972-75 Primary school teacher (Locarno) 1975-79 Graduation in Biology UNI ZH 1979-82 PhD curriculum UNI ZH, Mol. Bio. 1982-84 Research assistant UNI ZH

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Sandro Rusconi, Scientific Director NFP37 Report 10.12.02, NF Forschungsrat, Bern

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  1. UNIFR Rusconi 2002 Sandro Rusconi, Scientific Director NFP37Report 10.12.02, NF Forschungsrat, Bern 1972-75 Primary school teacher (Locarno) 1975-79 Graduation in Biology UNI ZH 1979-82 PhD curriculum UNI ZH, Mol. Bio. 1982-84 Research assistant UNI ZH 1984-86 Postdoc UCSF, K Yamamoto, (S. Francisco) 1987-91 Principal Investigator, Privaztdozent, UNI ZH 1994-todayProfessor Biochemistry UNI Fribourg 1996-today Director Swiss National Research Program 37 2002 USGEB President 2002-2005 The NFP37: Success, Failure, or Something Inbetween? a a a a a a

  2. UNIFR Rusconi2002 Gene therapy's principle is simpleYes, but the devil is in the details There are many things that are simple in principle, like... getting a train ticket... ! try this 5 min before departureand with a group of Chinese tourists in front parking your car... ! try this at noon, any given day in Zuerich or Geneva ... counting votes... ! ask Florida's officials ... gene therapy... look at NFP37 and not only ... a a a a a a

  3. UNIFR Rusconi2002 Somatic Gene Therapy's (SGT) Principles(somatic gene transfer) Chronic treatment Definition of SGT: 'Use genes as drugs': Correcting disorders by somatic gene transfer Acute treatment Preventive treatment Hereditary disorders Acquired disorders Loss-of-function Gain-of-function a a a a a a

  4. UNIFR Rusconi2002 Somatic Gene Therapy’s four fundamental questions Efficiency of gene transfer Specificity of gene transfer Persistence of gene transfer Toxicity of gene transfer Only partial solutions found so far a a a a a a

  5. UNIFR Rusconi 2001 TWO classes of gene transfer vehicles: non-viral & viral Non-viral transfer (transfection) a Viral gene transfer (Infection) b Nuclear envelope barrier! see, Nature Biotech December 2001 a a a a a a

  6. V UNIFR Rusconi 2002 THREE classes of anatomical gene delivery Ex-vivo In-vivo topical delivery In-vivo systemic delivery Examples: - bone marrow - liver cells - skin cells Examples: - brain - muscle - eye - joints - tumors Examples: - intravenous - intra-arterial - intra-peritoneal a a a a a a

  7. UNIFR Rusconi2002 Gene therapy turns teenage in 2003, but:has it really grown up? 1990 First clinical trial of a monogenic disease F. Anderson & Co: ADA deficiency ...does not work 2002 Same protocol as Anderson's for ADA gene therapy (C. Bordignon) ...it works! a a a a a a

  8. trials patients 100 1500 cancer 80 1000 60 hered. 40 500 vasc. 20 Infect. 1990 1992 1994 1996 1998 2000 UNIFR Rusconi2002 *Gene Therapy in the clinic: Trials Wordldwide As of Sept 2002:599 registered protocols 4000 treated patients 86% phase I 13% phase II 1 % phase III 21% overall still pending or not yet Initiated ! www.wiley.com a a a a a a

  9. Isner, 1998 Anderson, 1990 Fischer, 2000 Dzau, 1999 Kmiec, 1999 Aebischer, 2000 Kirn, 2001 Bordignon & Co, 2002 Science vol 296, page 2410 ff Clinical trials with ONYX-015, what we learned? (Review) Bordignon, 2000 (ESGT, Stockholm)proves efficacy of the same protocol UNIFR Rusconi2002 *Gene Therapy Milestones 1990, 1993, 2000 // ADA deficiency F Anderson, M Blaese // C Bordignon 1997, 2000, Critical limb ischemia J Isner († 4.11.2001), I Baumgartner, Circulation 1998 1998, Restenosis V Dzau, HGT 1998 1999, Crigler Njiar (animal) C Steer, PNAS 1999 2000, Hemophilia M Kay, K High 2000, SCID A Fischer, Science April 2000 2000, correction Parkinson P Aebischer, Science, Nov 2000 2001, ONYX oncolytic Viruses D Kirn (Gene Ther 8, p 89-98) 2002, ADA gene therapy Bordignon (Science, ) a a a a a a

