Antonio M. Persico
Unit of Child & Adolescent Neuropsichiatry
Lab. of Mol. Psychiatry & Neurogenetics
University “Campus Bio-Medico” , Roma
&
Mafalda Luce Center for
Pervasive Developmental Disorders, Milan
Translational pediatric
psychopharmacology
27th ECNP Congress
Berlin (Germany) - October 20, 2014
Priority list for drug development in
pediatric psychopharmacology
12
10
8
6
4
2
0
TNM expert meeting, Child Psychopharmacology Network, ECNP 2013
Translational pediatric psychopharmacology
Patient
(genetic syndrome)
Patients
(different syndromes,
similar mechanisms)
Drug development
Molecular models
Cellular models
Animal models
Chemical drug modelling
Bioinformatic analysis
Induced Pluripotent Stem Cells (iPSCs) in
personalized molecular medicine
c-Myc, Sox2,
Oct ¾, KLF4
Differentiated cells
iPS cells
Syndrome
Pathophysiology
Rett syndrome [MeCP2]
Abnormal regulation of gene expression,
01253317, 01777542
impairing neuritic sprouting and
(1-3) IGF1
Enhance neuritic sprouting
synaptogenesis
Disrupted scaffolding of the post-synaptic
[Mecasermin, Increlex] and synaptogenesis
01525901
elements, leading to reduced dendritic spines
and synaptogenesis
22q13 deletion/Phelan-McDermid
Syndrome [SHANK3]
Fragile X syndrome [FMR1]
Drug
MPEP
Increased translation in dendritic spines
Therapeutic target
mGLUR5 antagonism
Microglial activation
Tuberous Sclerosis [TSC1/TSC2]
Disinhibition of the mTOR pathway
Increased expression and activity of MMP9
01806415
STX107
01325740, 00965432
AFQ056 [Mavoglurant]
01357239, 01253629,
01482143, 01348087,
01433354, 00718341
STX209 [Arbaclofen]
GABA-B receptor
agonism
CX516 [Ampalex]
Positive allosteric
modulation of AMPA
receptors
Microglial inhibition
Minocycline
Rapamycin [Sirolimus]
Genetic variants in OXTR
CNVs affecting 15q11-13 implicating
GABRB3, GABRA5 and GABRG3
Excitatory effect GABAergic neurons due to Bumetanide
abnormally elevated intracellular chloride
00409747
01053156, 0858689
mTOR inhibition
00457808
01289912, 01070316,
01730209, 01713946
None
Autism with macrocephaly (PTEN)
Disinhibition of RAS activity & mTOR
pathway
Inadequate action of Oxytoxin
01750957, 01015430,
01517698
00788073, 01282268,
01555333 (terminated),
01325220
00054730
MMP9 inhibition
Everolimus [RAD001,
Afinitor]
Neurofibromatosis (NF1)
None
Fenobam
RO4917523
Fragile X syndrome and idiopathic
autism [neuroinflammation].
Clinical trials by NCT n.
Lovastatin
Ras activity inhibition
Oxytocin
Enhance Oxytocin activity 01337687, 01788072,
01624194, 01308749,
01183221, 1256060
Reinforcement of
01078714
GABAergic inhibition via
reduction of intracellular
chloride levels
00352599
Vorstman et al, Psychopharmacol, 231:1063-78, 2014
PNAS 106: 2029-34, 2009
PNAS 111: 4596-601, 2014
N=12, 4-wk multiple ascending dose (40-120 mg/kg twice daily)
and an open-label 20-wk extension at the maximum dose
PTEN inactivation yields tumors, overgrowth,
and autism or intellectual disability
Ref.
