Using genetic findings in autism for the development of new pharmaceutical compounds
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The main reason for the current lack of effective treatments for the core symptoms of autism is our limited understanding of the biological mechanisms underlying this heterogeneous group of disorders. A primary value of genetic research is enhancing our insight into the biology of autism through the study of identified autism risk genes.
In the current review we discuss (1) the genes and loci that are associated with autism, (2) how these provide us with essential cues as to what neurobiological mechanisms may be involved, and (3) how these mechanisms may be used as targets for novel treatments. Next, we provide an overview of currently ongoing clinical trials registered at clinicaltrials.gov with a variety of compounds. Finally, we review current approaches used to translate knowledge derived from gene discovery into novel pharmaceutical compounds and discuss their pitfalls and problems.
An increasing number of genetic variants associated with autism have been identified. This will generate new ideas about the biological mechanisms involved in autism, which in turn may provide new leads for the development of novel pharmaceutical compounds. To optimize this pipeline of drug discovery, large-scale international collaborations are needed for gene discovery, functional validation of risk genes, and improvement of clinical outcome measures and clinical trial methodology in autism.
KeywordsAutism Genes Neurobiology Pharmaceutical compounds Biomarker
The research of EU-AIMS receives support from the Innovative Medicines Initiative Joint Undertaking under grant agreement no. 115300, the resources of which are composed of financial contribution from the European Union's Seventh Framework Programme (FP7/2007-2013), from the EFPIA companies in kind contribution and from Autism Speaks.
Conflicts of interest
WS, SA, and RJ are employed by F. Hoffmann-La Roche. DC is employed by Eli Lilly & Co. JB has been in the past 3 years a consultant to/member of advisory board of and/or speaker for Janssen Cilag BV, Eli Lilly, Shire, Novartis, Roche, and Servier. He is not an employee of any of these companies and not a stock shareholder of any of these companies. He has no other financial or material support, including expert testimony, patents, and royalties. None of the remaining authors have declared any conflict of interest.
- Ameis SH, Szatmari P (2012) Imaging-genetics in autism spectrum disorder: advances, translational impact, and future directions. Front Psychiat 3:46Google Scholar
- American Psychiatric Association (2013) Diagnostic and statistical manual of mental disorders, fifth edition. American Psychiatric Publishing, ArlingtonGoogle Scholar
- Blankenberg D et al (2010) Galaxy: a web-based genome analysis tool for experimentalists. Chapter 19. Unit 19. Curr Protoc Mol Biol 10:1–21Google Scholar
- Calfa G, Percy AK, Pozzo-Miller L (2011) Experimental models of Rett syndrome based on Mecp2 dysfunction. Exp Biol Med (Maywood) 236(3–19)Google Scholar
- Ehninger D (2013) From genes to cognition in tuberous sclerosis: implications for mTOR inhibitor-based treatment approaches. Neuropharmacology 68:97–105Google Scholar
- Fox RJ (2010) Methods, systems and software for identifying functional biomolecules. US Patent 7,747,393 B2 (Maxygen, Inc.)Google Scholar
- Frith U (1991) Autism and Asperger syndrome. Cambridge University Press, CambridgeGoogle Scholar
- Gustafsson C, Govindarajan S, Emig RA, Fox RJ, Roy AK, Minshull JS, Davis C, Cox AR, Patten PA, Castle LA, Siehl DL, Gorton RL, Chen T (2010) Methods, systems and software for identifying functional biomolecules. Maxygen, Inc., Redwood CityGoogle Scholar
- Jacquemont S et al (2011) Epigenetic modification of the FMR1 gene in fragile X syndrome is associated with differential response to the mGluR5 antagonist AFQ056. Sci Transl Med 3:64Google Scholar
- Lancaster MA et al (2013) Cerebral organoids model human brain development and microcephaly. Nature 501:373–379Google Scholar
- Lucht MJ et al (2009) Associations between the oxytocin receptor gene (OXTR) and affect, loneliness and intelligence in normal subjects. Prog Neuropsychopharmacol Biol Psychiat 33:860–866Google Scholar
- Poelmans GFB, Glennon J, Pauls DL, Buitelaar JK (2013) AKAPs integrate genome-wide association findings for autism spectrum disorders into signalling networks regulating steroidogenesis, neurite outgrowth and synaptic function. Translational Psychiatry 3(6):e270Google Scholar
- Su T et al (2011) Early continuous inhibition of group 1 mGlu signaling partially rescues dendritic spine abnormalities in the Fmr1 knockout mouse model for fragile X syndrome. Psychopharmacology (Berl) 215:291–300Google Scholar
- Vorstman JA et al (2006) Identification of novel autism candidate regions through analysis of reported cytogenetic abnormalities associated with autism. Mol Psychiatry 11(1):18–28Google Scholar
- Vorstman JA et al (2013) No evidence that common genetic risk variation is shared between schizophrenia and autism. Am J Med Genet B Neuropsychiatr Genet 162:55–60Google Scholar
- Walsh KS et al (2013) Symptomatology of autism spectrum disorder in a population with neurofibromatosis type 1. Dev Med Child Neurol 55(2):131–138Google Scholar