Gene therapy

A l e s s a n d r o Aiuti

A A i s t h e P I of g e n e t h e r a p y clinical trials o n A D A - S C I D ,
WAS, MLD, Beta thalassemia sponsored by GSK.

Li sbon, M a r c h 19 t h 2 0 1 8

www .ebmt.or
# E B M T1 8
g
 G e n e a n d cell t h e r a p y
Gene therapy
• Administer the corrected gene
(gene addition) E n z y m e r ep l a c em e n t
• Turn off/replace/correct the therapy
defective gene
• Activate another gene
• Provide a gene with a new P H A R M A C O LO G IC
function AL THERAPY

g ene p ro te in function

GENE and Cell t h e r a py

CEL L T H E R A P Y Administration of
ce ll healthy or
ADVANCED
THERAPIES: corrected somatic
cells

2
 R e g (CE)1394/2007 Definitions
Article 2 D e f i n i t i o n s -
‘ A d v a n c e d t h e r a p y m e d i c i n a l p roduct ’ m e a n s
a n y of the following medicinal products for
h u m a n use:
➢ a g e n e therapy medicinal product as
defined
iinn PPaarI rVttof IIVA oofef xAAI nton eexx II ttoo2001/83/EC
i nPart V nn n nDirective
➢ SAogmenaettihcercaeplylsmtehd eicrinaapl pyromduecdt
iDDciirrine c t i v e 2 0 0 1 / 8 3/ /ECC
e c at li vper o2 0d 0u 1c /t 8 3 E
➢ Tmmiseesdan s a b io lo g i ca l
uiceinEalnpgriondeuecrtethdatphraosdtuhectfollowing
characteristics:
➢ C◈omIt bcoinnteadinsAaTnMactiP ve substance that contains or
consists of a re co m b in a n t n u cle ic a cid use d in or
adm inis tered to human beings with a view to regulating ,
◈ Its therapeutic, prophylactic or diagnostic effect re late s
repairing , adding or deleting a g e n e t i c s e q u e n c e
directly to the recombinant nucleic acid sequence it
contains, or to the product of genetic expression of this
sequence
http://www.genetherapynet.com/viral-
vectors.html

G e n e t h e r a p y viral v e c t o r s
 Gene therapy platforms

• Gene addition with integrating vectors

• Gene editing
• Gene correction • Gene
• Inside a gene (downstream of a promoter)
• In safe harbours
Technology
• Zinc fingers
(nuclease)
• TALEN
(nuclease)
• Crispr/Cas9
(RNA/protein)

• Gene disruption

• Gene addition with

inhibitory activity
(shRNA)
G e n e t h e r a p y a p p r o a c h e s for g e n e t i c d i s e a s e

Ex vivo I n vivo

Systemic delivery
Local ( C N S … )

Gene addition
Genome Editing

Primary immunodeficiencies Lysosomal storage disorders

Thrombocytopenia Other metabolic disorders
Lysosomal storage disorders FIX and FVIII deficiency
Haemoglobinopathies Eye disorder
B M failure Neuromuscular disorder
Gene therapy based d r u g s authorised
in th e w o rl d

Name Company Disease Current Positive

market Opi n i o n
area
S t r i mv eli s GSK ADA-SCID Europe 2016
Zalmoxis MolMed add-on treatment Europe 2016
in pts with
cancer who have
received a H S C
transplant
K y mr i h a Novartis B cell leukemia USA 2017
Yes kart a KITE Non Hodgkin USA 2017
Lymphoma
L uxtu rn a Spark Leber Amaurosis USA 2017
Therapeutics

March 2 0 1 8
7
G e n e th e r a p i e s for rare d i s e a s e s :
scientific c h a l l e n g e s

• Need to overcome:
- Bi o lo g i c al barrie rs to
engraftment an d regeneration
- I m m u n o l o g i c a l barriers to transplant of cells or
genes
• Limited comprehension of s t e m cell b i o l o g y
• Knowledge of d i s e a s e m e c h a n i s m s
• Need of adequate preclinical m o d e l s
• Need of regulated and efficient methods of g e n e
tra n sf er
• Overcome s a f e t y i s s e s (insertional
mutagenesis)
8
G e n e th e r ap i e s for rare d i s e a s e s :
o•pDeervaetloiopnmaelncthallenges
– Large scale production and according to regulatory
quality standard
• Clinical trials
– Dedicated clinical research unit for ATMP
– Development and validation of new tests and
analitical methods
– Special needs for infusion/implant
• Specific regulatory needs
• Financial support for research and development
• Industrial alliances to achieve approval and
availability of medicinal product to
patients
• High costs of the medicinal product
9
HEMATOPOIETIC S T E M CELL TRANSPLANT
A N D ADVANCED THERAPIES
Transplant of normal H S C
from an allogeneic
donor

Autologous transplant of
gene corrected H S C

Advanced therapy (GENE THERAPY)

“personalized therapy”
Producer cell Integrating Gene transfer
Viral
vector
Semi-random integration

Insertion site marks stem cells Transgene transferred to daughter cells

and their progeny
13
Adoptive T-cell therapy for cancer: The era
of genetically engineered cells

Viral or non
• Increasing the safety
viral mediated profile of T cells
gene transfer (suicide genes)
• Redirecting T
cell specificity
(CAR & TCR)
• Increasing function
Genom e
and persistence of T
Editing cells
• Modifying homing of
T cells….