Mut. carriers
Butler et al.,
2005
3/18 (13m, 5f) with
macrocephaly
16,6%
De novo
mutations
H93R (exon 4)
D252G (exon 7)
F241S (exon 7)
Clinical phenotype
Extreme macrocephaly
and macrosomy
Butler MG et al, J Med Genet, 42:318, 2005
Kwon CH et al, Neuron, 50:377, 2006
PTEN and the mTOR pathway
mRNA translation
Cell proliferation
Ma & Blenis, Mol Cell Biol 10:307, 2009
Rapamycin recovers the PTEN -/- phenotype
Zhou J et al, J Neurosci 29:1773, 2009
Rapamycin recovers the PTEN -/- phenotype
Zhou J et al, J Neurosci 29:1773, 2009
Everolimus has been approved for TS
Renal angiomyolipomas
Subependymal giant-cell astrocytomas
Treatment-refractory seizures
Facial angiofibromas
The pathophysiology of
fragile X syndrome
Levenga et al, Trends Mol Med 16:516, 2010
Jacquemont et al, Psychopharmacol 231:1237, 2014
The challenges of clinical trials in
fragile X syndrome
Challenges and limitations
Solutions
1) Patient heterogeneity
Use of genetic and epigenetic
biomarkers to stratify patients
2) Lack of reliable markers to according to underlying
predict response & severe mechanism(s) and target drug
therapy
side effects
3) Outcome measures
display low sensitivity
Modify existing scales, create
new ad hoc scales, choose
appropriate clinical endpoints
4) Short trial duration
Longer trial duration, more
complex designs including drug
+ non-pharmacological
intervention combined
5) Pharmacological
intervention only
Jacquemont et al, Psychopharmacol 231:1237, 2014
Scales sensitive to change in FXS studies
Jacquemont et al, Psychopharmacol 231:1237, 2014
Biomarker panels for targeted therapies
1 2 3 4 5 6 7 8 9 10 11 12 1314 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36
Metabolomics
Proteomics
Transcriptomics (coding & non)
Methylomics
Genomics: CNVs, SNPs, repeats
Biological foundations of neurodevelopmental disorders
Early intensive behavioral treatment for children aged < 2 years and ½:
20 hrs/wk (2 hrs twice a day x 5 days/wk x 2 yrs) + parent training
Mullen Scale for Early Learning
Vineland Adaptive Behavior Scale
Prolactin blood levels (ng/ml)
Severe adverse reactions in
cognitive disability
100
80
60
40
20
6+6
5+5
2+2
4+4
Risperidone dosage in drops
(1 mg = 17 drops)
1+1
Array-CGH in NHS child psychiatry
• Blood drawn from 334 families (3 families/wk)
• Diagnostic report provided to 124 families (100 simplex e 24 multiplex)
• Patients N=147
Autism
1
Cognitive disability
2
Genetic syndrome tbd
Learning disability
3
Language disorder
ADHD
Childhood SCZ
7
Developmental delay
Memory deficits
Depression
8
Dyspraxia
Catatonia & epilepsy
Bipolar & epilepsy
14
95
Rett syndrome
Neurofibromatosis
Multiple sclerosis
DESR
Binge eating
Polymicrogyria
Prader-Willi
Array-CGH outcome
(N=147 patients)
No variant
9%
Negative
51/147
(34%)
Common
variant
25%
Certainly
causal CNV
15%
Positive
60/147
(41%)
14 22
37
38
36
Possibly causal
CNV of uncertain
significance
25%
Probably
causal CNV
26%
V.M., 23 y.o., autism, cognitive disability, epilepsy
Crom
Banda
Inizio (bp)
Fine (bp)
Lunghezza (bp)
