Transcript DIMENSIONS

Sandro Rusconi, Scientific Director NFP37
Report 10.12.02, NF Forschungsrat, Bern
1972-75
1975-79
1979-82
1982-84
1984-86
1987-91
1994-today
1996-today
2002
Primary school teacher (Locarno)
Graduation in Biology UNI ZH
PhD curriculum UNI ZH, Mol. Bio.
Research assistant UNI ZH
Postdoc UCSF, K Yamamoto, (S. Francisco)
Principal Investigator, Privaztdozent, UNI ZH
Professor Biochemistry UNI Fribourg
Director Swiss National Research Program 37
USGEB President 2002-2005
The NFP37:
Success, Failure,
or Something
Inbetween?
UNIFR
Rusconi
2002
Gene therapy's principle is simple
Yes, but the devil is in the details
UNIFR
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2002
There are many things that are simple in principle, like...
getting a train ticket...
! try this 5 min before departure
and 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 ...
Somatic Gene Therapy's (SGT) Principles
(somatic gene transfer)
Definition of SGT:
'Use genes as drugs':
Correcting disorders by
somatic gene transfer
Chronic treatment
Acute treatment
Preventive treatment
Hereditary disorders
Acquired disorders
Loss-of-function
Gain-of-function
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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
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TWO classes of gene transfer vehicles: non-viral & viral
Non-viral transfer
(transfection)
Viral gene transfer
(Infection)
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a
b
Nuclear envelope barrier!
see, Nature Biotech
December 2001
THREE classes of anatomical gene delivery
Ex-vivo
In-vivo
topical delivery
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In-vivo
systemic delivery
V
Examples:
- bone marrow
- liver cells
- skin cells
Examples:
- brain
- muscle
- eye
- joints
- tumors
Examples:
- intravenous
- intra-arterial
- intra-peritoneal
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!
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*Gene Therapy in the clinic: Trials Wordldwide
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trials
patients
As of Sept 2002:
100
80
599 registered protocols
1500
4000 treated patients
cancer
60
hered.
40
86% phase I
13% phase II
1 % phase III
500
vasc.
21% overall still pending
Infect.
or not yet Initiated !
20
www.wiley.com
1990 1992
1000
1994
1996
1998
2000
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*Gene Therapy Milestones
Rusconi
2002
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, )
Anderson, 1990
Isner, 1998
Dzau, 1999
Kmiec, 1999
Fischer, 2000
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
The reality is that all current popular gene transfer vectors
have intrinsic limitations
Adenovirus
- no persistence
- limited packaging
- toxicity
- immunogenicity
Retrovirus (incl. HIV)
- limited package
- random insertion
- unstable genome
General
- antibody response
- limited packaging
- gene silencing
Solutions:
- synthetic viruses
(“Virosomes”)
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Biolistic bombardment
or local direct injection
- limited area
Electroporation
- limited organ access
Liposomes, gene correction & Co.
- very inefficient transfer
General
- low transfer efficiency
1/10’000 of viruses’ in vivo
Solutions:
- improved liposomes
with viral properties (“Virosomes”)
Ups and Downs of Gene Therapy:
a true roller coaster ride!
high
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Ergo1 :
A. Fischer
M. Kay
in spite of its respectable age,gene therapy is still in its infancy
R. Crystal
and still produces more
controversies than clinical results
Adeno I
mood
ADA
V.Dzau
lentivectors
in clinics?
C Bordignon
J. Isner
Ergo 2 :
many of the ups due to misplaced promises
III
many of the downs dueNIH
to disillusionAdeno
or malpractice
AAV
germline
in mice?
Motulski
report
Lentivectors
Ergo 3:
in pre-clinic
the NFP37 has ovelapped with the
strongest ups and downs
Adverse
event in
Paris
J. Wilson
J. Gelsinger
Low
NFP37
90
91
92
93
94
95
96
97
98
99
00
01
02
NFP37 early times: visions anno 1993/1995
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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»
NFP37 gets realistic: paradigm change in 1995/96
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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
based on 'lack of originality'
May 1. 1996
Information day for grantees
Aug.-Nov 1996
Start operational phase 1
 selected director
 18 granted projects (+1)
NFP37 operational phase 1, 1996-1999
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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)
NFP37 operational Phase 2, 1999-2001
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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
UNIFR
NFP37 research categories
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2002
NFP37
Submissions
Granted
Total requested
Granted
Direction
phase 1
(96-99)
30
19
32 Mio
7.6 Mio
0.7 Mio
phase 2
(99-01)
26
18
9 Mio
6 Mio
0.35 Mio
DISEASE ORIENTATION
Cancer
Acquired disorders
Vector development
Hereditary disorders
Infectious diseases
8
2
5
2
1
10
7
3
4
2
RESEARCH LEVEL
Fundamental
Preclinical (animal models)
Clinical phase I
Clinical Phase II
Clinical Phase III
Ethical/social aspects
10
5
2
0
0
1
7
9
3
1
0
1
The research trends within the
NFP37 reflected the world's
trends: cancer and
fundamental vectorology in
first place, less clinical trials
UNIFR
NFP37 Major outputs 1: publications
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Publications (out of 119, excluding abstracts)
Other outputs (out of 17)
high im pact
jour
13%
PhD the s e s
33%
w or k s hops
m e e tings
m ode r ate
im pact jour
32%
r e vie w s /
book chap
22%
com panie s
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
pate nts
NFP37 Major outputs 2: annual meetings
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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, ...
Major internationally renowned
speakers, lively posters and internal
presentations, fair amount of guest
abstacts
Facts
1028 attendants
212 abstracts
168 posters
48 guest abstracts
NFP37 Major outputs 3: public impact
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2002
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)
Players 1: Experts Board
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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)
The role of the experts board was important but needed encouragement by
 the
limited
availability
to overbusy
the scientific secretariate and
scientific
director.due
The presidents
of the
schedule
experts board left large maneuvering
space to the direction.
Players 2: Scientific Secretariate
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Authority
Extremely useful in:



