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Sandro Rusconi 09'03'52

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Title: Sandro Rusconi 09'03'52


1
Sandro Rusconi (09.03.52)
UNIFR Rusconi 2005
1972-75 School teacher (Locarno,
Switzerland) 1975-79 Graduation in Biology UNI
Zuerich, Switzerland 1979-82 PhD curriculum UNI
Zuerich, molecular biology 1982-84 Research
assistant UNI Zuerich 1984-86 Postdoc UCSF, K
Yamamoto, (San Francisco) 1987-93 Principal
Investigator, UNI Zuerich, PD 1994-today Professor
Biochemistry UNI Fribourg 1996-2002 Director
Swiss National Research Program 37 'Somatic Gene
Therapy' 2002-03 Sabbatical, Tufts Med. School
Boston and Univ. Milano, Pharmacology
Department 2002-05 President Union of Swiss
Societies for Experimental Biology (USGEB)
2002-06 Euregenethy Network (EU-harmonsiation
of biosafety and ethical aspects in gene therapy)
Sept 08, 2005 GTRV Debio
What have we learned from 15 years in gene
therapy?
2005-xx Director of governmental division for
culture and university affairs of Canton Ticino
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2
Gene therapy A 15-years hailstorm of highly
emotionalised good and bad news
UNIFR Rusconi 2005
BBC, NBC, CNN,...
Jesse Gelsinger Oct 1999
New York Times Washington Post Times Le
Monde Frankfurter Allgemeine ...
Feb 1990 First trial ADA deficiency
A Fischer, E Thrasher Paris UK Dec 2000
Dec 1988 IL-2 cancer treatment trial
No previous medical procedure generated that many
discussions so long before being ever clinically
applicable How many of you have heard mostly bad
news... ?mostly good news...?
AAV germline Sept 2000
Mar 1994 SAE cystic fibrosis
C Bordignon, Milano trial May 2002
Jun 1995 Motulsky NIH report
First SAE Paris Sep 2002
Feb 1996 r-lentiviruses
Nature Science NEJM ...
second SAE Paris Feb 2003
SiRNA preclinical 2004
Autoimmunity monkeys May 2004
Oct 1998 VEGF ischemia
third SAE Paris Jan 2005
Internet
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1 Gene -gt 1 or more functions
UNIFR Rusconi 2005
  • Ergo
  • to say 'one gene -gt one function' is like
    pretending'one disease -gt one drug'
  • Multifunctional character of genes implies
  • cross talk with different pathways
  • unclarified hyerarchical position
  • unclarified side-effects potential

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Recap what is a gene?a regulated nanodevice
for RNA production
UNIFR Rusconi 2005
  • Therefore, to fullfil its role, a transferred
    gene segment must include
  • regulatory sequences for Transcription
  • proper signals for RNA Maturation/transport
  • proper signals for mRNA Translation
  • proper signals for mRNA Degradation

coding
spacer
spacer
regulatory
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1 Organism -gt more than 105 developmentally and
genetically-controlled functions
UNIFR Rusconi 2005
  • Remember
  • 1 Cm3 of tissue
  • 1'000'000'000 cells!

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Reductionistic molecular biology paradigm(gene
defects and gene transfer)
UNIFR Rusconi 2005
  • Gene transfer implies either
  • transfer of new function, or
  • transfer of restoring function, or
  • transfer of interfering function

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Gene therapy as logical consequence 'the third
era'
UNIFR Rusconi 2003
  • Ergo
  • gene transfer is a logical development of
    molecular biology

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Somatic Gene Therapy (SGT) definition
UNIFR Rusconi 2005
Chronic treatment
Definition of SGT 'Use genes as
drugs' Correcting disorders by somatic gene
transfer
Acute treatment
Preventive treatment
NFP37 somatic gene therapy www.unifr.ch/nfp37
Hereditary disorders
Acquired disorders
Loss-of-function
Gain-of-function
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Why 'somatic'?
UNIFR Rusconi 2005
  • Germ Line Cells the cells (spermatocytes and
    oocytes and their precursors) that upon
    fertilisation can give rise to a descendant
    organism
  • Ergo
  • transformation of germ line cells is avoided, to
    exclude risk of erratic mutations due to
    insertional mutagenesis
  • germline changes are avoided also because of
    ethical problems
  • Requestioned?
  • whenever genomic repair systems will be
    perfectioned the issue of germ line therapy will
    probably be readdressed.