  10. UNIFR Rusconi 2002 The reality is that all current popular gene transfer vectors have intrinsic limitations Adenovirus - no persistence - limited packaging - toxicity - immunogenicity Biolistic bombardment or local direct injection - limited area Electroporation - limited organ access Retrovirus (incl. HIV) - limited package - random insertion - unstable genome Liposomes, gene correction & Co. - very inefficient transfer General - antibody response - limited packaging - gene silencing General - low transfer efficiency 1/10’000 of viruses’ in vivo Solutions: - synthetic viruses (“Virosomes”) Solutions: - improved liposomes with viral properties (“Virosomes”) a a a a a a

  11. high mood Low NFP37 90 91 92 93 94 95 96 97 98 99 00 01 02 UNIFR Rusconi2002 Ups and Downs of Gene Therapy: a true roller coaster ride! lentivectors in clinics? Ergo1 : in spite of its respectable age,gene therapy is still in its infancy and still produces more controversies than clinical results A. Fischer M. Kay R. Crystal Adeno I V.Dzau C Bordignon J. Isner Ergo 2 : many of the ups due to misplaced promisesmany of the downs due to disillusion or malpractice ADA AAV germline in mice? NIH Motulski report Adeno III Lentivectors in pre-clinic Ergo 3: the NFP37 has ovelapped with the strongest ups and downs Adverse event in Paris J. Wilson J. Gelsinger a a a a a a

  12. UNIFR Rusconi2002 NFP37 early times: visions anno 1993/1995 1993 Mach / Weissmann / Baggiolini, promoters: establish 2 centres (chairs) in Switzerland March1994 «rien d'innovatif, il s'agit de rattrappage» May 1994 «a strong linkage between basic and clinical science» June 1994 «the NRPs cannot grant professorships» January 1995 • first meeting of experts group: • «me too» also acceptable • problem of GMP core facility • back to basic sciences? • director as a «monitoring person» a a a a a a

  13. UNIFR Rusconi2002 NFP37 gets realistic: paradigm change in 1995/96 Sept. 1995 • Second meeting of experts group: • 57 project outlines • Motulski effect • focus definitely back to basic research Jan. 1996 • Third meeting of experts group: • 30projects sent for reviewing • some clinically-oriented rejected based on 'lack of originality' May 1. 1996 Information day for grantees Aug.-Nov 1996 • Start operational phase 1 • selected director • 18granted projects (+1) a a a a a a

  14. UNIFR Rusconi2002 NFP37 operational phase 1, 1996-1999 Oct 10. 1997 • First Annual meeting • H Lehrach, B Sullenger, H Möhler Oct 9. 1998 • Second Annual meeting • R Mulligan, M Perricaudet, J Wolff Aug. 1998 Call for proposals Phase 2 July 1999 • Evaluated proposals Phase 2 • 26 submissions Oct 7-8. 1999 • Third Annual meeting • I Verma, L Mitchell, H Pandha, C Steer, M Grace, P O'Hare, D Losordo Nov. 1999 • Start operational Phase 2 • 17 proposals granted (+2) a a a a a a

  15. UNIFR Rusconi2002 NFP37 operational Phase 2, 1999-2001 Oct 6. 2000 • Fourth annual meeting • Ph Felgner, I Kovesdi, T Caskey Oct 3-5. 2001 • Fifth annual meeting • L Johnson, O Danos, D Losordo, J Graham, M Blaese, K High, R Mertelsmann, H Scheider, A Colman June 2002 • receive last evaluations + summaries • working on final report a a a a a a

