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No Slide Title 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 Patients (genetic syndrome) (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 Drug Therapeutic target Clinical trials by NCT n. Rett syndrome [MeCP2] Abnormal regulation of gene expression, 01253317, 01777542 impairing neuritic sprouting and synaptogenesis (1-3) IGF1 Enhance neuritic sprouting 22q13 deletion/Phelan-McDermid Disrupted scaffolding of the post-synaptic [Mecasermin, Increlex] and synaptogenesis 01525901 Syndrome [SHANK3] elements, leading to reduced dendritic spines and synaptogenesis Fragile X syndrome [FMR1] Increased translation in dendritic spines MPEP mGLUR5 antagonism None Fenobam 01806415 STX107 01325740, 00965432 AFQ056 [Mavoglurant] 01357239, 01253629, 01482143, 01348087, 01433354, 00718341 RO4917523 01750957, 01015430, 01517698 STX209 [Arbaclofen] GABA-B receptor 00788073, 01282268, agonism 01555333 (terminated), 01325220 CX516 [Ampalex] Positive allosteric 00054730 modulation of AMPA receptors Fragile X syndrome and idiopathic Microglial activation Microglial inhibition 00409747 autism [neuroinflammation]. Minocycline Increased expression and activity of MMP9 MMP9 inhibition 01053156, 0858689 Tuberous Sclerosis [TSC1/TSC2] Disinhibition of the mTOR pathway Rapamycin [Sirolimus] mTOR inhibition 00457808 Everolimus [RAD001, 01289912, 01070316, Afinitor] 01730209, 01713946 Autism with macrocephaly (PTEN) None Neurofibromatosis (NF1) Disinhibition of RAS activity & mTOR Lovastatin Ras activity inhibition 00352599 pathway Genetic variants in OXTR Inadequate action of Oxytoxin Oxytocin Enhance Oxytocin activity 01337687, 01788072, 01624194, 01308749, 01183221, 1256060 CNVs affecting 15q11-13 implicating Excitatory effect GABAergic neurons due to Bumetanide Reinforcement of 01078714 GABRB3, GABRA5 and GABRG3 abnormally elevated intracellular chloride GABAergic inhibition via reduction of intracellular chloride levels 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 De novo Clinical phenotype mutations Butler et al., 3/18 (13m, 5f) with H93R (exon 4) Extreme macrocephaly 2005 macrocephaly D252G (exon 7) and macrosomy 16,6% F241S (exon 7) 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 side effects therapy 3) Outcome measures Modify existing scales, create display low sensitivity new ad hoc scales, choose appropriate clinical endpoints 4) Short trial duration Longer trial duration, more complex designs including drug 5) Pharmacological + non-pharmacological intervention only intervention combined 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 13 14 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 Severe adverse reactions in cognitive disability 100 /ml) ng ( 80 60 levels 40 blood 20 Prolactin 6+6 5+5 4+4 2+2 1+1 Risperidone dosage in drops (1 mg = 17 drops) 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 1 Autism 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% Certainly causal CNV 15% Common Negative Positive variant 14 22 51/147 60/147 25% 37 (34%) 38 (41%) 36 Probably causal CNV 26% Possibly causal CNV of uncertain significance 25% V.M., 23 y.o., autism, cognitive disability, epilepsy Crom Banda Inizio (bp) Fine (bp) Lunghezza (bp) Sonde Dup/Del Log2 ratio Geni Origine Dup totali in DGV Dup simili in DGV Del totali in DGV Del simili in DGV PRAMEF1, PRAMEF11, LOC649330, 1 p36.21 12.846.934 12.912.625 65.691 3 Del -1,303 HNRNPCL1 Comune