HUMAN MOLECULAR GENETICS GROUP Franco Pagani Franco

HUMAN MOLECULAR GENETICS GROUP
Tuesday, 17 May 2016
Franco Pagani
[email protected]
GENERAL PROGRAMME
09.00 - 10.30:
CSA session: Plenary meeting
10.30 - 11.00:
Coffee Break – ICGEB Atrium (CSA Members)
Malattie rare"
11.00 - 13.00:
CSA session: Plenary meeting (cont.)
Farmaci
biotecnologici personalizzati 13.00 -14.00:
14.00 -15.40:
Scientific Presentations by ICGEB
Research Groups (20+5’ per Group)
•
Bacteriology
Lunch Break – ICGEB Common Room (CSA Members)
•
Biotechnology ICGEB
Development Unit
•
Cluster
Biosafety
•
Smart Health FVG
Trieste
Human Molecular
Genetics
20 May 2016
15.40 - 16.00:
Coffee Break – ICGEB Atrium
16.00 - 17.40:
Scientific Presentations (continued)
Ilgruppodiricercae'interessatoallostudiodellemala;erareedallosviluppo
dinuovestrategieterapeu3chebasatesullRNAperlacuradiquestemala;e
PROJECTIDEA
Buildupaninnova1vebiotechnological
pla:orm,capableofprojec3ngandproducing
specificinnova1veRNA-BasedTherapiesbased
onExonSpecificsnRNAs
2
VISION&MISSION
Researching,developing&commercializa3onof
innova3ve,patented,RNA-BasedTherapeu1cs
(GeneTherapyMedicinalProducts-GTMPs),to
cureHumanGene1cDiseasewithunmet
medicalneeds,withaspecificfocusonRare
Diseases.
BuildingupStrategicAlliances,Partnerships,
M&ALicencing.
3
BusinessModel
DrugDiscoveryStage
Inves3ga3onalNew
Drug(IND)
Applica3onStage
NewDrug
Applica3on(NDA)
Phase
HumanClinicalTrials
PhaseI>PhaseII>
PhaseIII
4
THEINNOVATIVEAPPROACH:
ThebiotechnologicalplaXormallowstheproduc3on
ofspecificcompounds(NMEs)ac3ngatthepremRNAlevelandtarge3ngspecificgene3cdefects.
5
MECHANISMOFACTION
RNAmodula3ngtherapeu3cs.
Thetarget(pre-mRNA)istheSplicingprocess
occurringincellnuclei
6
ThePlaXorm
• 
biotechnologicalplaXorm
allowstheproduc3onof
specificcompounds
(NMEs)ac3ngatthepremRNAlevelandtarge3ng
specificgene3cdefects.
(FernandezAlanisE.etal,
HumMolGenet.2012)
Diseasesandexonskippingmuta3onscorrectedbyExSpeU1s
R116R
R116G
-9 T>G
-8 T>G
Hemophilia B
-2 A>G
-2 A>T
-2 A>C
FIX exon 5
Y577Y
Cystic Fibrosis
-1 G>A
-1 G>T +3 A>C
+3 A>G +5 G>A
CFTR exon 13
+3G>A
+3C>A
CFTR exon 5
+5G>A
CFTR exon 16
+6 C>T
Spinal Muscular Atrophy
SMN2 exon7
6846 G>C
Epidermolisis Bullosa
(dominant form)
6849 del
COL7A1 exon 87 +6 C>T
Netherthon Syndrome
Familial Dysautonomia
SPINK5 exon 11
IKAB exon 20
+6 C>T
SpinalMuscularAtrophy
•  Spinalmuscularatrophy(SMA)isasevere
neuromusculardiseaseandoneofmostcommon
gene3ccausesofinfantmortality.It’sthemost
commoninheritedcauseofearlychildhooddeathand
thesecondmostcommonautosomalrecessive
disorderabercys3cfibrosis.
•  SMAisa"raredisorder":approximately1in6,000
babiesbornareaffected
•  Thereiscurrentlynoeffec3vetreatmentforSMA.
•  Oneofthemostpromisingstrategiesistoredirectthe
splicingofaparalogousgene,SMN2,toproduce
func3onalSMNTerapies
• 
filedPatent.
9
HUMANMOLECULARGENETICS
AnovelstrategybasedonRNAcuresSpinalMuscularAtrophy
SMA
Het
ExSpeU1 SM25
SMA+ExSpeU1
Het
SMA mice
Percent survival
100
80
60
TaiwaneseSMAmice
40
Control mice
ExSpeU1 SM25 rescue mice
20
0
Untreated SMA mice
0
50
100
150
200
250
Days
Survival curve
19052016
RareDiseasesandExonSpecificU1smediatedsplicingrescue
Ongoingprojects
Disease
Gene1cs
protein
exonskipped
muta1ons
corrected
1ssue
HemophiliaB
X-linked
coagula3on
factor
FIXex5
11
liver
SMA
recessive
smprotein
SMN2ex7
1
brain(others?)
Cys3cfibrosis
recessive
Cl-channel
CFTRex13,ex 7ex12,1ex lung,pancreas,
5andex16
5,1ex16
other
Dominant
Epidermolysis
Bullosa
dominant collagenVII
COL7A1ex87
2
skin
Netherton
syndrome
recessive
protease
inhibitor
SPINK5ex11
1
skin(onlyinthe
granularlayer)
Transcrip3on
elongator
IKABPex20
1
brain,DRG,
sensoryneurons
Familial
recessive
Dysautonomia
Finalizzazioneaproge;regionali
•  Collaborazionetracentridiricercaspecializza3in
ingegneriagene3caconfortecompetenzeallo
sviluppodifarmaciinnova3viadRNA(ICGEB),un
centroingradodifornireservizidi
Sequenziamentodiul3magenerazioneed
eventualmenteunastartuplocaleingradodi
provvedereallosviluppopreclinicodelfarmaco
•  Ilcontributodistrunureclinico/ospedaliere
esperteinmala;erarepotra’essereu3leper
unaarmonizzazionedelprocessoinprevisione
dellafaseclinica
12
Partner&Collaborators
(seekinginvestors)
Confiden3al
Mul3na3onal
Biotech
13
HUMAN MOLECULAR
GENETICS LAB
Franco PAGANI
Erica BUSSANI
Giulia PIANIGIANI
Katarzyna RAJKOWSKA
Ivana PETROVIC
Former members:
Andrea DAL MAS
Malgorzata ROGALSKA
Mojca TAINJIK
Luca CAMPARINI
Chiara MATTIOLI
ICGEB, Trieste Italy