A pilot controlled trial of insulin-like growth factor-1 in children with Phelan-McDermid syndrome

Alexander Kolevzon, Lauren Bush, A Ting Wang, Danielle Halpern, Yitzchak Frank, David Grodberg, Robert Rapaport, Teresa Tavassoli, William Chaplin, Latha Soorya, Joseph D Buxbaum, Alexander Kolevzon, Lauren Bush, A Ting Wang, Danielle Halpern, Yitzchak Frank, David Grodberg, Robert Rapaport, Teresa Tavassoli, William Chaplin, Latha Soorya, Joseph D Buxbaum

Abstract

Background: Autism spectrum disorder (ASD) is now understood to have multiple genetic risk genes and one example is SHANK3. SHANK3 deletions and mutations disrupt synaptic function and result in Phelan-McDermid syndrome (PMS), which causes a monogenic form of ASD with a frequency of at least 0.5% of ASD cases. Recent evidence from preclinical studies with mouse and human neuronal models of SHANK3 deficiency suggest that insulin-like growth factor-1 (IGF-1) can reverse synaptic plasticity and motor learning deficits. The objective of this study was to pilot IGF-1 treatment in children with PMS to evaluate safety, tolerability, and efficacy for core deficits of ASD, including social impairment and restricted and repetitive behaviors.

Methods: Nine children with PMS aged 5 to 15 were enrolled in a placebo-controlled, double-blind, crossover design study, with 3 months of treatment with IGF-1 and 3 months of placebo in random order, separated by a 4-week wash-out period.

Results: Compared to the placebo phase, the IGF-1 phase was associated with significant improvement in both social impairment and restrictive behaviors, as measured by the Aberrant Behavior Checklist and the Repetitive Behavior Scale, respectively. IGF-1 was found to be well tolerated and there were no serious adverse events in any participants.

Conclusions: This study establishes the feasibility of IGF-1 treatment in PMS and contributes pilot data from the first controlled treatment trial in the syndrome. Results also provide proof of concept to advance knowledge about developing targeted treatments for additional causes of ASD associated with impaired synaptic development and function.

Figures

Figure 1
Figure 1
ABC-SW score between baseline and week 12 of drug or placebo. (A) Change in ABC-SW score between baseline and week 12 of drug or placebo for 9 subjects. In this and all subsequent figures, treatment condition (drug versus placebo) was combined across treatment phases. Error bars = ±1 SE. (B) Mean change in ABC-SW score between baseline and week 12 of drug or placebo. P = 0.040; error bars = ±1 SE. ABC-SW = Aberrant Behavior Checklist Social Withdrawal subscale; SE = standard error.
Figure 2
Figure 2
RBS-R Restricted Behavior score between baseline and week 12 of drug or placebo. (A) Change in RBS-R Restricted Behavior score between baseline and week 12 of drug or placebo. (B) Mean change in RBS-R Restricted Behavior score between baseline and week 12 of drug or placebo. P = 0.042; error bars = ±1 SE. RBS-R = Repetitive Behavior Scale-Revised. SE = standard error. The star reflects the p value and notes the significance.