C. Bonini
Toxicity and management in CAR T-cell therapy

Challice L Bonifant, Hollie J Jackson, Renier J Brentjens, Kevin J

Curran

Molecular Therapy - Oncolytics

Volume 3, (January 2016)
DOI: 10.1038/mto.2016.11
 T S C M -based therapeutic interventions
for human diseases

Luca Gattinoni, Daniel E. Speiser, Mathias Lichterfeld and Chiara Bonini ;

Nature Medicine
 D N A “Nano-Surgery”
CRISPR/Cas9
Zinc Finge r TA L E N s
Nucleases

Repair by Genomic D N A

Non
Hom olog ous
Gene
End Joining Loss of nucleotides Knock
Loss of Function
Out
Co re L e g a l F r a m e w o r k for A T M P s
in th e E U
M e d ical
Devices
Directive
93/42/E E C
and Directive
90/385/EEC

R e g u l a t i o n (EC )
N o 1394/2007
+
Directive
2001/83/EC +
C ells &
R e g u l a t i o n ( EC )
Blood
Tissues N o 726/2004
Directive
Directive
2 0 02/98/E C
2 0 0 4/23/EC
E U L e g a l / R e g u l a t o r y F r a m e w o r k for
Pharmaceuticals
Regulatory Framework
Applicability of v a r i o u s E U r e g u l a t i o n s a n d
directives t o s o m e e x a m p l e A T M P s
 R e g (CE)1394/20 E U Ce n t ra li se d
Procedure
- Often O D D = > M A A reviewed by C H M P & C A T + C O M P (re-
evaluation at the time of MAA)
- APPROVAL: Standard , Conditional, Under Exceptional Circustancies
- Accelerated v s standard review timelines for possible for Life
Threatening MP

GCP
Inspection
GMP
Ins pection
Standard Review
Process

Other topics of discussion:

- du ra ti o n of the post-approval registry: 1 5 year up vs.
lifelong follow up
-
inclusion of specific s a f e t y m o n i t o r i n g in the registry
 SR-Tiget C L I N I C A L R E S E A R C H U N I T A N D K E Y C O L L A B O R A T O R

l i n i c a l P e d i a t r i c R e s e a r c h UCnliitnical H a e m a t o l o g y R e s e a r c h Unit
A. Aiuti F. Ciceri S a n Raffaele S t e m Cell P r o g r a m
E B e r n a r d o - M P C ic alese (c oor d) S . M a r k t e l (coor d) ( H ea d : F. Ciceri)

ET clinical trial office (TCTPI m

a n c a n (c oor di nator)
Oem
)diatric
u n o h e m a t o l o g y Ad ult B M T and hematolo
F. Ciceri ( H e a d )
astagnaro (QA) A. Aiuti ( H e a d )
S. Marktel
asiraghi G. Antonioli
M E B e r n a r d o (RUF BM T Unit) B. G e n t n e r
arin M P C ic al ese (RUF Ped D H)
F. G ig lio
acchini S. Locatelli F. Ferrua
C. Soliman/A. Biella (head nurse)
Bergami A. Corti V. Calbi
M. Coppola R. Milani
ossati E. Albertazzi A. Assanelli
L. Santoleri
H ossa ry M. Migliavacca
S. Gattillo
om aselli F. Tucci F.
Other staff
M. Doglio
Ba rzag hi G. Prunotto
MolMEd
ucano, A. Cazzato “come a casa”
F. Ciotti /MP.Feradsicahitnriic (GMP CMO)
G E T clinical la b (TC L) M. Sarzana
MG N a ta l i S o r a
F. F u m a g a l l i
Zancan N
F. C alzatin Agi .y
e u r o l o
Castagnaro (QA) D. Canarutto
Albertini G. Consiglieri
Brigida S. Scaramuzza Z
R.a m bon
Pajno
G iannelli F. M . G a bS a. Rlde ocupero
D ionis io S artirana (Head Alliance Management
F. S alerio Acquati &Reg Affairs Manager)
Attanasio
D. RedaelliC. Rossi G. Farinelli
Mezzanotte A. Corti
Tommasoni External l a b s a n d c ollabor at ors 27
Examples of pr oc e s s e s NOT considered
“Substantial Manipulation” ( R e g 1394/2007/EC A N N E X I)

cut t i n g
cry o p res er
g rin d ing
v at i o n

freezi ng shaping

M a n ip u la tio n
s referred
ly o p h ilizati to in th e cen trifu g a
on tion
first i n de n t
of Article
2(1) (c) s o a k i n g in
antibiotic
or
filtering a n timicro b
cell ial
s ep a ra tio n s o lu t i o n s
,
s terilizatio
co n cen trat
n
ion or
purificatio irradiation
n
R e g (CE)1394/2007 I n c e n t i v es

ATMP
ATMP CE RTIFICATIO
CLASSIFICATIO N : Quality & N-
N
A TMClPinical
onlydata
)
In ce nti
( SME

SCIENTIFIC ves EMA FEE

AD V ICE REDUCTION