Drug discovery for autism spectrum disorder: Challenges and opportunities

Nature Reviews Drug Discovery

Volumn 12, Issue 10, 2013, Pages 777-790

  Ghosh, Anirvan ^a   Michalon, Aubin ^a,b   Lindemann, Lothar ^a   Fontoura, Paulo ^a   Santarelli, Luca ^a  

^a Pharma Research and Early Development   (Switzerland)

^b Neurimmune Therapeutics   (Switzerland)

Author keywords

[No Author keywords available]

Indexed keywords

ARBACLOFEN; CHEMICAL COMPOUND; EVEROLIMUS; LITHIUM; MAVOGLURANT; MINOCYCLINE; NEW MOLECULAR ENTITY; PLACEBO; RAPAMYCIN; UNCLASSIFIED DRUG;

AUTISM; CONCEPTUAL FRAMEWORK; DISEASE MODEL; DRUG ANALYSIS; DRUG DEVELOPMENT; DRUG INDUSTRY; DRUG SCREENING; DRUG TARGETING; FRAGILE X SYNDROME; GENE MUTATION; HUMAN; IN VITRO STUDY; IN VIVO STUDY; NONHUMAN; PATHOPHYSIOLOGY; PLURIPOTENT STEM CELL; PRIORITY JOURNAL; REVIEW; TUBEROUS SCLEROSIS;

ANIMALS; CHILD; CHILD DEVELOPMENT DISORDERS, PERVASIVE; CLINICAL TRIALS AS TOPIC; COOPERATIVE BEHAVIOR; DISEASE MODELS, ANIMAL; DRUG DESIGN; DRUG DISCOVERY; DRUG INDUSTRY; HUMANS; MOLECULAR TARGETED THERAPY;

EID: 84885015079     PISSN: 14741776     EISSN: 14741784     Source Type: Journal    
DOI: 10.1038/nrd4102     Document Type: Review

References (86)