References

    1. Durand CM, Betancur C, Boeckers TM, Bockmann J, Chaste P, Fauchereau F, Nygren G, Rastam M, Gillberg IC, Anckarsater H, Sponheim E, Goubran-Botros H, Delorme R, Chabane N, Mouren-Simeoni MC, de Mas P, Bieth E, Roge B, Heron D, Burglen L, Gillberg C, Leboyer M, Bourgeron T. Mutations in the gene encoding the synaptic scaffolding protein SHANK3 are associated with autism spectrum disorders. Nat Genet. 2007;39(1):25–27. doi: 10.1038/ng1933.
    1. Gauthier J, Spiegelman D, Piton A, Lafreniere RG, Laurent S, St-Onge J, Lapointe L, Hamdan FF, Cossette P, Mottron L, Fombonne E, Joober R, Marineau C, Drapeau P, Rouleau GA. Novel de novo SHANK3 mutation in autistic patients. Am J Med Genet B Neuropsychiatr Genet. 2009;150B(3):421–424. doi: 10.1002/ajmg.b.30822.
    1. Marshall CR, Noor A, Vincent JB, Lionel AC, Feuk L, Skaug J, Shago M, Moessner R, Pinto D, Ren Y, Thiruvahindrapduram B, Fiebig A, Schreiber S, Friedman J, Ketelaars CE, Vos YJ, Ficicioglu C, Kirkpatrick S, Nicolson R, Sloman L, Summers A, Gibbons CA, Teebi A, Chitayat D, Weksberg R, Thompson A, Vardy C, Crosbie V, Luscombe S, Baatjes R, et al. Structural variation of chromosomes in autism spectrum disorder. Am J Hum Genet. 2008;82(2):477–488. doi: 10.1016/j.ajhg.2007.12.009.
    1. Moessner R, Marshall CR, Sutcliffe JS, Skaug J, Pinto D, Vincent J, Zwaigenbaum L, Fernandez B, Roberts W, Szatmari P, Scherer SW. Contribution of SHANK3 mutations to autism spectrum disorder. Am J Hum Genet. 2007;81(6):1289–1297. doi: 10.1086/522590.
    1. Boeckers TM. The postsynaptic density. Cell Tissue Res. 2006;326(2):409–422. doi: 10.1007/s00441-006-0274-5.
    1. Bonaglia MC, Giorda R, Beri S, De Agostini C, Novara F, Fichera M, Grillo L, Galesi O, Vetro A, Ciccone R, Bonati MT, Giglio S, Guerrini R, Osimani S, Marelli S, Zucca C, Grasso R, Borgatti R, Mani E, Motta C, Molteni M, Romano C, Greco D, Reitano S, Baroncini A, Lapi E, Cecconi A, Arrigo G, Patricelli MG, Pantaleoni C, et al. Molecular mechanisms generating and stabilizing terminal 22q13 deletions in 44 subjects with Phelan/McDermid syndrome. PLoS Genet. 2011;7(7):e1002173. doi: 10.1371/journal.pgen.1002173.
    1. Bonaglia MC, Giorda R, Mani E, Aceti G, Anderlid BM, Baroncini A, Pramparo T, Zuffardi O. Identification of a recurrent breakpoint within the SHANK3 gene in the 22q13.3 deletion syndrome. J Med Genet. 2006;43(10):822–828. doi: 10.1136/jmg.2005.038604.
    1. Denayer A, Van Esch H, de Ravel T, Frijns JP, Van Buggenhout G, Vogels A, Devriendt K, Geutjens J, Thiry P, Swillen A. Neuropsychopathology in 7 patients with the 22q13 deletion syndrome: presence of bipolar disorder and progressive loss of skills. Mol Syndromol. 2012;3(1):14–20.
    1. Dhar SU, del Gaudio D, German JR, Peters SU, Ou Z, Bader PI, Berg JS, Blazo M, Brown CW, Graham BH, Grebe TA, Lalani S, Irons M, Sparagana S, Williams M, Phillips JA, 3rd, Beaudet AL, Stankiewicz P, Patel A, Cheung SW, Sahoo T. 22q13.3 deletion syndrome: clinical and molecular analysis using array CGH. Am J Med Genet A. 2010;152A(3):573–581. doi: 10.1002/ajmg.a.33253.
    1. Jeffries AR, Curran S, Elmslie F, Sharma A, Wenger S, Hummel M, Powell J. Molecular and phenotypic characterization of ring chromosome 22. Am J Med Genet A. 2005;137(2):139–147. doi: 10.1002/ajmg.a.30780.
    1. Koolen DA, Reardon W, Rosser EM, Lacombe D, Hurst JA, Law CJ, Bongers EM, van Ravenswaaij-Arts CM, Leisink MA, van Kessel AG, Veltman JA, de Vries BB. Molecular characterisation of patients with subtelomeric 22q abnormalities using chromosome specific array-based comparative genomic hybridisation. Eur J Hum Genet. 2005;13(9):1019–1024. doi: 10.1038/sj.ejhg.5201456.