i.e. somatic gene therapy is a treatment aiming
at somatic cells and conse-quently does not lead
to a hereditary transmission of the genetic
alteration
  • Somatic Cells all the other cells of the body

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When/where/ may be SGT (currently) indicated?
UNIFR Rusconi 2005
  • No existing cure or treatment
  • most monogenic diseases
  • Side effects and limitations of protein injection
  • interleukin 12 (cancer)-gt toxic effects and
    rapid degradation
  • VEGF (ischemias)-gt angiomas
  • Factor VIII or IV (hemophilia)-gt insufficient
    basal level
  • Ergo
  • there are many indications for SGT as stand-alone
    or as complementary therapy
  • Complement to conventional
  • increases specificity of conventional therapy
    (cancer)
  • increases efficacy of conventional therapy
    (hemophilia)
  • Perverse deviation dreams (with current
    technologyI
  • gene-based sports doping
  • performance amelioration
  • cosmetics
  • Life quality burden of patient
  • costs of enzyme therapy (ex. ADA)
  • burden of daily injections (ex. Insulin)

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Pharmacological considerations for DNA transfer
UNIFR Rusconi 2005
Classical Drugs
Protein Drugs
Nucleic Acids
  • Mw 20 000- 100 000 Da
  • Biologically prepared
  • Slower diffusion/action
  • Oral delivery not possible
  • Cellular delivery - act extracellularly
  • Can be delivered as soluble moleculesnm size
  • rapidly reversible treatment
  • Mw 50- 500 Daltons
  • Synthetically prepared
  • Rapid diffusion/action
  • Oral delivery possible
  • Cellular delivery - act at cell surface-
    permeate cell membrane- imported through
    channels
  • Can be delivered as soluble moleculesÅngstrom/nm
    size
  • rapidly reversible treatment
  • Mw N x 1000000 Da
  • Biologically prepared
  • Slow diffusion
  • Oral delivery inconceivable
  • Cellular delivery- no membrane translocation -
    no nuclear translocation- no biological import
  • Must be delivered as complex carrier
    particles50-200 nm size
  • slowly or not reversible

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  • Ergo Therapy with nucleic acids
  • requires particulated formulation
  • is much more complex than previous drug
    deliveries
  • has a different degree of reversibility
    (intrinsic dosage / titration problem)

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SGT's FOUR fundamental questions players
UNIFR Rusconi 2005
Efficiency of gene transfer
Specificity of gene transfer
Persistence of gene transfer
Toxicity of gene transfer
  • The variables
  • which disease?
  • which gene?
  • which vector?
  • which target organ?
  • which type of delivery?

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THREE classes of anatomical gene delivery
UNIFR Rusconi 2005
Ex-vivo
In-vivo topical delivery
In-vivo systemic delivery
  • Ergo
  • ex vivo or local delivery are currently preferred
    over systemic delivery

Examples - bone marrow - liver cells - skin cells
Examples - brain - muscle - eye - joints - tumors
Examples - intravenous - intra-arterial -
intra-peritoneal
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TWO classes of gene transfer vectors non-viral
viral delivery
UNIFR Rusconi 2005
Non-viral transfer (transfection of plasmids)
  • Ergo
  • viral transfer is much more efficient
  • nonviral transfer must solve a number of hurdles

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Viral gene transfer (Infection by r-vectors)
b
Nuclear envelope barrier! see, Nature
Biotech December 2001
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Transfection versus Infection
UNIFR Rusconi 2005
Transfection
exposed to 106 particles/cell 12 hours
Infection
exposed to 1 particle/cell 30 min
  • Ergo
  • virally mediated gene transfer is millions of
    times more efficent than nonviral transfer (when
    calculated in terms of transfer/particle)