1. Kanner, L. Autistic disturbances of affective contact. Nerv. Child. 2, 217-250 (1943).
2. Asperger, H. The psychically abnormal child, Wien Klin. Wochenschr. 51, 1314-1317 (1938).
3. Centers for Disease Control and Prevention. Prevalence of autism spectrum disorders - Autism and Developmental Disabilities Monitoring Network, 14 sites, United States, 2008. MMWR Surveill. Summ. 61, 1-19 (2012).
4. Politte, L. C. & McDougle, C. J. Atypical antipsychotics in the treatment of children and adolescents with pervasive developmental disorders. Psychopharmacology (Berl). 2013 (dx.http://dx.doi. org/10.1007/s00213-013-3068- y).
5. Ehninger, D. et al. Reversal of learning deficits in a Tsc2 mouse model of tuberous sclerosis. Nature Med. 14, 843-848 (2008).
6. Michalon, A. et al. Chronic pharmacological mGlu5 inhibition corrects fragile X in adult mice. Neuron 74, 49-56 (2012).
7. Costa, R. M. et al. Mechanism for the learning deficits in a mouse model of neurofibromatosis type 1. Nature 415, 526-530 (2002).
8. Tropea, D. et al. Partial reversal of Rett syndrome-like symptoms in MeCP2 mutant mice. Proc. Natl Acad. Sci. USA 106, 2029-2034 (2009).
9. Meikle, L. et al. Response of a neuronal model of tuberous sclerosis to mammalian target of rapamycin (mTOR) inhibitors: effects on mTORC1 and Akt signaling lead to improved survival and function. J. Neurosci. 28, 5422-5432 (2008).
10. Ronald, A. & Hoekstra, R. A. Autism spectrum disorders and autistic traits: a decade of new twin studies. Am. J. Med. Genet. B Neuropsychiatr. Genet. 156B, 255-274 (2011).
11. Kumar, R. A. & Christian, S. L. Genetics of autism spectrum disorders. Curr. Neurol. Neurosci. Rep. 9, 188-197 (2009).
12. Betancur, C. Etiological heterogeneity in autism spectrum disorders: more than 100 genetic and genomic disorders and still counting. Brain Res. 1380, 42-77 (2011).
13. Marshall, C. R. & Scherer, S. W. Detection and characterization of copy number variation in autism spectrum disorder. Methods Mol. Biol. 838, 115-135 (2012).
14. Kong, A. et al. Rate of de novo mutations and the importance of father's age to disease risk. Nature 488, 471-475 (2012).
15. Gibson, G. Rare and common variants: twenty arguments. Nature Rev. Genet. 13, 135-145 (2012).
16. Barabasi, A. L., Gulbahce, N. & Loscalzo, J. Network medicine: a network-based approach to human disease. Nature Rev. Genet. 12, 56-68 (2011).
17. Peca, J. & Feng, G. Cellular and synaptic network defects in autism. Curr. Opin. Neurobiol. 22, 866-872 (2012).
18. Etherton, M. R., Tabuchi, K., Sharma, M., Ko, J. & Sudhof, T. C. An autism-associated point mutation in the neuroligin cytoplasmic tail selectively impairs AMPA receptor-mediated synaptic transmission in hippocampus. EMBO J. 30, 2908-2919 (2011).
19. Etherton, M. et al. Autism-linked neuroligin-3 R451C mutation differentially alters hippocampal and cortical synaptic function. Proc. Natl Acad. Sci. USA 108, 13764-13769 (2011).
20. Kelleher, R. J., 3rd & Bear, M. F. The autistic neuron: troubled translation? Cell 135, 401-406 (2008).
21. van Bokhoven, H. Genetic and epigenetic networks in intellectual disabilities. Annu. Rev. Genet. 45, 81-104 (2011).
22. Schneider, A., Hagerman, R. J. & Hessl, D. Fragile X syndrome - from genes to cognition. Dev. Disabil Res. Rev. 15, 333-342 (2009).
23. Krueger, D. D. & Bear, M. F. Toward fulfilling the promise of molecular medicine in fragile X syndrome. Annu. Rev. Med. 62, 411-429 (2011).
24. Dölen, G. et al. Correction of fragile X syndrome in mice. Neuron 56, 955-962 (2007).
25. Hur, E. M. & Zhou, F. Q. GSK3 signalling in neural development. Nature Rev. Neurosci. 11, 539-551 (2010).
26. Bilousova, T. V. et al. Minocycline promotes dendritic spine maturation and improves behavioural performance in the fragile X mouse model. J. Med. Genet. 46, 94-102 (2009).
27. Yuskaitis, C. J. et al. Lithium ameliorates altered glycogen synthase kinase-3 and behavior in a mouse model of fragile X syndrome. Biochem. Pharmacol. 79, 632-646 (2010).
28. Mines, M. A., Yuskaitis, C. J., King, M. K., Beurel, E. & Jope, R. S. GSK3 influences social preference and anxiety-related behaviors during social interaction in a mouse model of fragile X syndrome and autism. PLoS ONE 5, e9706 (2010).
29. Paluszkiewicz, S. M., Martin, B. S. & Huntsman, M. M. Fragile X syndrome: the GABAergic system and circuit dysfunction. Dev. Neurosci. 33, 349-364 (2011).
30. Henderson, C. et al. Reversal of disease-related pathologies in the fragile X mouse model by selective activation of GABAB receptors with arbaclofen. Sci. Transl. Med. 4, 152ra128 (2012).
31. Curatolo, P., Bombardieri, R. & Jozwiak, S. Tuberous sclerosis. Lancet 372, 657-668 (2008).