    1. Luciani JJ, de Mas P, Depetris D, Mignon-Ravix C, Bottani A, Prieur M, Jonveaux P, Philippe A, Bourrouillou G, de Martinville B, Delobel B, Vallee L, Croquette MF, Mattei MG. Telomeric 22q13 deletions resulting from rings, simple deletions, and translocations: cytogenetic, molecular, and clinical analyses of 32 new observations. J Med Genet. 2003;40(9):690–696. doi: 10.1136/jmg.40.9.690.
    1. Manning MA, Cassidy SB, Clericuzio C, Cherry AM, Schwartz S, Hudgins L, Enns GM, Hoyme HE. Terminal 22q deletion syndrome: a newly recognized cause of speech and language disability in the autism spectrum. Pediatrics. 2004;114(2):451–457. doi: 10.1542/peds.114.2.451.
    1. Nesslinger NJ, Gorski JL, Kurczynski TW, Shapira SK, Siegel-Bartelt J, Dumanski JP, Cullen RF, Jr, French BN, McDermid HE. Clinical, cytogenetic, and molecular characterization of seven patients with deletions of chromosome 22q13.3. Am J Hum Genet. 1994;54(3):464–472.
    1. Phelan MC, Rogers RC, Saul RA, Stapleton GA, Sweet K, McDermid H, Shaw SR, Claytor J, Willis J, Kelly DP. 22q13 deletion syndrome. Am J Med Genet. 2001;101(2):91–99. doi: 10.1002/1096-8628(20010615)101:2<91::AID-AJMG1340>;2-C.
    1. Philippe A, Boddaert N, Vaivre-Douret L, Robel L, Danon-Boileau L, Malan V, de Blois MC, Heron D, Colleaux L, Golse B, Zilbovicius M, Munnich A. Neurobehavioral profile and brain imaging study of the 22q13.3 deletion syndrome in childhood. Pediatrics. 2008;122(2):e376–e382. doi: 10.1542/peds.2007-2584.
    1. Soorya L, Kolevzon A, Zweifach J, Lim T, Dobry Y, Schwartz L, Frank Y, Wang AT, Cai G, Parkhomenko E, Halpern D, Grodberg D, Angarita B, Willner JP, Yang A, Canitano R, Chaplin W, Betancur C, Buxbaum JD. Prospective investigation of autism and genotype-phenotype correlations in 22q13 deletion syndrome and SHANK3 deficiency. Molecular Autism. 2013;4(1):18. doi: 10.1186/2040-2392-4-18.
    1. Darnell JC. Defects in translational regulation contributing to human cognitive and behavioral disease. Curr Opin Genet Dev. 2011;21(4):465–473. doi: 10.1016/j.gde.2011.05.002.
    1. Sakai Y, Shaw CA, Dawson BC, Dugas DV, Al-Mohtaseb Z, Hill DE, Zoghbi HY. Protein interactome reveals converging molecular pathways among autism disorders. Sci Transl Med. 2011;3(86):86ra49. doi: 10.1126/scitranslmed.3002166.
    1. Bozdagi O, Sakurai T, Papapetrou D, Wang X, Dickstein DL, Takahashi N, Kajiwara Y, Yang M, Katz AM, Scattoni ML, Harris MJ, Saxena R, Silverman JL, Crawley JN, Zhou Q, Hof PR, Buxbaum JD. Haploinsufficiency of the autism-associated Shank3 gene leads to deficits in synaptic function, social interaction, and social communication. Molecular Autism. 2010;1(1):15. doi: 10.1186/2040-2392-1-15.
    1. Bozdagi O, Tavassoli T, Buxbaum JD. Insulin-like growth factor-1 rescues synaptic and motor deficits in a mouse model of autism and developmental delay. Mol Autism. 2013;4(1):9. doi: 10.1186/2040-2392-4-9.
    1. Marchetto MC, Carromeu C, Acab A, Yu D, Yeo GW, Mu Y, Chen G, Gage FH, Muotri AR. A model for neural development and treatment of Rett syndrome using human induced pluripotent stem cells. Cell. 2010;143(4):527–539. doi: 10.1016/j.cell.2010.10.016.
    1. Jou RJ, Mateljevic N, Kaiser MD, Sugrue DR, Volkmar FR, Pelphrey KA. Structural neural phenotype of autism: preliminary evidence from a diffusion tensor imaging study using tract-based spatial statistics. AJNR Am J Neuroradiol. 2011;32(9):1607–1613. doi: 10.3174/ajnr.A2558.
