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Sandro Rusconi (09.03.52)Sandro Rusconi (09.03.52)UNIFRRusconi
2005
UNIFRRusconi
2005
What have we learned from 15 years in gene
therapy?
Sept 08, 2005GTRV Debio
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 andUniv. 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)
2005-xx Director of governmental division for cultureand university affairs of Canton Ticino
Gene therapy: A 15-years hailstorm of highly emotionalised good and bad news
Gene therapy: A 15-years hailstorm of highly emotionalised good and bad news
UNIFRRusconi
2005
UNIFRRusconi
2005
BBC, NBC, CNN,...
New York TimesWashington PostTimesLe MondeFrankfurter Allgemeine...
Feb 1990 First trial ADA deficiency
Dec 1988 IL-2 cancer treatment trial
Mar 1994 SAE cystic fibrosis
NatureScienceNEJM...
Jun 1995 Motulsky NIH report
Feb 1996 r-lentiviruses
Oct 1998 VEGF ischemia
Jess
e Gelsi
nger Oct
1999
A Fischer, E Thrasher Paris & UK Dec 2000
AAV germline Sept 2000
C Bordignon, Milano trial May 2002
First SAE Paris Sep 2002 second SAE Paris Feb 2003
Internet
Autoimmunity monkeys May 2004
SiRNA preclinical 2004
third SAE Paris Jan 2005No 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...?
1 Gene -> 1 or more functions1 Gene -> 1 or more functions
RNA(s)DNA
GENE
Protein(s)
2-5 FUNCTIONS
Gene expression
Transcription / translation
>300 ’000 functions(>150 ’000 functions)
100 ’000 genes(50 ’000 genes?)
UNIFRRusconi
2005
UNIFRRusconi
2005
Multifunctional character of genes implies: cross talk with different pathways unclarified hyerarchical position unclarified side-effects potential
Ergo to say
'one gene -> one function' is like pretending'one disease -> one drug'
Recap: what is a gene?:a regulated nanodevice for RNA production
Recap: what is a gene?:a regulated nanodevice for RNA production
RNA(s)DNA Protein(s)
GENE FUNCTIONTranscription / translation
codingspacer spacerregulatoryDNA
RNA
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
UNIFRRusconi
2005
UNIFRRusconi
2005
1 Organism -> more than 105 developmentally and genetically-controlled functions
1 Organism -> more than 105 developmentally and genetically-controlled functions
2m 2 mm 0.2mm
0.02mm
DNA RNA Protein
0.001mm Remember1 Cm3 of tissue 1'000'000'000 cells!
UNIFRRusconi
2005
UNIFRRusconi
2005
Reductionistic molecular biology paradigm(gene defects and gene transfer)
Reductionistic molecular biology paradigm(gene defects and gene transfer)
GENE transfer FUNCTION transfer
GENE KO FUNCTION KO
GENE OK FUNCTION OK
DNA
GENE
Protein
FUNCTION(s)
Gene transfer implies either: transfer of new function, or transfer of restoring function, or transfer of interfering function
UNIFRRusconi
2005
UNIFRRusconi
2005
Gene therapy as logical consequence: 'the third era'Gene therapy as logical consequence: 'the third era'UNIFRRusconi
2003
UNIFRRusconi
2003EightiesGenes as probes
ok ** ** **ok1 2 4 53
NinetiesGenes as factories
80 85 90 95 99
10
50
Y2KGenes as drugs
80 85 90 95 00
1000
3000
Ergo gene transfer is a logical
development of molecular biology
Somatic Gene Therapy (SGT) definitionSomatic Gene Therapy (SGT) definition
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
NFP37 somatic gene therapywww.unifr.ch/nfp37
UNIFRRusconi
2005
UNIFRRusconi
2005
Why 'somatic'?Why 'somatic'?
Germ Line Cells: the cells (spermatocytes and oocytes 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 therapyis a treatment aiming atsomatic cells and conse-quently does not lead to a hereditary transmission of the genetic alteration
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.
UNIFRRusconi
2005
UNIFRRusconi
2005
When/where/ may be SGT (currently) indicated?When/where/ may be SGT (currently) indicated?