32. Tavazoie, S. F., Alvarez, V. A., Ridenour, D. A., Kwiatkowski, D. J. & Sabatini, B. L. Regulation of neuronal morphology and function by the tumor suppressors Tsc1 and Tsc2. Nature Neurosci. 8, 1727-1734 (2005).
33. Meikle, L. et al. A mouse model of tuberous sclerosis: neuronal loss of Tsc1 causes dysplastic and ectopic neurons, reduced myelination, seizure activity, and limited survival. J. Neurosci. 27, 5546-5558 (2007).
34. Davies, D. M. et al. Sirolimus therapy for angiomyolipoma in tuberous sclerosis and sporadic lymphangioleiomyomatosis: a phase 2 trial. Clin. Cancer Res. 17, 4071-4081 (2011).
35. Bissler, J. J. et al. Sirolimus for angiomyolipoma in tuberous sclerosis complex or lymphangioleiomyomatosis. N. Engl. J. Med. 358, 140-151 (2008).
36. Dabora, S. L. et al. Multicenter phase 2 trial of sirolimus for tuberous sclerosis: kidney angiomyolipomas and other tumors regress and VEGF- D levels decrease. PLoS ONE 6, e23379 (2011).
37. Silverman, J. L. et al. Negative allosteric modulation of the mGluR5 receptor reduces repetitive behaviors and rescues social deficits in mouse models of autism. Sci. Transl. Med. 4, 131ra51 (2012).
38. Auerbach, B. D., Osterweil, E. K. & Bear, M. F. Mutations causing syndromic autism define an axis of synaptic pathophysiology. Nature 480, 63-68 (2011).
39. Spooren, W., Lindemann, L., Ghosh, A. & Santarelli, L. Synapse dysfunction in autism: a molecular medicine approach to drug discovery in neurodevelopmental disorders. Trends Pharm. Sci 33, 669-684 (2012).
40. Mabb, A. M., Judson, M. C., Zylka, M. J. & Philpot, B. D. Angelman syndrome: insights into genomic imprinting and neurodevelopmental phenotypes. Trends Neurosci. 34, 293-303 (2012).
41. Kim, J. E. et al. Investigating synapse formation and function using human pluripotent stem cell-derived neurons. Proc. Natl Acad. Sci. USA 108, 3005-3010 (2011).
42. Dimos, J. T. et al. Induced pluripotent stem cells generated from patients with ALS can be differentiated into motor neurons. Science 321, 1218-1221 (2008).
43. Marchetto, M. C. et al. A model for neural development and treatment of Rett syndrome using human induced pluripotent stem cells. Cell 143, 527-539 (2010).
44. Pasca, S. P. et al. Using iPSC-derived neurons to uncover cellular phenotypes associated with Timothy syndrome. Nature Med. 17, 1657-1662 (2011).
45. McFarlane, H. G. et al. Autism-like behavioral phenotypes in BTBR T? mice. Genes Brain Behav. 7, 152-163 (2008).
46. Roullet, F. I., Lai, J. K. & Foster, J. A. In utero exposure to valproic acid and autism - a current review of clinical and animal studies. Neurotoxicol. Teratol. 36, 47-56 (2013).
47. Silverman, J. L., Yang, M., Lord, C. & Crawley, J. N. Behavioural phenotyping assays for mouse models of autism. Nature Rev. Neurosci. 11, 490-502 (2010).
48. Crawley, J. N. Translational animal models of autism and neurodevelopmental disorders. Dialogues Clin. Neurosci. 14, 293-305 (2012).
49. Scattoni, M. L., Ricceri, L. & Crawley, J. N. Unusual repertoire of vocalizations in adult BTBR T? mice during three types of social encounters. Genes Brain Behav. 10, 44-56 (2011).
50. Young, D. M., Schenk, A. K., Yang, S. B., Jan, Y. N. & Jan, L. Y. Altered ultrasonic vocalizations in a tuberous sclerosis mouse model of autism. Proc. Natl Acad. Sci. USA 107, 11074-11079 (2010).
51. Roy, S., Watkins, N. & Heck, D. Comprehensive analysis of ultrasonic vocalizations in a mouse model of fragile X syndrome reveals limited, call type specific deficits. PLoS ONE 7, e44816 (2012).
52. Rotschafer, S. E., Trujillo, M. S., Dansie, L. E., Ethell, I. M. & Razak, K. A. Minocycline treatment reverses ultrasonic vocalization production deficit in a mouse model of fragile X syndrome. Brain Res. 1439, 7-14 (2012).
53. Constantino, J. N. et al. The factor structure of autistic traits. J. Child Psychol. Psychiatry 45, 719-726 (2004).
54. Jacquemont, S. et al. Epigenetic modification of the FMR1 gene in fragile X syndrome is associated with differential response to the mGluR5 antagonist AFQ056. Sci. Transl. Med. 3, 64ra1 (2011).
55. Berry-Kravis, E. M. et al. Effects of STX209 (arbaclofen) on neurobehavioral function in children and adults with fragile X syndrome: a randomized, controlled, Phase 2 trial. Sci. Transl. Med. 4, 152ra127 (2012).
56. Berry-Kravis, E. et al. Open-label treatment trial of lithium to target the underlying defect in fragile X syndrome. J. Dev. Behav. Pediatr. 29, 293-302 (2008).
57. Paribello, C. et al. Open-label add-on treatment trial of minocycline in fragile X syndrome. BMC Neurol. 10, 91 (2010).