Sonde
Dup/Del
Log2 ratio
1
p36.21
12.846.934
12.912.625
65.691
3
Del
-1,303
1
p36.13
17.051.180
17.257.997
152.556.449
196.386.440
152.586.281
196.711.149
6
206.817
29.832
324.709
1
1
q21.3
q31.3
2
p11.2
87.370.476
88.018.726
3
4
q26.1
q13.2
162.556.223
69.392.545
162.594.653
69.462.438
648.250
38.430
69.893
5
5
6
8
11
q13.2
q33.1
q14.1
p11.22
q11
68.849.594
151.792.610
78.979.172
39.237.438
55.372.753
70.369.959
151.839.164
79.023.328
39.374.789
55.453.023
12
q24.31
121.006.068
14
14
q11.2
q11.2
15
3
26
9
0,585
Dup
Del
Dup
-1,097
0,296
0,418
3
6
Dup
Dup
Del
5,840
-3,290
1.520.365
46.554
44.156
137.351
80.270
3
3
3
12
8
Del
Dup
Dup
Del
Del
-1,045
0,955
-0,798
-3,461
0,585
121.273.301
267.233
25
Dup
0,481
19.376.762
22.368.864
20.427.242
22.964.922
1.050.480
596.058
15
53
Dup
Dup
0,441
-0,286
q11.1q11.2
20.394.220
22.669.111
15
q13.3
31.972.646
32.438.943
2.274.891
466.297
26
Del
Dup
0,400
16
17
17
p11.2
q12
q21.31
32.573.808
34.437.475
44.221.743
33.961.233
34.475.514
44.345.038
1.387.425
38.039
123.295
17
4
8
Dup
Del
Del
-0,608
-0,742
-0,558
17
22
X
q21.32
q11.23
q28
47.069.742
24.347.959
154.396.991
47.318.413
24.390.254
154.425.684
248.671
42.295
28.693
16
5
3
Del
Dup
Dup
0,538
0,874
-4,572
55
0,585
Geni
PRAMEF1, PRAMEF11, LOC649330,
HNRNPCL1
RNVU1-18;RNU1-27P;RNU128P;RNU1-3;RNU1-2;RNU1-1;RNU14,LOC100132147;LOC101927806;LOC4
40570,CROCC
LCE3C
KCNT2, CFH
LOC101930107,LINC00152;MIR44351HG
UGT2B17, UGT2B15
OCLN, GTF2H2C, GTF2H2D,
LOC100272216, GUSBP3, SERF1A,
SERF1B, SMN1, SMN2,
LOC100170939, GTF2H2B, SMA5,
LOC100049076, NAIP, GTF2H2
ADAM5P, ADAM3A
OR4C6,OR4P4,OR4S2
RNF10, POP5, CABP1, MLEC,
UNC119B, ACADS, SPPL3
OR11H12, POTEG, POTEM, OR11H2,
OR4Q3, OR4M1, OR4N2, OR4K2,
OR4K5, OR4K1
Origine
Dup totali in DGV
Dup simili in DGV
Del totali in DGV
Del simili in DGV
Comune ereditata dalla madre
38
17
50
15
Comune ereditata dal padre
Comune ereditata dalla madre
De novo
27
6
21
5
5
0
26
26
41
4
22
0
Comune ereditata dal padre
Comune ereditata dal padre
Comune ereditata dalla madre
56
13
23
4
10
14
28
22
39
3
21
15
Comune ereditata dalla madre
Rara ereditata parzialmente dal padre
Comune ereditata dalla madre
Comune ereditata dal padre
Comune presente in ambedue i genitori
113
1
22
26
18
4
0
17
11
11
104
2
41
38
53
5
1
26
23
25
Rara ereditata dal padre
2
1
9
0
De novo
Rara ereditata dal padre
82
20
3
0
58
72
5
2
200
37
9
11
197
27
5
5
150
34
30
3
22
19
200
10
15
4
8
9
2
19
5
0
18
5
13
33
3
0
19
1
HERC2P3,GOLGA6L6,MIR1268A,OR4
N4,GOLGA8CP,POTEB2;LOC10028896
6;POTEB;POTED,POTEB2;POTEB,LOC
646214,OR4M2
Comune ereditata dal padre
CHRNA7
Comune ereditata dal padre
TP53TG3, TP53TG3B, LOC653550,
SLC6A10P, LOC390705
Comune ereditata dalla madre
Comune ereditata dal padre
KIAA1267, LOC644246
Comune presente in ambedue i genitori
IGF2BP1, B4GALNT2, GNGT2, ABI3,
PHOSPHO1
Rara ereditata dal padre
LOC391322, GSTT1, GSTTP2
Comune ereditata dal padre
Rara ereditata dalla madre
D.M., 20 y.o., high functioning autism
Crom
1
2
4
5
Banda
Inizio (bp)
Fine (bp)
p36.13
17.051.180
