Sandro Rusconi, Scientific Director NFP37Report 10.12.02, NF Forschungsrat, Bern

Sandro Rusconi, Scientific Director NFP37Report 10.12.02, NF Forschungsrat, Bern

UNIFRRusconi

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UNIFRRusconi

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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 ...

counting votes... ! ask Florida's officials ...

gene therapy... look at NFP37and not only ...

Somatic Gene Therapy's (SGT) Principles(somatic gene transfer)

Somatic Gene Therapy's (SGT) Principles(somatic gene transfer)

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UNIFRRusconi2002

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

Somatic Gene Therapy’s four fundamental questions

Somatic Gene Therapy’s four fundamental questions

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UNIFRRusconi2002

Efficiency of gene transfer

Specificity of gene transfer

Persistence of gene transfer

Toxicity of gene transfer

Only partial solutions found so far

TWO classes of gene transfer vehicles: non-viral & viralTWO classes of gene transfer vehicles: non-viral & viralUNIFR

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a

b

Non-viral transfer(transfection)

Viral gene transfer(Infection)

Nuclear envelope barrier! see, Nature BiotechDecember 2001

THREE classes of anatomical gene deliveryTHREE classes of anatomical gene deliveryUNIFR

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Ex-vivo In-vivotopical delivery

In-vivosystemic 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?

Gene therapy turns teenage in 2003, but:has it really grown up?

UNIFRRusconi2002

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1990 First clinical trial of a monogenic diseaseF. Anderson & Co: ADA deficiency

2002 Same protocol as Anderson's for ADAgene therapy (C. Bordignon)

...it works!

...does not work

*Gene Therapy in the clinic: Trials Wordldwide*Gene Therapy in the clinic: Trials WordldwideUNIFRRusconi2002

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cancer

hered.

Infect.vasc.

40

60

100

20

80

trials

500

1500

1000

patients

1992 1994 1996 19981990 2000

21% overall still pending or not yet Initiated !www.wiley.com

86% phase I13% phase II1 % phase III

As of Sept 2002:599 registered protocols4000 treated patients

*Gene Therapy Milestones*Gene Therapy MilestonesUNIFRRusconi2002

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1990, 1993, 2000 // ADA deficiencyF Anderson, M Blaese // C Bordignon

Anderson, 1990

Bordignon, 2000 (ESGT, Stockholm)proves efficacy of the same protocol

1997, 2000, Critical limb ischemiaJ Isner († 4.11.2001), I Baumgartner, Circulation 1998

Isner, 1998

1998, RestenosisV Dzau, HGT 1998

Dzau, 1999

1999, Crigler Njiar (animal)C Steer, PNAS 1999

Kmiec, 1999

2000, HemophiliaM Kay, K High

Fischer, 2000

2000, SCIDA Fischer, Science April 2000

Aebischer, 2000

2000, correction ParkinsonP Aebischer, Science, Nov 2000

2001, ONYX oncolytic VirusesD Kirn (Gene Ther 8, p 89-98)

Kirn, 2001

Clinical trials with ONYX-015,what we learned?

(Review)

2002, ADA gene therapyBordignon (Science, )

Bordignon & Co, 2002

Science vol 296, page 2410 ff

The reality is that all current popular gene transfer vectors have intrinsic limitations

The reality is that all current popular gene transfer vectors have intrinsic limitations

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Adenovirus- no persistence- limited packaging- toxicity- immunogenicity

Biolistic bombardmentor local direct injection- limited area

Retrovirus (incl. HIV)- limited package- random insertion- unstable genome

General- antibody response- limited packaging- gene silencing

Solutions:- synthetic viruses (“Virosomes”)

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!

Ups and Downs of Gene Therapy: a true roller coaster ride!

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high

Low

moo

d

NIHMotulskireport

Lentivectorsin pre-clinic

Adeno III

J. Isner

J. WilsonJ. Gelsinger

ADA

R. CrystalAdeno I

90 91 92 93 94 95 96 97 98 99 00 01 02

AAV germline in mice?