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16
Comparing relevant issues in the two main
'vectorology' sectors (viral versus nonviral)
UNIFR Rusconi 2005
  • Viral vectors
  • Packaging capacity from 4 to 30 kb problem for
    some large genes (ex. dystrophin gene or CFTR
    gene)
  • important toxic load ratio infectious/non-infecti
    ous particles from 1/10 to 1/100
  • strong immunogenicity capsid and envelope
    proteins, residual viral genes
  • contaminants replication-competent viruses (ex.
    wild type revertant viruses)
  • Viral amount (titre) obtainable with recombinants
    (ex. 10exp5 poor, 10exp10excellent)
  • Complexity of manufacturing (existence or not of
    packaging cell systems)
  • Emotional problems linked to pathogenicity of
    donor vectors (ex. lentiviruses)
  • Nonviral vectors
  • Packaging capacity not an issue, even very large
    constructs can be used (example entire loci up to
    150 kb)
  • minor toxic load small percentage of non
    relevant adventitious materials
  • moderate immunogenicity methylation status of
    DNA (example CpG motifs)
  • contaminants adventitious pathogens from poor
    DNA purification (ex endotoxins)
  • Amount of DNA molecules is usually not a problem,
    the other components depends on chemical
    synthesis
  • No particular complexity, except for specially
    formulated liposomes
  • no particular emotional problems linked to the
    nature of the reagents
  • Ergo
  • problems that must be solved to be suitable for
    clinical treatment and for manufacturing are
    different between viral and non-viral vectors
  • when ignoring thir low efficiency, nonviral
    vectors appears largely superior

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Short list of popular vectors/methods
UNIFR Rusconi 2005
Naked DNA Liposomes Co. Oligonucleotides
r-Adenovirus r-Adeno-associated
V. r-Retrovirus (incl. HIV)
but remember... "Nobody's perfect "!
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Recombinant Adenoviruses
UNIFR Rusconi 2005
  • Manufacturing
  • Generation I/ II
  • Generation III
  • Hybrid adenos
  • Adeno-RV
  • Adeno-AAV
  • Adeno-Transposase
  • Advantages / Limitations
  • 8 Kb capacity Generation I / IIgt30 Kb capacity
    Generation IIIAdeno can be grown at very high
    titers,However
  • Do not integrate in host genome
  • Can contain RCAs
  • Are toxic /immunogenic
  • Examples
  • OTC deficiency (clin, ---)
  • Cystic Fibrosis (clin, --- )
  • Oncolytic viruses (clin, )

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Recombinant Adeno-associated-virus (AAV)
UNIFR Rusconi 2005
  • Advantages / Limitations
  • Persistence in the genome permits long-
  • term expression, high titers are easily
  • obtained, immunogenicity is very low,
  • However the major problems are
  • insertional mutagenesis
  • Promotes autoimmunity?
  • Small capacity (lt4.5 kb) which does not allow to
    accommodate large genes or gene clusters.

Manufacturing Helper-dependent production Helper
independent production Cis-complementing
vectors Co-infection
  • Examples
  • Hemophilia A (clin, animal, (autoimm?)
  • Gaucher (clin, animal, )
  • Brain Ischemia (animal, )
  • Cystic fibrosis (animal, /-)
  • retinopathy (animal (/-)

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Recombinant retroviruses (incl. HIV)
UNIFR Rusconi 2005
Manufacturing Murine Retroviruses VSV-pseudotyped
RV Lentiviruses ! Self-inactivating
RV Combination viruses
  • Advantages / Limitations
  • 9 Kb capacity integration through
  • transposition also in quiescent cells
  • (HIV), permit in principle long-term
  • treatments, however disturbed by
  • Insertional mutagenesis
  • Gene silencing
  • High mutation rate
  • Low titer in manufacturing
  • Examples
  • SCID (IL2R defect, Paris) (clin, )
  • Adenosine Deaminase deficiency (clin, !!!)
  • Parkinson (preclin, )
  • Anti cancer (clin /-)

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Naked or complexed DNA
UNIFR Rusconi 2005
Approaches Naked DNA injection /biolistic Naked
DNA pressure Naked DNA electroporation Liposom
al formulations Combinations
  • Advantages / Limitations
  • Unlimited size capacity lower
  • immunogenicity and lower bio-risk
  • of non viral formulations is
  • disturbed by
  • Low efficiency of gene transfer
  • Even lower stable integration
  • Examples
  • Critical limb Ischemia (clin, )
  • Cardiac Ischemia (clin, /-)
  • Vaccination (clin, /-)
  • Anti restenosis (preclin. /-)