    1. Bakhtiari R, Zurcher NR, Rogier O, Russo B, Hippolyte L, Granziera C, Araabi BN, Nili Ahmadabadi M, Hadjikhani N. Differences in white matter reflect atypical developmental trajectory in autism: A Tract-based Spatial Statistics study. NeuroImage Clinical. 2012;1(1):48–56. doi: 10.1016/j.nicl.2012.09.001.
    1. Altman NR, Bernal B. Brain activation in sedated children: auditory and visual functional MR imaging. Radiology. 2001;221(1):56–63. doi: 10.1148/radiol.2211010074.
    1. Bernal B, Altman NR. Speech delay in children: a functional MR imaging study. Radiology. 2003;229(3):651–658. doi: 10.1148/radiol.2293021746.
    1. Ederberg S, Westerlind A, Houltz E, Svensson SE, Elam M, Ricksten SE. The effects of propofol on cerebral blood flow velocity and cerebral oxygen extraction during cardiopulmonary bypass. Anesth Analg. 1998;86(6):1201–1206.
    1. Aman MG, Singh NN, Stewart AW, Field CJ. The aberrant behavior checklist: a behavior rating scale for the assessment of treatment effects. Am J Ment Defic. 1985;89(5):485–491.
    1. Bodfish JW, Symons FJ, Parker DE, Lewis MH. Varieties of repetitive behavior in autism: comparisons to mental retardation. J Autism Dev Disord. 2000;30(3):237–243. doi: 10.1023/A:1005596502855.
    1. Mullen EM. Mullen Scales of Early Learning. Circle Pines, MN: American Guidance Service; 1995.
    1. Roid GH, Miller LJ. Leiter International Performance Scale-Revised. Wood Dale, IL: Stoelting Co.; 1997.
    1. Sparrow SS, Cicchetti DV, Balla DA. Vineland-II Survey Forms Manual (Vineland Adaptive Behavior Scales) 2. Minneapolis, MN: AGS Publishing; 2005.
    1. Lord C, Risi S, Lambrecht L, Cook EH, Jr, Leventhal BL, DiLavore PC, Pickles A, Rutter M. The Autism Diagnostic Observation Schedule-Generic: a standard measure of social and communication deficits associated with the spectrum of autism. J Autism Dev Disord. 2000;30(3):205–223. doi: 10.1023/A:1005592401947.
    1. Lord C, Rutter M, Le Couteur A. Autism Diagnostic Interview-Revised: a revised version of a diagnostic interview for caregivers of individuals with possible pervasive developmental disorders. J Autism Dev Disord. 1994;24(5):659–685. doi: 10.1007/BF02172145.
    1. American Psychiatric Association . Diagnostic and statistical manual of mental disorders. 5. Arlington, VA: American Psychiatric Publishing; 2013.
    1. Schmidt H, Kern W, Giese R, Hallschmid M, Enders A. Intranasal insulin to improve developmental delay in children with 22q13 deletion syndrome: an exploratory clinical trial. J Med Genet. 2009;46(4):217–222. doi: 10.1136/jmg.2008.062141.
    1. Pasini A, D’Agati E, Casarelli L, Curatolo P. Dose-dependent effect of risperidone treatment in a case of 22q13.3 deletion syndrome. Brain Dev. 2010;32(5):425–427. doi: 10.1016/j.braindev.2009.04.005.
    1. Guy W. U.S. Department of Health, Education, and Welfare, Public Health Service, Alcohol, Drug Abuse, and Mental Health Administration, NIMH Psychopharmacology Research Branch, Division of Extramural Research Programs. Rockville, MD: DHEW Publication Number ADM 76338; 1976. Assessment manual for psychopharmacology-revised; pp. 218–222.
    1. Betancur C, Buxbaum JD. SHANK3 haploinsufficiency: a ‘common’ but underdiagnosed highly penetrant monogenic cause of autism spectrum disorders. Mol Autism. 2013;4(1):17. doi: 10.1186/2040-2392-4-17.

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