Grant Award Details
- The project objective is to develop a fluorescence-based drug screening assay for autism spectrum disorders (ASD). they are using iPSC lines derived from ASD patients and have described phenotypic abnormalities in ASD patient-derived iPSC-neurons relative to controls. They are developing a platform using those phenotypes to look for drugs to revert those phenotypes.
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Grant Application Details
- Developing a drug-screening system for Autism Spectrum Disorders using human neurons
Autism and autism spectrum disorders (ASD) are complex neurodevelopmental diseases that affect 1 in 150 children in the United States. Such diseases are mainly characterized by deficits in verbal communication, impaired social interaction, and limited and repetitive interests and behavior. Because autism is a complex spectrum of disorders, a different combination of genetic mutations is likely to play a role in each individual. One of the major impediments to ASD research is the lack of relevant human disease models. ASD animal models are limited and cannot reproduce the important language and social behavior impairment of ASD patients. Moreover, mouse models do not represent the vast human genetic variation. Reprogramming of somatic cells to a pluripotent state (induced pluripotent stem cells, iPSCs) has been accomplished using human cells. Isogenic pluripotent cells are attractive from the prospective to understanding complex diseases, such as ASD. Our preliminary data provide evidence for an unexplored developmental window in ASD wherein potential therapies could be successfully employed. The model recapitulates early stages of ASD and represents a promising cellular tool for drug screening, diagnosis and personalized treatment. By testing whether drugs have differential effects in iPSC-derived neurons from different ASD backgrounds, we can begin to unravel how genetic variation in ASD dictates responses to different drugs or modulation of different pathways. If we succeed, we may find new molecular mechanisms in ASD and new compounds that may interfere and rescue these pathways. The impact of this approach is significant, since it will help better design and anticipate results for translational medicine. Moreover, the collection and molecular/cellular characterization of these iPSCs will be an extremely valuable tool to understand the fundamental mechanism behind ASD. The current proposal uses human somatic cells converted into iPSC-derived neurons. The proposed experiments bring our analyses to real human cell models for the first time. We anticipate gaining insights into the causal molecular mechanisms of ASD and to discover potential biomarkers and specific therapeutic targets for ASD.
Autism spectrum disorders, including Rett syndrome, Angelman syndrome, Timothy syndrome, Fragile X syndrome, Tuberous sclerosis, Asperger syndrome or childhood disintegrative disorder, affect many Californian children. In the absence of a functionally effective cure or early diagnostic tool, the cost of caring for patients with such pediatric diseases is high, in addition to a major personal and family impact since childhood. The strikingly high prevalence of ASD, dramatically increasing over the past years, has led to the emotional view that ASD can be traced to a single source, such as vaccine, preservatives or other environmental factors. Such perspective has a negative impact on science and society in general. Our major goal is to develop a drug-screening platform to rescue deficiencies showed from neurons derived from induced pluripotent stem cells generated from patients with ASD. If successful, our model will bring novel insights on the dentification of potential diagnostics for early detection of ASD risk, or ability to predict severity of particular symptoms. In addition, the development of this type of pharmacological therapeutic approach in California will serve as an important proof of principle and stimulate the formation of businesses that seek to develop these types of therapies (providing banks of inducible pluripotent stem cells) in California with consequent economic benefit.
Publications
- EMBO Mol Med (2021) Pharmacological reversal of synaptic and network pathology in human MECP2-KO neurons and cortical organoids. (PubMed: 33501759)
- PLoS One (2019) Proteomic analyses reveal misregulation of LIN28 expression and delayed timing of glial differentiation in human iPS cells with MECP2 loss-of-function. (PubMed: 30789962)
- Sci Transl Med (2018) Survival of syngeneic and allogeneic iPSC-derived neural precursors after spinal grafting in minipigs. (PubMed: 29743351)
- Biochem Biophys Res Commun (2017) The L1 adhesion molecule normalizes neuritogenesis in Rett syndrome-derived neural precursor cells. (PubMed: 29050935)
- Adv Exp Med Biol (2017) TRPC Channels and Mental Disorders. (PubMed: 28508319)
- Hum Mol Genet (2016) Cockayne Syndrome-derived neurons display reduced synapse density and altered neural network synchrony. (PubMed: 26755826)
- Proc Natl Acad Sci U S A (2016) Layered hydrogels accelerate iPSC-derived neuronal maturation and reveal migration defects caused by MeCP2 dysfunction. (PubMed: 26944080)
- Mol Psychiatry (2016) Altered proliferation and networks in neural cells derived from idiopathic autistic individuals. (PubMed: 27378147)
- Nature (2016) A human neurodevelopmental model for Williams syndrome. (PubMed: 27509850)
- Hum Mol Genet (2016) IGF1 neuronal response in the absence of MECP2 is dependent on TRalpha 3. (PubMed: 28007906)
- Neuroscience (2015) Altered iPSC-derived neurons' sodium channel properties in subjects with Monge's disease. (PubMed: 25559931)
- Sci Rep (2015) Systematic optimization of human pluripotent stem cells media using Design of Experiments. (PubMed: 25940691)
- Neurotherapeutics (2015) The Use of Induced Pluripotent Stem Cell Technology to Advance Autism Research and Treatment. (PubMed: 25851569)
- Biol Psychiatry (2015) The Human Model: Changing Focus on Autism Research. (PubMed: 25861701)
- Mol Psychiatry (2015) Altered neuronal network and rescue in a human MECP2 duplication model. (PubMed: 26347316)
- Mol Psychiatry (2014) Modeling non-syndromic autism and the impact of TRPC6 disruption in human neurons. (PubMed: 25385366)
- Nat Neurosci (2014) Polyglutamine-expanded androgen receptor interferes with TFEB to elicit autophagy defects in SBMA. (PubMed: 25108912)
- Biol Psychiatry (2013) Novel Tools, Classic Techniques: Evolutionary Studies Using Primate Pluripotent Stem Cells. (PubMed: 24041506)
- Stem Cell Res (2013) Astroglial cells regulate the developmental timeline of human neurons differentiated from induced pluripotent stem cells. (PubMed: 23759711)
- Curr Opin Neurobiol (2012) Modeling neurodevelopmental disorders using human neurons. (PubMed: 22717528)
- Exp Neurol (2012) Stem cells and modeling of autism spectrum disorders. (PubMed: 23036599)
- J Neurosci (2011) Cellular Reprogramming: Recent Advances in Modeling Neurological Diseases. (PubMed: 22072658)