  16. UNIFR Rusconi2002 NFP37 research categories NFP37phase 1phase 2 (96-99) (99-01) Submissions 30 26 Granted 19 18 Total requested 32 Mio 9 Mio Granted 7.6 Mio 6 Mio Direction 0.7 Mio 0.35 Mio DISEASE ORIENTATION Cancer 8 10 Acquired disorders 2 7 Vector development 5 3 Hereditary disorders 2 4 Infectious diseases 1 2 RESEARCH LEVEL Fundamental 10 7 Preclinical (animal models) 5 9 Clinical phase I 2 3 Clinical Phase II 0 1 Clinical Phase III 0 0 Ethical/social aspects 1 1 The research trends within the NFP37 reflected the world's trends: cancer and fundamental vectorology in first place, less clinical trials a a a a a a

  17. UNIFR Rusconi2002 NFP37 Major outputs 1: publications Publications (out of 119, excluding abstracts) Other outputs (out of 17) The NFP37 produced many valid publications, about 40 PhD theses, 5 postdoctoral trainings, several patents, 2 startup companies, and a fair number of interested visitors on the WEB site a a a a a a

  18. UNIFR Rusconi2002 NFP37 Major outputs 2: annual meetings Among the 27 invited main speakers: Jon Wolff, Imre Kovesdi, Tom Caskey, Phil Felgner, Inder Verma, Kathy High, , Mike Blaese, Olivier Danos, Doug Losordo, George Dickson, Alan Colman, Lloyd Mitchell, Savio Woo, Irving Weissmann, Michel Perricaudet, Clifford Steer, ... Facts 1028 attendants 212 abstracts 168 posters 48 guest abstracts Major internationally renowned speakers, lively posters and internal presentations, fair amount of guest abstacts a a a a a a

  19. UNIFR Rusconi2002 NFP37 Major outputs 3: public impact • By the program director: • 59 public conferences • 24 scientific conferences • 15 business-oriented conferences • 12 newspaper & media articles / interviews Visits at our WEB site www.unifr.ch/nfp37 Increasing public interest, peaks around major events (Gelsinger, Paris) a a a a a a

  20. UNIFR Rusconi2002 Players 1: Experts Board board of experts • Good News • excellent competence level • good feedback by some thereof • Bad News (there were exceptions..) • limited availability of many thereof • lack of punctuality • marginal compliance to duty President of expert's board • Good News • extremely wise vision • excellent political flair • Bad News • change Weissmann-Mach (2000) • limited availability due to overbusy schedule The role of the experts board was important but needed encouragement by the scientific secretariate and the scientific director. The presidents of the experts board left large maneuvering space to the direction. a a a a a a

  21. UNIFR Rusconi2002 Players 2: Scientific Secretariate Authority • Extremely useful in: • reminding grantees • reminding referees • taking technical decisions Routine • Iindispensable in: • forwarding information (reports) • organising general schedules • organise the experts meetings Advice • Precious in: • how to deal with the NF structures • how to proceed in critical or bureacratic situations • other useful ad hoc advice Without this scientific secretariate I would not have achieved much I wish other NFPs can continue having this kind of help a a a a a a

  22. UNIFR Rusconi2002 Players 3: Scientific Director Competence • reasonable understanding of gene regulation • not a medical doctor • not a 'real' gene therapy specialist Location • 'neutral' between german and french-speaking part • no medical faculty in Fribourg Disadvantages • just installed in Fribourg • few / no contacts with industry • not familiar with NFPs • not carismatic at all levels • several additional mandates Much of this activity was performed as 'learning by doing' a a a a a a

  23. UNIFR Rusconi2002 Players 4: Service Presse et Communication advantages • long standing competence • good contacts list • reasonable infrastructure disadvantages • no pro-active assistance • change in direction • some skeptical attitude Unfortunately I could not or pehaps I was not able to get much assistance from the Service de Presse et Communication. This situation could be ameliorated. a a a a a a

