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Developing Gene Therapies
for Rare Genetic Diseases
Frederic Revah Ph.D., CEO
• Dedicated to funding R&D for rare genetic diseases and support to patients
• Organized by AFM-Telethon
• First French Telethon 1987
• 30 hours TV marathon
• One third of all French cities offer local activities on Telethon day
• 2 000 voluntary workers on a yearly basis
• Over 200 000 voluntary workers during Telethon
• 5 million participants, 1 million donors
• € 89 million raised in 2013
The French Telethon : a national popular mobilization
> € 60 M/y in R&D funding, 1 Billion € invested in R&D since 1987
Academic
Research Groups
40%300 R&D programs
400 peer-reviewed publications / y
55 proprietary patent families
> 20 strategic projects
35 active clinical trials in 30 different
diseases (50% non-neuromuscular) 60%
230 scientists
>80% funded by AFM
Gene Therapy for Rare
Diseases
270 MDs, PhDs, scientists,
50 % funded by AFM, 50 % Hospital/
INSERM / UPMC / others
Expert center for the dev. of
biotherapies and clin. trials for
neuromus. diseases
80 scientists
50 % AFM
50 % INSERM
Stem cells for
rare diseases
80 scientists
Gene Therapy /
translational
research
AFM-Telethon’s R&D centers :
650 experts dedicated to Biotherapies for Rare Disease
Consistent support to EB research, > 2,2 M €
since 2001
Prix Galien 2012
Genethon : Gene Therapy for Rare Diseases
� Created in 1990 by patient organization AFM-Telethon non-profit with the mission of delivering
gene therapy drugs for rare disease; budget in 2013 : € 32 Millions
� Therapeutic areas : muscular dystrophies, immune system, eye, liver, CNS, skin
� Located in Evry (France)
� Established the first maps of the human genome in 1992
� Now a fully integrated pharmaceutical organization dedicated to gene therapy from research to
clinical demonstration, including manufacturing
� Staff 230, scientists and experts covering research, preclinical and clinical, bioprocess and
bioproduction, regulatory
Gene Replacement, Gene Surgery, Vectors
Therapeutic gene
Viralvector
The gene is inserted in the viral vector
The vector penetrates the cell and delivers the gene in the nucleus
Cell
Cell Membrane
Nucleus
Cytoplasm
organ
• 80% rare diseases are of genetic origin
• Gene replacement : providing the
diseased cells with a copy of the wild
type gene
• Gene surgery : in situ correction of the
mRNA. Example « exon skipping » ie
mRNA rescue by skipping mutated
exons without destroying the reading
frame
• Vectors : the therapeutic gene is
delivered to the target cells using a
vector, generally a “disarmed” virus.
Most currently used are Adeno-
Associated Viruses and HIV-derived
Lentiviruses
Muscular Dystrophies, Eye
disorders, Hemophilia,,
Huntington, Lipoprotein Lipase
Deficiency…
in vivo delivery
Gene therapy via direct administration (in vivo)
or Hematopoietic Stem Cell transduction (ex vivo)
Recombinant AAV vectors
are directly injected into
the target organ
Hematopoietic stem cells
taken from the patient are
tansduced with an HIV-
derived lentivector and
reinfused
Immune deficiencies,
adrenoleukodystrophy, blood
disorders
ex vivo delivery
Adeno Associated Virus
VIHVirus Ebola
Baculovirus
Sindbis
Viral Vectors
1999: First trials for the treatment of X-SCID, Pr. Alain Fischer, Pr. Cavazzana-Calvo
(Hal Necker, Paris). ex-vivo retroviral therapy
Retrospective analysis of the 8 patients treated at
Necker, after 13 years follow up :
7/8 patients show persistent immune reconstitution
(follow up median 9 y);
1 patient deceased from a leukemia linked to
insertionnal mutagenesis. Salima Hacein-Bey-Abina, et al. N Engl J Med 2010; 363:355-
364, July 22, 2010
Proof of Concept: Severe Combined Immunodeficiency
• Demonstrates major benefit for patients,
• > 70 patients affected with SCID treated ww
• Importance of improvements of vectors to eliminate risks in insertionnal mutagenesis →
development of HIV-derived lentiviral vectors.
1999: Trials for the treatment of X-SCID,
Pr. Alain Fischer, Pr. Cavazzana-Calvo
Treated
+ 12 mo
+ 16 mo
Not Treated
+ 12 mo
+ 18 mo
X-linked Adrenoleukodystrophy:
Cartier N., …Aubourg P. , Science, nov 2009
β-thalassemia:
Cavazzana-Calvo,…., Leboulch; Nature, sept 2010
Leber Congenital Amaurosis
Bainbridge et al, NEJM 2008
Cideciyan et al NEJM 2009
Maguire et al, Lancet 2009
The last decade has seen demonstration of efficacy
of Gene Therapies in Patients
Gene therapy : from an academic driven field
to pharmaceutical products
The objective is now product registration, no
more “1st in man” :
• Integrate from the start the constraints of
development down to registration.
• Development of enabling technologies.
• Solve the complexity of the large scale GMP
manufacturing of vectors
• Design of regulatory pathway
• Few players are able to translate an upstream
“proof of concept” into a drug validated in the
clinic
Proof of efficacy in patient for several type of
disorders : Severe Combined Immuno
Deficiency, b-thalassemia, Leukodystrophies,
Congenital Leber Amaurosis.