17.257.997
p11.2
q13.2
p15.33
87.370.476
69.392.545
715.757
88.018.726
69.462.438
806.629
Lunghezza (bp)
206.817
648.250
69.893
90.872
Sonde
6
9
6
3
Dup/Del
Dup
Dup
Del
Dup
Log2 ratio
0,585
0,418
-3,134
0,585
5
5
6
8
11
12
q13.2
q33.1
q14.1
p11.22
q11
q24.31
68.849.594 70.369.959
151.792.610 151.839.164
78.979.172 79.023.328
39.237.438 39.374.789
55.372.753 55.453.023
121.006.068 121.273.301
1.520.365
46.554
44.156
137.351
80.270
267.233
3
3
3
12
8
25
Del
Dup
Del
Del
Dup
Dup
-1,032
0,874
-0,835
-3,530
0,585
0,479
14
q11.2
19.376.762
1.037.470
14
Dup
0,486
15
15
15
16
17
17
17
22
X
q11.1-q11.2
q13.2
q13.3
p11.2
q12
q21.31
q21.32
q11.23
q28
20.414.232
20.394.220 22.669.111
30.943.903 31.004.749
32.021.733 32.510.863
32.573.808 33.625.989
34.437.475 34.475.514
44.221.743 44.345.038
47.069.742 47.304.479
24.347.959 24.390.254
154.396.991 154.425.684
2.274.891
60.846
489.130
1.052.181
38.039
123.295
234.737
42.295
28.693
55
4
27
15
4
8
15
5
3
Dup
Del
Dup
Del
Del
Del
Dup
Dup
Del
0,585
-0,637
0,466
-0,633
-0,692
-0,568
0,526
0,857
-4,729
Geni
RNVU1-18RNU1-27PRNU1-28PRNU1-3RNU1-2RNU1-1RNU14,LOC100132147LOC101927806LOC440570,CROCC
LOC101930107,LINC00152MIR4435-1HG
UGT2B17, UGT2B15
ZDHHC11,ZDHHC11B
Origine
Comune ereditata dal padre
Comune ereditata dal padre
Comune ereditata dalla madre
Comune ereditata dalla madre
OCLN, GTF2H2C, GTF2H2D, LOC100272216, GUSBP3, SERF1A, SERF1B,
SMN1, SMN2, LOC100170939, GTF2H2B, SMA5, LOC100049076, NAIP,
GTF2H2
Comune ereditata dalla madre
Rara ereditata parzialmente dal padre
Comune ereditata dalla madre
ADAM5P, ADAM3A
Comune ereditata dal padre
OR4C6,OR4P4,OR4S2
Comune presente in ambedue i genitori
RNF10, POP5, CABP1, MLEC, UNC119B, ACADS, SPPL3
Rara ereditata dal padre
OR11H12, POTEG, POTEM, OR11H2, OR4Q3, OR4M1, OR4N2, OR4K2,
OR4K5, OR4K1
De novo
HERC2P3,GOLGA6L6,MIR1268A,OR4N4,GOLGA8CP,POTEB2LOC10028
8966POTEBPOTED,POTEB2POTEB,LOC646214,OR4M2
Comune ereditata dal padre
Comune non presente nei genitori
CHRNA7
Comune ereditata dal padre
TP53TG3, TP53TG3B, LOC653550, SLC6A10P, LOC390705
Comune ereditata dalla madre
Comune ereditata dal padre
KIAA1267, LOC644246
Comune presente in ambedue i genitori
IGF2BP1, B4GALNT2, GNGT2, ABI3, PHOSPHO1
Rara ereditata dal padre
LOC391322, GSTT1, GSTTP2
Comune ereditata dal padre
Rara ereditata dalla madre
Dup totali in DGV
Dup simili in DGV
Del totali in DGV
Del simili in DGV
27
56
23
52
5
4
14
29
26
28
39
42
4
3
15
20
113
1
22
26
18
2
4
0
17
11
11
1
104
2
41
38
53
9
5
1
26
23
25
0
81
3
58
5
200
16
51
121
34
30
2
19
5
9
13
10
7
22
19
0
18
5
197
16
45
131
10
15
13
33
3
5
7
5
4
8
9
0
19
1
Biomarkers and molecular psychopharmacology
in Autism Spectrum Disorder
Biomarker panel
Vorstman et al, Psychopharmacol, 231:1063-78, 2014
Pathophysiology-driven
Child Psychopharmacology
Adult-derived &
non-specific
psychopharmacology
Comorbidities
Personalized
molecular drug therapy
Core symptoms
Thank you!
Carla Lintas
Roberto Sacco
Antonio M. Persico
Valerio Napolioni
Stefano Gabriele
Sarah F. Hastings
Ignazio S. Piras