No existing cure or treatment most monogenic diseases
Side effects and limitations of protein injection interleukin 12 (cancer)
-> toxic effects and rapid degradation VEGF (ischemias)
-> angiomas Factor VIII or IV (hemophilia)
-> insufficient basal level
Complement to conventional increases specificity of conventional therapy (cancer) increases efficacy of conventional therapy (hemophilia)
Life quality burden of patient costs of enzyme therapy (ex. ADA) burden of daily injections (ex. Insulin)
Ergo: there are many indications
for SGT as stand-alone or as complementary therapy
Perverse deviation dreams (with current technologyI:
gene-based sports doping performance amelioration cosmetics
UNIFRRusconi
2005
UNIFRRusconi
2005
UNIFRRusconi
2005
UNIFRRusconi
2005Pharmacological considerations for DNA transferPharmacological considerations for DNA transfer
OHOH
O
OHOH
O
O
OHOH
O
O
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
Classical Drugs
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
Protein Drugs
Mw N x 1’000’000 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
Nucleic Acids
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)
SGT's FOUR fundamental questions & playersSGT's FOUR fundamental questions & players
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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2005
UNIFRRusconi
2005
THREE classes of anatomical gene deliveryTHREE classes of anatomical gene delivery
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
UNIFRRusconi
2005
UNIFRRusconi
2005
Ergo ex vivo or local delivery are
currently preferred over systemic delivery
TWO classes of gene transfer vectors: non-viral & viral delivery
TWO classes of gene transfer vectors: non-viral & viral delivery
a
b
Non-viral transfer(transfection of plasmids)
Viral gene transfer(Infection by r-vectors)
Nuclear envelope barrier! see, Nature BiotechDecember 2001
UNIFRRusconi
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UNIFRRusconi
2005
Ergo viral transfer is much more efficient nonviral transfer must solve a
number of hurdles
Transfection versus InfectionTransfection versus Infection
Transfection
Infection
exposed to106 particles/cell12 hours
exposed to 1 particle/cell30 min
Ergo virally mediated gene transfer is millions of times more efficent than nonviral
transfer (when calculated in terms of transfer/particle)
UNIFRRusconi
2005
UNIFRRusconi
2005
Comparing relevant issues in the two main 'vectorology' sectors (viral versus nonviral)
Comparing relevant issues in the two main 'vectorology' sectors (viral versus nonviral)
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-infectious 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, 10exp10=excellent)
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
UNIFRRusconi
2005
UNIFRRusconi
2005
Short list of popular vectors/methodsShort list of popular vectors/methods
r-Adenovirus
r-Adeno-associated V.
r-Retrovirus (incl. HIV)
Naked DNA
Liposomes & Co.
Oligonucleotides
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2005
UNIFRRusconi
2005
Recombinant AdenovirusesRecombinant AdenovirusesUNIFRRusconi2005
UNIFRRusconi2005
Manufacturing
Generation I/ II
Generation III
Hybrid adenos: Adeno-RV Adeno-AAV Adeno-Transposase
Examples OTC deficiency (clin, ---) Cystic Fibrosis (clin, --- ) Oncolytic viruses (clin, +++)
Advantages / Limitations
8 Kb capacity Generation I / II>30 Kb capacity Generation IIIAdeno can be grown at very high titers,However Do not integrate in host genome
Can contain RCAs
Are toxic /immunogenic
Recombinant Adeno-associated-virus (AAV)Recombinant Adeno-associated-virus (AAV)
Examples Hemophilia A (clin, animal, +++(autoimm?) Gaucher (clin, animal, +++) Brain Ischemia (animal, +++) Cystic fibrosis (animal, +/-) retinopathy (animal (+/-)
Advantages / Limitations
Persistence in the genome permits long-term expression, high titers are easilyobtained, immunogenicity is very low,However the major problems are: insertional mutagenesis Promotes autoimmunity? Small capacity (<4.5 kb) which does
not allow to accommodate large genes or gene clusters.
Manufacturing
Helper-dependent production
Helper independent production
Cis-complementing vectors
Co-infection
UNIFRRusconi2005
UNIFRRusconi2005
Recombinant retroviruses (incl. HIV)Recombinant retroviruses (incl. HIV)
Manufacturing
Murine Retroviruses
VSV-pseudotyped RV
Lentiviruses !
Self-inactivating RV
Combination viruses
Examples SCID (IL2R defect, Paris) (clin, +++) Adenosine Deaminase deficiency (clin, +++!!!) Parkinson (preclin, +++) Anti cancer (clin +/-)
Advantages / Limitations
9 Kb capacity + integration throughtransposition also in quiescent cells(HIV), permit in principle long-termtreatments, however disturbed by: Insertional mutagenesis
Gene silencing
High mutation rate
Low titer in manufacturing
UNIFRRusconi2005
UNIFRRusconi2005
Naked or complexed DNANaked or complexed DNA
Approaches
Naked DNA injection /biolistic
Naked DNA + pressure
Naked DNA + electroporation
Liposomal formulations
Combinations
Advantages / Limitations
Unlimited size capacity + lowerimmunogenicity and lower bio-riskof non viral formulations isdisturbed by
Low efficiency of gene transfer
Even lower stable integration
Examples Critical limb Ischemia (clin, +++) Cardiac Ischemia (clin, +/-) Vaccination (clin, +/-) Anti restenosis (preclin. +/-)
UNIFRRusconi2005
UNIFRRusconi2005
OligonucleotidesOligonucleotides
Approaches
Antisense
Ribozymes
DNAzymes
SiRNA
Triple helix
Aptamers
Decoy / competitors
Gene-correcting oligos √ !