ereditata dalla madre 38 17 50 15 RNVU1-18;RNU1-27P;RNU1- 28P;RNU1-3;RNU1-2;RNU1-1;RNU1- 1 p36.13 17.051.180 17.257.997 6 0,585 4,LOC100132147;LOC101927806;LOC4 206.817 Dup 40570,CROCC Comune ereditata dal padre 27 5 26 4 1 q21.3 152.556.449 152.586.281 29.832 3 Del -1,097 LCE3C Comune ereditata dalla madre 6 5 26 22 1 q31.3 196.386.440 196.711.149 324.709 26 Dup 0,296 KCNT2, CFH De novo 21 0 41 0 LOC101930107,LINC00152;MIR4435- 2 p11.2 87.370.476 88.018.726 9 0,418 648.250 Dup 1HG Comune ereditata dal padre 56 4 28 3 3 q26.1 162.556.223 162.594.653 38.430 3 Dup 5,840 Comune ereditata dal padre 13 10 22 21 4 q13.2 69.392.545 69.462.438 69.893 6 Del -3,290 UGT2B17, UGT2B15 Comune ereditata dalla madre 23 14 39 15 OCLN, GTF2H2C, GTF2H2D, LOC100272216, GUSBP3, SERF1A, SERF1B, SMN1, SMN2, LOC100170939, GTF2H2B, SMA5, 5 q13.2 68.849.594 70.369.959 1.520.365 3 Del -1,045 LOC100049076, NAIP, GTF2H2 Comune ereditata dalla madre 113 4 104 5 5 q33.1 151.792.610 151.839.164 46.554 3 Dup 0,955 Rara ereditata parzialmente dal padre 1 0 2 1 6 q14.1 78.979.172 79.023.328 44.156 3 Dup -0,798 Comune ereditata dalla madre 22 17 41 26 8 p11.22 39.237.438 39.374.789 137.351 12 Del -3,461 ADAM5P, ADAM3A Comune ereditata dal padre 26 11 38 23 11 q11 55.372.753 55.453.023 80.270 8 Del 0,585 OR4C6,OR4P4,OR4S2 Comune presente in ambedue i genitori 18 11 53 25 RNF10, POP5, CABP1, MLEC, 12 q24.31 121.006.068 121.273.301 267.233 25 Dup 0,481 UNC119B, ACADS, SPPL3 Rara ereditata dal padre 2 1 9 0 OR11H12, POTEG, POTEM, OR11H2, OR4Q3, OR4M1, OR4N2, OR4K2, 14 q11.2 19.376.762 20.427.242 1.050.480 15 Dup 0,441 OR4K5, OR4K1 De novo 82 3 58 5 14 q11.2 22.368.864 22.964.922 596.058 53 Dup -0,286 Rara ereditata dal padre 20 0 72 2 HERC2P3,GOLGA6L6,MIR1268A,OR4 q11.1- N4,GOLGA8CP,POTEB2;LOC10028896 15 20.394.220 22.669.111 55 0,585 q11.2 6;POTEB;POTED,POTEB2;POTEB,LOC 2.274.891 Del 646214,OR4M2 Comune ereditata dal padre 200 9 197 5 15 q13.3 31.972.646 32.438.943 466.297 26 Dup 0,400 CHRNA7 Comune ereditata dal padre 37 11 27 5 TP53TG3, TP53TG3B, LOC653550, 16 p11.2 32.573.808 33.961.233 1.387.425 17 Dup -0,608 SLC6A10P, LOC390705 Comune ereditata dalla madre 150 3 200 4 17 q12 34.437.475 34.475.514 38.039 4 Del -0,742 Comune ereditata dal padre 34 22 10 8 17 q21.31 44.221.743 44.345.038 123.295 8 Del -0,558 KIAA1267, LOC644246 Comune presente in ambedue i genitori 30 19 15 9 IGF2BP1, B4GALNT2, GNGT2, ABI3, 17 q21.32 47.069.742 47.318.413 248.671 16 Del 0,538 PHOSPHO1 Rara ereditata dal padre 2 0 13 0 22 q11.23 24.347.959 24.390.254 42.295 5 Dup 0,874 LOC391322, GSTT1, GSTTP2 Comune ereditata dal padre 19 18 33 19 X q28 154.396.991 154.425.684 28.693 3 Dup -4,572 Rara ereditata dalla madre 5 5 3 1 D.M., 20 y.o., high functioning autism Crom Banda Inizio (bp) Fine (bp) Lunghezza (bp) Sonde Dup/Del Log2 ratio Geni Origine Dup totali in DGV Dup simili in DGV Del totali in DGV Del simili in DGV RNVU1-18RNU1-27PRNU1-28PRNU1-3RNU1-2RNU1-1RNU1- p36.13 17.051.180 17.257.997 6 0,585 1 206.817 Dup 4,LOC100132147LOC101927806LOC440570,CROCC Comune ereditata dal padre 27 5 26 4 2 p11.2 87.370.476 88.018.726 648.250 9 Dup 0,418 LOC101930107,LINC00152MIR4435-1HG Comune ereditata dal padre 56 4 28 3 4 q13.2 69.392.545 69.462.438 69.893 6 Del -3,134 UGT2B17, UGT2B15 Comune ereditata dalla madre 23 14 39 15 5 p15.33 715.757 806.629 90.872 3 Dup 0,585 ZDHHC11,ZDHHC11B Comune ereditata dalla madre 52 29 42 20 OCLN, GTF2H2C,
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