  24. UNIFR Rusconi2002 Players 5: Grantees basic scientists • good news • enthousiasm in young investigators • originality of thinking • bad news • alibi research (discontinued after program) • 'looking down' on clinicians: «they don't know what a gene is...» clinicians • good news • genuine interest in some clinicians Many grantees did not apply because they were genuinely attracted by gene therapy but just to get another source of financing They could not be mobilised after ending of the funding • bad news • 'looking down' on scientists: «they don't know what a patient is... » a a a a a a

  25. UNIFR Rusconi2002 Grantees evaluation, human resources Full Time involvement (4395 person-months) Part Time involvement (3142 person-months) The NFP 37 put into action about 7000 months-person, which corresponds to 210'000 man-days a a a a a a

  26. UNIFR Rusconi2002 Grantees evaluation, funding considerations Type of expenditures(total 14'180 KFr) Perception of funding amount by grantees (according to needs) The funded amount was felt to be sufficient and was mostlyinvested in salary, with 750 Kfr on GMP clinical grade materials a a a a a a

  27. UNIFR Rusconi2002 Grantees evaluation, Perception of inputs from the program Opinion on quality of annual meetings (out of 26) Usefulness of annual meetings for encounter/exchange (out of 24) Influence / impact of NFP37 on my research activity (out of 24) The NFP37 provided good annual reunions, promoted encounters, and had a positive influence on the majority of the funded teams a a a a a a

  28. certainly overestated! UNIFR Rusconi2002 Grantees evaluation, Opinions on own future Will your research team maintain a focus on SGT? (out of 26) Will your research team size be changed ? (out of 24) What does CH-SGT research need from public funds? (out of 30) 14 teams are 'commited' to continue (but 13 did not return the forms!), few have been reinforced. The PIs believe that Gene Therapy should be allotted a specific fund a a a a a a

  29. UNIFR Rusconi2002 Players 6: Institutions Universities • good news • good environment for research / training • bad news • they essentially dont care about NFPs • they are not specifically asked to care Companies • good news • excellent environment for implementation • bad news • totally disinterested in this NFP There is no specific incentive for those important partners. A 'contrat de prestations' should be established between Universities and NFPs. a a a a a a

  30. UNIFR Rusconi 2002 The 'Swiss Gene Therapy Army', as of March 2002 NFP37 legacy 14 research teams with 2 world-level 5 postdoctoral trainees 40 doctoral trainees 2 companies, 7 patents There is no follow-up structure / intention: who is going to measure the impact (and how) of the NFP37 in 2,5 or 10 years? Outside NFP37 5 additional identifiable, qualified and competent research teams, +20 interested MDs 2 pre-existing companies, 2 large pharma companies a a a a a a

  31. UNIFR Rusconi2002 What was achieved / not achieved Permanent centers • Achieved • four pre-existing or emerging clinical/preclinical teams became reinforced • Not achieved • many Univ's did not reinforce the successful emerging teams (exception ZH) Initial goals were only partially achieved clinicians - scientists cooperation • Achieved • in two teams this appeared to happen thank to the NFP37 • Not achieved • in all other cases there was conflict either during or after or in spite of the NFP37 training • Achieved • 40 PhD + 5 postdoctoral fellowships a a a a a a

  32. UNIFR Rusconi2002 Own personal costs and benefits from the direction activity costs • good news • could hire a part time secretary for routine admi & congress organisation • bad news • could not find good senior postdoc taking care of lab • scientific record down to absolute minimum The balance looks positive in terms of public visibility, less good in terms of scientific credibility benefits • good news • public and scientific exposure • novel personal knowledge • bad news • knowledge may be quickly lost after program end a a a a a a

  33. UNIFR Rusconi2002 Limiting factors: structures, mentalities and functions Follow up / fall out not guaranteed, mid-term and long term fall-out not measurable Universities Concerned attitude is neither forced nor encouraged Clinicians/ scientists the relationship has traditional friction-points, these can be diminished by appropriate training programs (e.g MD-PhD) • The mid- long-term impact NFPs cannot be assessed • Universities are not encouraged to implement • The fracture between clinics and science remains a a a a a a