Advantages / Limitations
reversible (except gene correcting oligos),easy manufacturing, easy deliverythese 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, +++)
UNIFRRusconi2005
UNIFRRusconi2005
Recap: current limitations of popular vectorsRecap: current limitations of popular vectors
r-Adenovirus- no persistence- limited packaging- toxicity, immunogenicity
Biolistic bombardmentor local direct injection- limited area
Electroporation- limited organ access
Liposomes, gene correction & Co.- rather inefficient transfer
General- low transfer efficiency- no or little genomic integration
Solutions:- improved liposomes with viral properties (“Virosomes”)
UNIFRRusconi
2004
UNIFRRusconi
2004
r-AAV- no integration in host g.- very limited packaging- autoimmunity?
r-Retrovirus (incl. HIV) - limited packaging- random insertion- unstable genome
General- antibody response- limited packaging- gene silencing- Manufacturing limitations
Solutions:- synthetic viruses (“Virosomes”)
Ergo the future will probably see an increasing
interest in viral-like, but artificial particles
Technologies related to-, but not all genuinely definable as 'gene therapy'
Technologies related to-, but not all genuinely definable as 'gene therapy'
Transiently bioactive oligonucleotides antisense decoy dsDNA, decoy RNA ribozymes DNAzymes Si RNA oligonucleotides
Oncolytic viruses ONYX-15, ONYX-638 (r-adeno) r-HSV r-FSV Implants of encapsulated cells
neurotrophic factor producer cell implants hormone-producing cells
UNIFRRusconi
2005
UNIFRRusconi
2005
from www.nature.com
Genuine gene therapy oligos chimeroplasts (*gene correction induction)
Ergoamong 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
Gene Therapy in the clinics: Trials Worldwide (cumulative)
Gene Therapy in the clinics: Trials Worldwide (cumulative)
cancer
hered.
Infect.vasc.
40
60
100
20
80
trials
500
1500
1000
patients
1992 1994 1996 19981990 2000
20% overall still pending or not yet Initiated !www.wiley.com/genetherapy
66% phase I19% phase I-II13% phase II0.8% phase II-III1.7% phase III
As of January 2005:938 cumulative protocols (90-2005)4700 treated /enrolled patients
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
II-II
II
UNIFRRusconi
2005
UNIFRRusconi
2005
! As of Jan 1, 2004:1 approved product in China (Gendicine, by Sibiono Inc. 2004
Gene Therapy Clinical and Preclinical MilestonesGene Therapy Clinical and Preclinical Milestones
1990, 1993, 2000, 2004 // ADA deficiencyF Anderson, M Blaese // C Bordignon
Anderson, 1990
Bordignon, 2000 (ESGT, Stockholm)2002, science 296, 2410 ff)
1997, 2000, Critical limb ischemiaJ Isner († 4.11.2001), I Baumgartner, Circulation 1998
Isner, 1998
1998, RestenosisV Dzau, HGT 1998
Dzau, 1999
2000, HemophiliaM Kay, K High
2000, 2002, X-SCIDA Fischer, Science April 2000, UK trials 2003
Fischer, 20002002
2001, 2003 ONYX oncolytic VirusesD Kirn (Cancer Gene Ther 9, p 979-86)
Kirn, 2000,200120022003
Intravascular adenoviral agents in cancer patients:
Lessons from clinical trials(review)
2004, Chronic Granulomatous DiseaseM Grez Frankfurt; R Seger Zürich
Manuel GrezHans Peter HossleReinhard Seger2004
very encouraging data from just initiated clinical trial,prospected >10 patients
UNIFRRusconi
2005
UNIFRRusconi
2005
Approved commercialisation of Gendicine (Jan 2004) for cancer treatment in China
SibionoShenzen
2004, Gendicine (adeno-p53 vector)L Peng, Sibiono Inc, Shenzen, China
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)
Two persisting major SGT frustration casesTwo persisting major SGT frustration cases
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'
UNIFRRusconi
2005
UNIFRRusconi
2005
The most feared potential side-effects of gene transferThe most feared potential side-effects of gene transfer
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
-> insertional mutagenesis (-> cancer risk)
Contamination of germ line cells
Random integration in genome
-> insertional mutagenesis (-> 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
UNIFRRusconi
2004
UNIFRRusconi
2004
immune response or long term side effects from
new or foreign gene product -> autoimmunity
Paris, Jan 14, 2003, A Fischer: retrovirus X-SCID (bone marrow) same cohorta second patient developed a similar leukemia 30 trials in USA were temporarily suspended
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.
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).