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Oligonucleotides
UNIFR Rusconi 2005
Approaches Antisense RibozymesDNAzymes SiRNA Trip
le helix Aptamers Decoy / competitors Gene-correct
ing oligos
  • Advantages / Limitations
  • reversible (except gene correcting oligos),
  • easy manufacturing, easy delivery
  • these procedures may be suitable for
  • handling dominant defects
  • transient treatments (gene modulation)
  • permanent treatments (gene correction)
  • efficacy still questionable in most cases
  • Examples
  • Anti cancer (clin,preclin., /-)
  • Restenosis (clin, )
  • Muscular Distrophy (animal, )

v !
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Recap current limitations of popular vectors
UNIFR Rusconi 2004
r-Adenovirus - no persistence - limited
packaging - toxicity, immunogenicity
Biolistic bombardment or local direct injection -
limited area
Electroporation - limited organ access
r-AAV - no integration in host g. - very limited
packaging - autoimmunity?
Liposomes, gene correction Co. - rather
inefficient transfer
r-Retrovirus (incl. HIV) - limited packaging -
random insertion - unstable genome
General - low transfer efficiency - no or little
genomic integration
General - antibody response - limited packaging -
gene silencing - Manufacturing limitations
  • Ergo
  • the future will probably see an increasing
    interest in viral-like, but artificial particles

Solutions - improved liposomes with viral
properties (Virosomes)
Solutions - synthetic viruses (Virosomes)
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Technologies related to-, but not all genuinely
definable as 'gene therapy'
UNIFR Rusconi 2005
  • Transiently bioactive oligonucleotides
  • antisense
  • decoy dsDNA, decoy RNA
  • ribozymes DNAzymes
  • Si RNA oligonucleotides
  • Genuine gene therapy oligos
  • chimeroplasts (gene correction induction)
  • Ergo
  • among all the above, SiRNA is among the most
    promising inhibitor factors, and can conceived as
    transienttly acting oligo (improper gene therapy)
    or as permanently expressed from DNA vectors
  • Oncolytic viruses
  • ONYX-15, ONYX-638 (r-adeno)
  • r-HSV
  • r-FSV

from www.nature.com
  • Implants of encapsulated cells
  • neurotrophic factor producer cell implants
  • hormone-producing cells

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Gene Therapy in the clinics Trials Worldwide
(cumulative)
UNIFR Rusconi 2005
  • Ergo
  • in spite of 13 year- research only less than 2
    of the trials has reached phase III
  • not necessarily due to the novel'fail early,
    fail fast' paradigm

As of January 2005938 cumulative protocols
(90-2005) 4700 treated /enrolled patients
66 phase I 19 phase I-II 13 phase II 0.8
phase II-III 1.7 phase III
! As of Jan 1, 2004 1 approved product in China
(Gendicine, by Sibiono Inc. 2004
20 overall still pending or not yet Initiated
! www.wiley.com/genetherapy
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Gene Therapy Clinical and Preclinical Milestones
UNIFR Rusconi 2005
1990, 1993, 2000, 2004 // 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
2000, Hemophilia M Kay, K High
21 lives were so far documentedly saved by GT in
european trials (x-SCID, ADA, CGD) (France, UK,
Italy) (all in phase I) 200 lives
quality-improved in several other phase I and II
trial nnn lives saved or quality-improved ?by
Gendicine (still undocumented)
2000, 2002, X-SCID A Fischer, Science April 2000,
UK trials 2003
2001, 2003 ONYX oncolytic Viruses D Kirn (Cancer
Gene Ther 9, p 979-86)
2004, Chronic Granulomatous Disease M Grez
Frankfurt R Seger Zürich
2004, Gendicine (adeno-p53 vector) L Peng,
Sibiono Inc, Shenzen, China
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Two persisting major SGT frustration cases
UNIFR Rusconi 2005
  • Muscular dystrophy (incidence 1 3000 newborn
    males)
  • requires persistence of expression
  • extremely large gene (14 kb transcript, 2 megaBP
    gene
  • unclear whether regulation necessary
  • unclear at which point disease is irreversible
  • Cystic fibrosis (incidence 1 2500 newborns)
  • most luminal attempts failed because of
    anatomical / biochemical barrier no receptors,
    mucus layer
  • large gene that requires probably regulation
  • requires long term regulation
  • unclear at which point disease becomes
    irreversible
  • In spite of genes discovered in the 90ties
  • lacking suitable vector
  • no satisfactory delivery method
  • no persistence
  • treatment 'too late'