  34. UNIFR Rusconi2002 Gene transfer research, are Swiss structures adequate? concentration of resources know-how? Number of patients ? Training system ? Funding system ? The global answer to several of those questions is (was) probably 'no'. However, recent signs of changes in the funding level and in the clinical monitoring system are very possitive a a a a a a

  35. UNIFR Rusconi2002 Fundamental versus applied research: a dilemma for public funding agencies If you are in the clinics you are usually not adopting a 'greatly original strategy' If you are developing a 'greatly original strategy', you are usually far from the clinics Required different selection criteria different refereeing systemdistinct levels of confidentiality different amounts of financing applied fundamental 'smart' 'intelligent' solve problems generate problems targeted training open-end training 'commercial' 'pure' concentration dispersion confidentiality exchange privately sponsorable publically funded a a a a a a

  36. UNIFR Rusconi 2002 NFP37 follow up, needs to continue somatic gene therapy efforts, public understanding and political implications NFP37 terminated scientific operations by end 2001 NFP37 has revealed a strong interest at the basic and applied research level NFP37 WEB site can continue until 2005, thanks to EU funds NFP37 Final report will be most likely in form of a CD-ROM and partly on the WEB We may need to further coordinate efforts and ensure sharing of experiences towards a NETWORK Some NCCRs that include SGT have been proposed but not accepted Some further NFPs that include SGT are on the way of being proposed We may bring together a core-team of SGT interessees So..., let's hope a a a a a a

  37. UNIFR Rusconi2002 END (opening discussion …) • Thanks to • Françoise Kästli • Charles Weissmann • Bernard Mach • Experts board • Grantees • My lab collaborators • Nationalfonds div. IV Thank you all for the attention a a a a a a

  38. UNIFR Rusconi2002 possible discussion slides a a a a a a

  39. UNIFR Rusconi2001 Why 'somatic'? • Germ Line Cells: the cells (and their precursors) that upon fertilisation can give rise to a descendant organism i.e. somatic gene transfer is a treatment aiming at somatic cells and conse-quently does not lead to a hereditary transmission of the genetic alteration dolly1.mov2 • Somatic Cells: all the other cells of the body a a a a a a

  40. UNIFR Rusconi2002 The most feared potential side-effects of gene transfer • Immune response to vector • immune response to new or foreign gene product • General toxicity of viral vectors • Adventitious contaminants in recombinant viruses • Random integration in genome-> insertional mutagenesis (-> cancer risk) • Contamination of germ line cells • Random integration in genome-> insertional mutagenesis (-> cancer risk) a a a a a a

  41. UNIFR Rusconi2002 Gene Therapy Adverse events: NY 1995 // UPenn 1999 // Paris 2002 NY May 5, 1995, R. Crystal: in a trial with adenovirus mediated gene transfer to treat cystic fibrosis (lung)one patient developed a mild pneumonia-like condition and recovered in two weeks.The trial was interrupted and many others were put on hold. UPenn, Sept. 19, 1999, J. Wilson: in a trial with adenovirus mediated gene transfer to treat OTC deficiency (liver)one patient (Jesse Gelsinger) died of a severe septic shock.Many trials were put on hold for several months (years). dolly1.mov2 Paris, Oct 2, 2002, A Fischer: in a trial with retrovirus mediated gene transfer to treat SCID (bone marrow) one patient developed a leukemia-like condition.The trial has been suspended to clarify the issue of insertional mutagenesis, and some trials in US and Germany have been put on hold. a a a a a a

  42. UNIFR Rusconi2002 Why so many cancer trials? Risk/benefit concept and high emotional acceptance (Terminal patients, Ethical committees) Market potential higher than monogenic diseases Many more diversified approaches envisageable than in monogenic diseases Much higher number of patients/center than in monogenic diseases a a a a a a

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