58. Leigh, M. J. et al. A randomized double-blind, placebo-controlled trial of minocycline in children and adolescents with fragile X syndrome. J. Dev. Behav. Pediatr. 34, 147-155 (2013).
59. Pelphrey, K. A., Shultz, S., Hudac, C. M. & Vander Wyk, B. C. Research review: Constraining heterogeneity: the social brain and its development in autism spectrum disorder. J. Child Psychol. Psychiatry 52, 631-644 (2011).
60. Farzin, F., Scaggs, F., Hervey, C., Berry-Kravis, E. & Hessl, D. Reliability of eye tracking and pupillometry measures in individuals with fragile X syndrome. J. Autism Dev. Disord. 41, 1515-1522 (2011).
61. Zink, C. F. & Meyer-Lindenberg, A. Human neuroimaging of oxytocin and vasopressin in social cognition. Horm. Behav. 61, 400-409 (2012).
62. Andari, E. et al. Promoting social behavior with oxytocin in high-functioning autism spectrum disorders. Proc. Natl Acad. Sci. USA 107, 4389-4394 (2010).
63. Sansone, S. M. et al. Psychometric study of the aberrant behavior checklist in fragile X syndrome and implications for targeted treatment. J. Autism Dev. Disord. 42, 1377-1392 (2012).
64. Veenstra-VanderWeele, J. et al. Randomized, controlled, Phase 2 trial of STX209 for social function in ASD. International Society for Autism Research [online], https://imfar.confex.com/imfar/2013/webprogram/Paper15177.html (2013).
65. Chakrabarti, S. & Fombonne, E. Pervasive developmental disorders in preschool children: confirmation of high prevalence. Am. J. Psychiatry 162, 1133-1141 (2005).
66. Simonoff, E. et al. Psychiatric disorders in children with autism spectrum disorders: prevalence, comorbidity, and associated factors in a population-derived sample. J. Am. Acad. Child Adolesc. Psychiatry 47, 921-929 (2008).
67. Mattila, M. L. et al. Comorbid psychiatric disorders associated with Asperger syndrome/high-functioning autism: a community- and clinic-based study. J. Autism Dev. Disord. 40, 1080-1093 (2010).
68. Boyd, B. A. et al. Sensory features and repetitive behaviors in children with autism and developmental delays. Autism Res. 3, 78-87 (2010).
69. Chez, M. G. et al. Frequency of epileptiform EEG abnormalities in a sequential screening of autistic patients with no known clinical epilepsy from 1996 to 2005. Epilepsy Behav. 8, 267-271 (2006).
70. Buie, T. et al. Evaluation, diagnosis, and treatment of gastrointestinal disorders in individuals with ASDs: a consensus report. Pediatrics 125 (Suppl. 1), 1-18 (2010).
71. Stefanatos, G. A. Regression in autistic spectrum disorders. Neuropsychol. Rev. 18, 305-319 (2008).
72. Fombonne, E. Epidemiology of pervasive developmental disorders. Pediatr. Res. 65, 591-598 (2009).
73. Goldman, M. The innovative medicines initiative: a European response to the innovation challenge. Clin. Pharmacol. Ther. 91, 418-425 (2012).
74. Laverty, H., Gunn, M. & Goldman, M. Improving R&D productivity of pharmaceutical companies through public-private partnership: experiences from the Innovative Medicines Initiative. Expert Rev. Pharmacoecon. Outcomes Res. 12, 545-548 (2012).
75. Murphy, D. & Spooren, W. EU-AIMS: a boost to autism research. Nature Rev. Drug Discov. 11, 815-816 (2012).
76. Klei, L. et al. Common genetic variants, acting additively, are a major source of risk for autism. Mol. Autism 3, 9 (2012).
77. Neale, B. M. et al. Patterns and rates of exonic de novo mutations in autism spectrum disorders. Nature 485, 242-245 (2012).
78. Michaelson, J. J. et al. Whole-genome sequencing in autism identifies hot spots for de novo germline mutation. Cell 151, 1431-1442 (2012).
79. Manolio, T. A. et al. Finding the missing heritability of complex diseases. Nature 461, 747-753 (2009).
80. Girirajan, S. et al. Phenotypic heterogeneity of genomic disorders and rare copy-number variants. N. Engl. J. Med. 367, 1321-1331 (2012).
81. Ollikainen, M. & Craig, J. M. Epigenetic discordance at imprinting control regions in twins. Epigenomics 3, 295-306 (2011).
82. McCarthy, M. I. et al. Genome-wide association studies for complex traits: consensus, uncertainty and challenges. Nature Rev. Genet. 9, 356-369 (2008).
83. Betancur, C., Sakurai, T. & Buxbaum, J. D. The emerging role of synaptic cell-adhesion pathways in the pathogenesis of autism spectrum disorders. Trends Neurosci. 32, 402-412 (2009).
84. Franceschini, A. et al. STRING v9.1: protein-protein interaction networks, with increased coverage and integration. Nucleic Acids Res. 41, D808-D815 (2013).
85. Darnell, J. C. et al. FMRP stalls ribosomal translocation on mRNAs linked to synaptic function and autism. Cell 146, 247-261 (2011).
86. Saito, R. et al. A travel guide to Cytoscape plugins. Nature Methods 9, 1069-1076 (2012).