Therapeutic projects Enabling technologies BioManufacturing
Objective : Develop products
from bench to clinical validation
Therapeutic areas :
� Muscle (AAV)
� Immune deficiencies and
blood diseases (LV)
� Retinal disorders (AAV)
� Liver (AAV)
� CNS (AAV, LV)
Objective : Develop innovative
enabling technologies for viral
gene transfer
� Improvement of productivity
for manufacturing
� Introducing paradigm shifts
for improved scalability.
� Targeted delivery/expression
� Characterization, control and
bypassing of immune
response
� Biomarkers
Bio-manufacturing to support
increasing demand from
clinical development
« Regulatory » innovation
Adapt the design of clinical
trials to rare diseases and gene
therapy products
Gene Therapy R&D at Genethon:
A multifaceted approach
Genethon : translational R&D for gene therapy
Therapeutic
conceptPreclinical
development
Clinical
trialIND
Therapeutic
Research Groups
(internal + network
of external coll.)
Upstream Research
Proof of
efficacy in
disease model
Proof of efficacy in large animal
Tox Biodistribution
GMP bioproduction
and BioProcess� Largest production plant for
clinical GT products ww
Bioprocess development
GMP Bioproduction
Clinical and
Regulatory
Clinical phase
Enabling technologies
Primary Genetic Immune Deficiencies and Blood diseases
Eye Diseases
Leber’s Hereditary Optic Neuropathy
� Sudden loss of vision in adolescents or young adults
� 1 /30 000
� No cure
In collaboration with Institut de la Vision and Gensight
IND approved, trial ongoing
� Loss of the capacity to resist otherwise benign
micro-organisms
� Leads to patient death during adolescence or
early 20ies
� No cure
� Human Stem Cells+Lentivirus
2 ongoing international clinical programs Europe & US :
Wiskott Aldrich and Chronic Granulomatous disease
Other programs :
Fanconi anemia (trial ongoing)
X-SCID, RS-SCID,
β-thalassemia
Muscular Dystrophies and Neuromuscular Diseases
Duchenne Muscular Dystrophy (AAV)
� Irreversible muscular wasting
� Confined to wheel chair with respiratory support by the year of 12,
death usually in the 20ies, no cure
� 1 in 3500 newborn boys
IND to be filed in 2015
Myotubular Myopathy (AAV): Preclinical stage, collaboration with Audentes IND
to be filed in 2015
Spinal Muscular Atrophy (AAV): Preclinical stage, IND 2016
Limb Girdle Dystrophies (AAV): Research
α-dystroglycan
β-dystroglycan
Sarcospan
Calpain3
TRIM32
FKRP
Actin MyosinTitin
Telethonin
αβ
βα
γδ
Sarcoglycans
Dysferlin
Sarcolemma
Golgi
Sarcomere
Ano5
Other DiseasesCNS : Huntington Disease, Research
Liver Diseases : Crigler Najjar, Research
EB, research
Major Programs
� Production methods for gene therapy drugs have often been directly scaled up from
bench molecular biology methods.
� Insufficient quantities for a large number of indications (muscular diseases, blood
disorders) and for commercial purposes.
� Cost of Goods limiting.
� Technologies ill-adapted to Good Manufacturing Practices.
→ Strong need for innovative process development :
� Introducing paradigm shifts for improved scalability.
� Improvement of productivity for production and purification.
Focus on Production:
The Manufacturing challenges
Prozac, molecular weight 309
Recombinant AAV: molecular weight > 4000 103 , ie x 104 Prozac
X 50 patients
Retinopathy
X 24 CF10
X 1 Duchenne
patient
1 patient1000 L culture
166 weeks
(>3 years)
Example of AAV Vector Production
200l Bioreactor
1 patient1000 L culture
166 weeks (>3 years)
10 patients200 L culture
6 weeks
Sf9 cells/baculo
system (Rob Kotin NIH)
scaled-up at GNT
200l Bioreactor
100 patients200 L culture
6 weeks
X10 increase in
yield
An example of paradigm shift :
the use of Sf9 producer cells in suspension
� The largest production center ww for clinical
grade gene therapy drugs, from clinical batches to
commercial production
� € 28,5 M investment
� Opened 2013
� Supporting GMP production for 4 international
clinical trials in 2014 and 6 international trials in
2015
Focus on Production : Genethon’s Production plant
Genethon’s Production plant : key figures
Key Figures
� 50 000sq ft 2 floors + 1 technical level for access to air
treatment engines
� 4 production suites ISO10000/BL3 (500m2)
� 2000 sp ft for pilot productions
� 6000 sp ft QC labs
� 2 rooms for aseptic fill and finish (class A/ISO 100
isolators)
� 15 HVAC systems for independent air treatment
� Controlled personnel/materials flows
� Segregated air treatments
� Electronic control of environmental parameters
� Liquid waste treatment through decontamination station
� Rooms decontamination through central gassing system
� Under completion:
� 2 suites for the GMP production of modified patient
Hematopoietic Stem Cells
� 2 suites for the GMP production of stem cells
Capacity
� 20 to 30 GMP lots/year of AAV or LV
depending on process
T cell
B cell
NK cell
Bone marrow
Thymus
Blood
dendritic cell
macrophage
monocyte
erythrocyte
granulocyte
Tissues
platelet
CD34+ bone marrow cells
Retro/Lentiviral vector
First Proof of concept in human :
Genetic correction of genetic blood disorders
Stem cells
Leber’s congenital amaurosis
� Retinal degeneration
� Progressive vision loss
� Treatment: Injection of AAV2/2-RPE65 sub-retinally
� Restoration of retinal function (3mo. post injection)
Gene therapy for retinal disorders