Routine
Iindispensable in:



Advice
reminding grantees
reminding referees
taking technical decisions
forwarding information (reports)
organising general schedules
organise the experts meetings
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
Players 3: Scientific Director
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Competence



Location


Disadvantages





reasonable understanding of
gene regulation
not a medical doctor
not a 'real' gene therapy
specialist
'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
Much of this activity was performed as 'learning by doing'
Players 4: Service Presse et Communication
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2002
advantages



disadvantages



long standing competence
good contacts list
reasonable infrastructure
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.
UNIFR
Players 5: Grantees
Rusconi
2002
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
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
good news
 genuine interest in some clinicians
bad news
 'looking down' on scientists: «they don't
know what a patient is... »
UNIFR
Grantees evaluation, human resources
Rusconi
2002
Full Time involvement (4395 person-months)
Te chnical
as s is tants
11%
Part Time involvement (3142 person-months)
Pr incipal
Inve s tigator
s
30% Te chnical
Gr aduate
Stude nts
26%
Pr incipal
Inve s tigator
s
23%
as s is tants
15%
Acade m ic
(pos tdoc)
33%
Gr aduate
Stude nts
14%
Acade m ic
(pos tdoc)
48%
The NFP 37 put into action about 7000 months-person, which
corresponds to 210'000 man-days
UNIFR
Grantees evaluation, funding considerations
Rusconi
2002
Type of expenditures (total 14'180 KFr)
cons um able s
11%
m e e tings
+s e cr
4%
Perception of funding amount by grantees (according to needs)
GMP
5%
ge ne rous
11%
m uch below
15%
s alar ie s
80%
jus t OK
44%
The funded amount was felt to be sufficient and was mostly
invested in salary, with 750 Kfr on GMP clinical grade materials
s om e w hat
be low
30%
Grantees evaluation, Perception of
inputs from the program
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Opinion on quality of annual meetings (out of 26)
Usefulness of
othe r s
17%
low le ve l
0% meetings for encounter/exchange (out of 24)
annual
inte rm e d
le ve l
4%us e ful
not
Influence
/ impact of NFP37 on my research activity
5%
indis pe ns
able
18%
ne gative
0%ional
occas
14%
not s ignif
5%
s tr ongly
pos itive
e xcelle
nt
33%
le ve l
79%
us e ful
63%
The NFP37 provided good annual reunions, promoted encounters,
and had a positive influence on the majority of the funded teams
pos itive
62%
(out of 24)
UNIFR
Grantees evaluation, Opinions on own future
Rusconi
2002
Will your research team maintain a focus on SGT? (out of 26)
Will
r e m ain
m ajor focus
s ignificantly
m aintaine d
totally
abandone
d
your
research
team size be changed ? (out of 24)
What does CH-SGT research need
from
r e duce
d public funds? (out of 30)
incr e as ed
s tr ongly
incr e as ed no s pe cial
atte ntion
partly
abandone d
othe r s
s om e
e ncourage m e nt
about s am e
certainly overestated!
a s pe cific
funding s lot
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
Players 6: Institutions
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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 2002
NFP37 legacy
14 research teams with 2 world-level
5 postdoctoral trainees
40 doctoral trainees
2 companies, 7 patents
Outside NFP37
5 additional identifiable, qualified and
competent research teams, +20
interested MDs
2 pre-existing companies, 2 large
pharma companies
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?
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What was achieved / not achieved
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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
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
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Limiting factors: structures, mentalities and functions
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2002
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
Gene transfer research, are Swiss structures adequate?
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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
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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
Required
different selection criteria
different refereeing system
distinct levels of confidentiality
different amounts of financing
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
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END (opening discussion …)
UNIFR
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2002
Thanks to
 Françoise Kästli
 Charles Weissmann
 Bernard Mach
 Experts board
 Grantees
 My lab collaborators
 Nationalfonds div. IV
Thank you all for the attention
possible discussion slides
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2002
Why 'somatic'?
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2001

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 consequently does not lead to
a hereditary transmission
of the genetic alteration

Somatic Cells: all the other cells of the body
The most feared potential side-effects of gene transfer
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2002

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
Gene Therapy Adverse events:
NY 1995 // UPenn 1999 // Paris 2002
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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?
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2002
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