V.Dzau

A. FischerM. Kay

lentivectorsin clinics?

NFP37

Adverseevent inParis

C Bordignon

Ergo1 :in spite of its respectable age,gene therapy is still in its infancyand still produces more controversies than clinical results

Ergo 3:the NFP37 has ovelapped with the strongest ups and downs

Ergo 2 :many of the ups due to misplaced promisesmany of the downs due to disillusion or malpractice

NFP37 early times: visions anno 1993/1995NFP37 early times: visions anno 1993/1995UNIFRRusconi2002

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March1994

May 1994

1993

June 1994

«rien d'innovatif, il s'agit de rattrappage»

«a strong linkage between basic and clinical science»

Mach / Weissmann / Baggiolini, promoters: establish 2 centres (chairs) in Switzerland

«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 1995/96NFP37 gets realistic: paradigm change in 1995/96UNIFRRusconi2002

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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, 1996-1999NFP37 operational phase 1, 1996-1999UNIFRRusconi2002

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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

Oct 7-8. 1999 Third Annual meeting I Verma, L Mitchell, H Pandha, C

Steer, M Grace, P O'Hare, D Losordo

Aug. 1998 Call for proposals Phase 2

Nov. 1999 Start operational Phase 2 17 proposals granted (+2)

July 1999 Evaluated proposals Phase 2 26 submissions

NFP37 operational Phase 2, 1999-2001NFP37 operational Phase 2, 1999-2001UNIFRRusconi2002

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Oct 3-5. 2001

Oct 6. 2000 Fourth annual meeting Ph Felgner, I Kovesdi, T

Caskey

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

NFP37 research categoriesNFP37 research categoriesUNIFRRusconi2002

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NFP37 phase 1 phase 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

NFP37 Major outputs 1: publicationsNFP37 Major outputs 1: publicationsUNIFRRusconi2002

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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

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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, ...

Facts1028 attendants212 abstracts168 posters48 guest abstracts

Major internationally renowned speakers, lively posters and internal presentations, fair amount of guest abstacts

NFP37 Major outputs 3: public impactNFP37 Major outputs 3: public impactUNIFRRusconi2002

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0

2000

4000

6000

8000

10000

12000

14000

1997 1998 1999 2000 2001

Visits at our WEB site www.unifr.ch/nfp37

By the program director: 59 public conferences 24 scientific

conferences 15 business-oriented

conferences 12 newspaper & media

articles / interviews

Increasing public interest, peaks around major events (Gelsinger, Paris)

Players 1: Experts BoardPlayers 1: Experts BoardUNIFRRusconi2002

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board ofexperts

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.

Players 2: Scientific SecretariatePlayers 2: Scientific SecretariateUNIFRRusconi2002

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Authority Extremely useful in: reminding grantees reminding referees taking technical decisions

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 muchI wish other NFPs can continue having this kind of help

Routine Iindispensable in: forwarding information (reports) organising general schedules organise the experts meetings

Players 3: Scientific DirectorPlayers 3: Scientific DirectorUNIFRRusconi2002

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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

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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

Players 5: GranteesPlayers 5: GranteesUNIFRRusconi2002

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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

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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

Grantees evaluation, funding considerationsGrantees evaluation, funding considerationsUNIFRRusconi2002

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salaries80%

meetings +secr

4%

GMP5%

consuma-bles11%

Type of expenditures (total 14'180 KFr)

much below15%

somewhat below30%

generous11%

just OK44%

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

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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

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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

certainly overestated!

Players 6: InstitutionsPlayers 6: InstitutionsUNIFRRusconi2002

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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 2002The 'Swiss Gene Therapy Army', as of March 2002UNIFR

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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

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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)

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

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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

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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

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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

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

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

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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

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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

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Why 'somatic'?Why 'somatic'?UNIFRRusconi2001

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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

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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

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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?Why so many cancer trials?UNIFRRusconi2002

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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