SAEs1: established cases: acute and long term SAEs: from Gelsingers' death to Paris' Leukaemias
SAEs1: established cases: acute and long term SAEs: from Gelsingers' death to Paris' Leukaemias
NY May 5, 1995, R. Crystal: adenovirus, cystic fibrosis (lung) one patient mild pneumonia-like conditionTrial interrupted and many others on hold.
UNIFRRusconi
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UNIFRRusconi
2005
Most Recent Paris' Trial Newsdiscussed 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
Paris, Jan 24, 2005, A Fischer:
retrovirus X-SCID (bone marrow) same cohort
a third patient developed a similar leukemia
what will happen?
Ergogene therapy can produce both short-term and long-term severe side effects through acute immunogenicity or insertional mutagenesis (cancer risk)
Parenthesis: future solutions to insertional mutagenesis: targeted gene transfer approaches
Parenthesis: future solutions to insertional mutagenesis: targeted gene transfer approaches
Random integrating vectors r-retroviruses r-lentiviruses r-AAV plasmids (low frequency) plasmids + transposase (eg 'sleeping beauty')
Transient, non integrating vectors adenovirus plasmid RNA virus based oligonucleotides (SiRNA, antisense, ribozymes) artificial chromosomes
Gene correction vectors chimeroplasts (RNA-DNA chimeric oligos) single stranded DNA (homologous recom)
Ergo genotoxic non-genotoxic
Specifically integrating vectors hybrid vectors (HSV-AAV) Phage 31 integrase-based designer integrases (ZnFinger proteins)
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UNIFRRusconi
2005
Ergovector systems that allow specific or at least better location-controlled gene delivery are experimentally well advanced (see accompanying text)
SAEs2: emerging cases mid-term effects documented by recent Autoimmunity Reports
SAEs2: emerging cases mid-term effects documented by recent Autoimmunity Reports
Blood, 1 May 2004, Vol. 103, No. 9, comment: pp. 3248-3249Autoimmunity 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
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UNIFRRusconi
2005
K High, ASGT June meeting 2004[Abstract1002] Immune Responses to AAV and to Factor IX in a Phase I Study of AAV-Mediated, Liver-DirectedGene Transfer for Hemophilia B
Ergosomatic gene transfer can generate mid-term auto- immunity under certain circumstances
SAEs3: Non-science factors that have disturbed progress and image of gene therapy
SAEs3: Non-science factors that have disturbed progress and image of gene therapy
'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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2005
UNIFRRusconi
2005
1625
Ups and Downs of Gene Therapy: a true roller-coaster ride!
Ups and Downs of Gene Therapy: a true roller-coaster ride!
>90
high
Low
moo
d
NIHMotulskireport
Lentivectors
Adeno III
J. Isner
F Anderson
R. Crystal
Adeno I
A. FischerM. Kay
AAV germline in mice?
Ergo whenever a reasonable cruise
speed was achieved, a major adverse event has brought us back «square one» or even below
V.Dzau
Paris I and IILeukaemias
J. Gelsinger
90 91 92 93 94 95 96 97 98 99 00 01 02 03 04
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UNIFRRusconi
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05
C Bordignon
5
lentivectorshopes
Auto-immunity
gendicine
Paris III
?
?
?
4 companies
Conclusions: GT has proven several concepts, has several tools, but is still in the pioneering phase
Conclusions: GT has proven several concepts, has several tools, but is still in the pioneering phase
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
Clinically over 600 trials and >4000 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)
Ergo we are somewhat ahead but still
in the pioneering phase !
«failure of evidence» does not mean «evidence of failure» !
UNIFRRusconi
2005
UNIFRRusconi
2005
Perspectives: somatic gene therapy will progress in spite of all past, present and future incidents/accidents
Perspectives: somatic gene therapy will progress in spite of all past, present and future incidents/accidents
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
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
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
UNIFRRusconi
2005
UNIFRRusconi
2005
Proust's questionnaire to myself and to you, concerning gene therapy
Proust's questionnaire to myself and to you, concerning gene therapy
UNIFRRusconi
2005
UNIFRRusconi
2005
will GT ever make it into routine clinical practice ? yes
The most worrying side-effect? immunity
Which will bloom: viral or non viral transfer? combination thereof
Is insertional mutagenesis an important hurdle? No
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
Thank you all for the patience and attention,
[email protected] visit:
www.unifr.ch/nfp37/
...Thanks, and let's remain optimistic...Thanks, and let's remain optimistic
The other organisers
Sergio Capancioni, Christiane Damgé
GTRV Debio summer school
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2005
UNIFRRusconi
2005
Ergo let's look forward
to a safe landing
That's all, folks!That's all, folks!UNIFRRusconi
2005
UNIFRRusconi
2005
www.unifr.ch/nfp37
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2004
UNIFRRusconi
2004