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The most feared potential side-effects of gene
transfer
UNIFR Rusconi 2004
  • Immune response to vector
  • immune response or long term side effects from
    new or foreign gene product
  • General toxicity of viral vectors
  • Adventitious contaminants in recombinant viruses
  • Random integration in genome-gt insertional
    mutagenesis (-gt cancer risk)
  • Contamination of germ line cells
  • immune response or long term side effects from
    new or foreign gene product -gt autoimmunity
  • Random integration in genome-gt insertional
    mutagenesis (-gt cancer risk)
  • Ergo
  • The more effective is a drug, the more side
    effects it will generate.
  • SGT enjoyed a side-effect-free illusion during
    its first 10-year of non-working early period
  • Many side effects are still related to the rather
    primitive state of the vectorology/delivery

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SAEs1 established cases acute and long term
SAEs from Gelsingers' death to Paris'
Leukaemias
UNIFR Rusconi 2005
NY May 5, 1995, R. Crystal adenovirus, cystic
fibrosis (lung) one patient mild pneumonia-like
condition Trial interrupted and many others on
hold.
Most Recent Paris' Trial News discussed
at www.unifr.ch/nfp37/adverse03.html it is now
rather established (2004) that the Paris'
leukaemia events were caused by
treatment-specific circumstances (type of
transferred gene, dosing, type of vector,
predisposition) The third SAE might delay the
nextly planned restart of patients recruitment
UPenn, Sept. 19, 1999, J. Wilson adenovirus ,
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 retrovirus ,
x-SCID (bone marrow) one patient developed a
leukemia-like condition. Trial suspended and some
trials in US and Germany on hold until 2003.
Paris, Jan 14, 2003, A Fischer retrovirus
X-SCID (bone marrow) same cohort a second patient
developed a similar leukemia 30 trials in USA
were temporarily suspended
Ergo gene therapy can produce both short-term and
long-term severe side effects through acute
immunogenicity or insertional mutagenesis (cancer
risk)
Paris, Jan 24, 2005, A Fischer retrovirus
X-SCID (bone marrow) same cohort a third patient
developed a similar leukemia what will happen?
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Parenthesis future solutions to insertional
mutagenesis targeted gene transfer approaches
UNIFR Rusconi 2005
  • Ergo
  • genotoxic
  • non-genotoxic
  • Random integrating vectors
  • r-retroviruses
  • r-lentiviruses
  • r-AAV
  • plasmids (low frequency)
  • plasmids transposase (eg 'sleeping beauty')
  • Specifically integrating vectors
  • hybrid vectors (HSV-AAV)
  • Phage 31 integrase-based
  • designer integrases (ZnFinger proteins)
  • Transient, non integrating vectors
  • adenovirus
  • plasmid
  • RNA virus based
  • oligonucleotides (SiRNA, antisense, ribozymes)
  • artificial chromosomes

Ergo vector systems that allow specific or at
least better location-controlled gene delivery
are experimentally well advanced (see
accompanying text)
  • Gene correction vectors
  • chimeroplasts (RNA-DNA chimeric oligos)
  • single stranded DNA (homologous recom)

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SAEs2 emerging cases mid-term effects documented
by recent Autoimmunity Reports
UNIFR Rusconi 2005
Blood, 1 May 2004, Vol. 103, No. 9, comment pp.
3248-3249 Autoimmunity in EPO gene transfer
(macaques) Els Verhoeyen and François-Loïc
Cosset Papers - Chenuaud and colleagues (page
3303) - Gao and colleagues (page
3300) inadvertent autoimmune response in
nonhuman primates resulting from transfer of a
gene encoding a self-antigen. - delivered the
homologous EPO cDNA driven by ubiquitous and/or
regulatable promoters via AAV vectors injected in
muscle or aerosolized in lung, resulting in
supra-physiologic serum levels of EPO, from 10-
to 100 000- fold over the baseline
K High, ASGT June meeting 2004 Abstract1002
Immune Responses to AAV and to Factor IX in a
Phase I Study of AAV-Mediated, Liver-Directed Gene
Transfer for Hemophilia B
Ergo somatic gene transfer can generate mid-term
auto- immunity under certain circumstances
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SAEs3 Non-science factors that have disturbed
progress and image of gene therapy
UNIFR Rusconi 2005
  • 'Naive' statements in the early 90ties
  • Excess of speculative financing in mid-late
    90ties.
  • Concomitance with stock-market euphoria
  • Reckless statements/promises or misreporting in
    late 90ties
  • Tendency by the media to spectacularise good
    and/or bad news
  • Ergo
  • too much money, too much time pressure, too much
    media exposure among the image killer factors.
  • The fundamental error we pretended making a
    business issue out of a scientific issue

