Sandro Rusconi, Scientific Director NFP37 Report 10.12.02, NF Forschungsrat, Bern UNIFR Rusconi 2002 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-today Professor Biochemistry UNI Fribourg 1996-today Director Swiss National Research Program 37 2002 USGEB President 2002-2005 The NFP37: Success, Failure, or Something Inbetween?
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Sandro Rusconi, Scientific Director NFP37Report 10.12.02, NF Forschungsrat, Bern
Sandro Rusconi, Scientific Director NFP37Report 10.12.02, NF Forschungsrat, Bern
UNIFRRusconi
2002
UNIFRRusconi
2002
1972-75 Primary school teacher (Locarno)1975-79 Graduation in Biology UNI ZH1979-82 PhD curriculum UNI ZH, Mol. Bio.1982-84 Research assistant UNI ZH1984-86 Postdoc UCSF, K Yamamoto, (S. Francisco)1987-91 Principal Investigator, Privaztdozent, UNI ZH1994-today Professor Biochemistry UNI Fribourg1996-today Director Swiss National Research Program 37 2002 USGEB President 2002-2005
The NFP37:Success, Failure,
or Something Inbetween?
Gene therapy's principle is simpleYes, but the devil is in the details
Gene therapy's principle is simpleYes, but the devil is in the details
UNIFRRusconi2002
UNIFRRusconi2002
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 ...
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»
NFP37 gets realistic: paradigm change in 1995/96NFP37 gets realistic: paradigm change in 1995/96UNIFRRusconi2002
UNIFRRusconi2002
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: 30 projects sent for reviewing some clinically-oriented rejected
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
NFP37 Major outputs 1: publicationsNFP37 Major outputs 1: publicationsUNIFRRusconi2002
UNIFRRusconi2002
high impact jour13%
PhD theses33%
reviews / book chap
22%
moderate impact jour
32%
Publications (out of 119, excluding abstracts)
meetings
workshops
patents
companies
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
NFP37 Major outputs 2: annual meetingsNFP37 Major outputs 2: annual meetingsUNIFRRusconi2002
UNIFRRusconi2002
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, ...
Good News excellent competence level good feedback by some thereof
President of expert's board
Good News extremely wise vision excellent political flair
Bad News (there were exceptions..) limited availability of many thereof lack of punctuality marginal compliance to duty
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.
Competence reasonable understanding of gene regulation
not a medical doctor not a 'real' gene therapy
specialist
Location
Disadvantages
Much of this activity was performed as 'learning by doing'
'neutral' between german and french-speaking part
no medical faculty in Fribourg
just installed in Fribourg few / no contacts with industry not familiar with NFPs not carismatic at all levels several additional mandates
Players 4: Service Presse et CommunicationPlayers 4: Service Presse et CommunicationUNIFRRusconi2002
UNIFRRusconi2002
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.
advantages long standing competence good contacts list reasonable infrastructure
disadvantages no pro-active assistance change in direction some skeptical attitude
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
bad news 'looking down' on scientists: «they don't
know what a patient is... »
Many grantees did not apply because they were genuinely attracted by gene therapy but just to get another source of financingThey could not be mobilised after ending of the funding
Grantees evaluation, human resourcesGrantees evaluation, human resourcesUNIFRRusconi2002
UNIFRRusconi2002
Principal Investigator
s30%
Academic (postdoc)
33%
Graduate Students
26%
Technical assistants
11%
Principal Investigator
s23%
Academic (postdoc)
48%
Graduate Students
14%
Technical assistants
15%
Part Time involvement (3142 person-months)
Full Time involvement (4395 person-months)
The NFP 37 put into action about 7000 months-person, whichcorresponds to 210'000 man-days
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
Grantees evaluation, Perception of inputs from the program
Grantees evaluation, Perception of inputs from the program
UNIFRRusconi2002
UNIFRRusconi2002
others17%
low level0%
intermed level 4%
excellent level79%
Opinion on quality of annual meetings (out of 26)
indispens able18%
not useful5%
occasional14%
useful63%
strongly positive
33%
negative0%
not signif5%
positive62%
Influence / impact of NFP37 on my research activity (out of 24)
Usefulness of annual meetings for encounter/exchange (out of 24)
The NFP37 provided good annual reunions, promoted encounters,and had a positive influence on the majority of the funded teams
Grantees evaluation, Opinions on own futureGrantees evaluation, Opinions on own futureUNIFRRusconi2002
UNIFRRusconi2002
remain major focus
totally abandoned
partly abandoned
significantly maintained
Will your research team maintain a focus on SGT? (out of 26)
strongly increased
reduced
about same
increased
Will your research team size be changed ? (out of 24)
others
no special attention
some encoura- gement
a specific funding slot
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
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.