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Ups and Downs of Gene Therapy a true
roller-coaster ride!
UNIFR Rusconi 2005
A. Fischer M. Kay
high
R. Crystal
  • Ergo
  • whenever a reasonable cruise speed was achieved,
    a major adverse event has brought us back square
    one or even below

V.Dzau
C Bordignon
Adeno I
J. Isner
F Anderson
lentivectors hopes
AAV germline in mice?
NIH Motulski report
Adeno III
mood
Lentivectors
gendi cine
Auto-immunity
Low
Paris I and II Leukaemias
J. Gelsinger
companies
Paris III
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Conclusions GT has proven several concepts, has
several tools, but is still in the pioneering
phase
UNIFR Rusconi 2005
  • Fundamentally
  • many new potentially therapeutic genes identified
  • All types of diseases can be virtually treated
    by gene transfer
  • we start to manage efficiency, specificity,
    persistence and toxicity
  • Vectors and models
  • Choice of among a number of viral and non viral
    vectors
  • Viral vectors have the advantage of efficiency
  • nonviral vector the advantage of lower
    toxicity/danger.
  • Viral vectors have the disadvantage of limited
    packaging and some toxicity
  • nonviral vectors have the major disadvantage of
    low efficiency of transfer
  • Ergo
  • we are somewhat ahead but still in the pioneering
    phase !
  • failure of evidence does not mean evidence of
    failure !
  • Clinically
  • over 600 trials and gt4000 patients in 15 years
  • only a handful of trials is now reaching phase
    III
  • Progress further slowed down by periodical
    pitfalls
  • 1 product/treatment approved in China 2004
    (gendicine)

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Perspectives somatic gene therapy will progress
in spite of all past, present and future
incidents/accidents
UNIFR Rusconi 2005
  • Fundamental level vectorology
  • Better understanding of gene interactions and
    networking
  • Gene inhibition through Si RNA, Zn finger
  • specifically integrating gene constructs
  • artificial chromosomes become more realistic
  • novel, semi-artificial particles
  • Preclinically
  • scaling up to larger animal models (dog and
    monkey)
  • new transgenic models may give improved
    similarities to human diseases
  • Ergo
  • many adverse events were due rather to human
    errors than to intrinsic dangers
  • other undesired effects are due to prototypic
    state of tools
  • hurdles can be overcome
  • the genuine potential of SGT is intact
  • Clinically
  • Use of recombinant lentiviruses
  • Increase of Phase III procedures over the next 5
    years
  • therapeutical applications may be registered
    within 3-5 years
  • challenge by other emerging therapies

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Proust's questionnaire to myself and to you,
concerning gene therapy
UNIFR Rusconi 2005
will GT ever make it into routine clinical
practice ?
yes
The most worrying side-effect?
immunity
Is insertional mutagenesis an important hurdle?
No
Which will bloom viral or non viral transfer?
combination thereof
Who will 'win' the race gene transfer or cell
therapy?
both or neither
Will GT be applicable also for non-severe
conditions?
yes
Which will be the best inhibitor function
antisense, intrabodies, aptamers, ribozymes,
SiRNA, designer Zn Fingers, triple helix, small
drugs, ...whatever ?
...whatever
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...Thanks, and let's remain optimistic
UNIFR Rusconi 2005
GTRV Debio summer school

Sergio Capancioni, Christiane Damgé
The other organisers
  • Ergo
  • let's look forward to a safe landing

Thank you all for the patience and attention,
sandro.rusconi_at_unifr.ch or visit www.unifr.ch/n
fp37/
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That's all, folks!
UNIFR Rusconi 2005
www.unifr.ch/nfp37
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UNIFR Rusconi 2004
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