The 'Swiss Gene Therapy Army', as of March 2002The 'Swiss Gene Therapy Army', as of March 2002UNIFR
Rusconi
2002
UNIFR
Rusconi
2002
2 companies, 7 patents
5 postdoctoral trainees
14 research teams with 2 world-level
5 additional identifiable, qualified and competent research teams, +20 interested MDs
40 doctoral trainees
2 pre-existing companies, 2 large pharma companies
Outside NFP37
NFP37 legacy
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?
What was achieved / not achievedWhat was achieved / not achievedUNIFRRusconi2002
UNIFRRusconi2002
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)
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
Initial goals were only partially achieved
Own personal costs and benefits from the direction activity
Own personal costs and benefits from the direction activity
UNIFRRusconi2002
UNIFRRusconi2002
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
benefits good news public and scientific exposure novel personal knowledge
bad news knowledge may be quickly lost after
program end
The balance looks positive in terms of public visibility, less good in terms of scientific credibility
Limiting factors: structures, mentalities and functionsLimiting factors: structures, mentalities and functionsUNIFRRusconi2002
UNIFRRusconi2002
The mid- long-term impact NFPs cannot be assessed Universities are not encouraged to implement The fracture between clinics and science remains
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)
Gene transfer research, are Swiss structures adequate?Gene transfer research, are Swiss structures adequate?UNIFRRusconi2002
UNIFRRusconi2002
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
Fundamental versus applied research: a dilemma for public funding agencies
Fundamental versus applied research: a dilemma for public funding agencies
UNIFRRusconi2002
UNIFRRusconi2002
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
applied fundamental
'smart' 'intelligent'
solve problems generate problems
targeted training open-end training
'commercial' 'pure'
concentration dispersion
confidentiality exchange
privately sponsorable publically funded
Requireddifferent selection criteriadifferent refereeing systemdistinct levels of confidentialitydifferent amounts of financing
NFP37 follow up, needs to continue somatic gene therapy efforts, public understanding and political implications
NFP37 follow up, needs to continue somatic gene therapy efforts, public understanding and political implications
UNIFR
Rusconi
2002
UNIFR
Rusconi
2002
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
So..., let's hope
We may bring together a core-team of SGT interessees
END (opening discussion …)END (opening discussion …)UNIFRRusconi2002
UNIFRRusconi2002
Thank you all for the attention
Thanks to Françoise Kästli Charles Weissmann Bernard Mach Experts board Grantees My lab collaborators Nationalfonds div. IV
possible discussion slidespossible discussion slidesUNIFRRusconi2002
UNIFRRusconi2002
Why 'somatic'?Why 'somatic'?UNIFRRusconi2001
UNIFRRusconi2001
Germ Line Cells: the cells (and their precursors) that upon fertilisation can give rise to a descendant organism
Somatic Cells: all the other cells of the body
i.e. somatic gene transferis a treatment aiming atsomatic cells and conse-quently does not lead to a hereditary transmission of the genetic alteration
The most feared potential side-effects of gene transferThe most feared potential side-effects of gene transferUNIFRRusconi2002
UNIFRRusconi2002
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)
Gene Therapy Adverse events: NY 1995 // UPenn 1999 // Paris 2002
Gene Therapy Adverse events: NY 1995 // UPenn 1999 // Paris 2002
UNIFRRusconi2002
UNIFRRusconi2002
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).
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.
Why so many cancer trials?Why so many cancer trials?UNIFRRusconi2002
UNIFRRusconi2002
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