Grant Award Details
- This project is a CFP collaboration between Muotri and the Ferrer lab at NIH which is part of the NCATS and has expertise in high throughput screening technologies. The project is examining astrocyte dysfunction in autism spectrum disorders (ASDs) and specifically Rett syndrome (RTT). They are using iPSCs from RTT and control patients to differentiate astrocytes and look for phenotypic differences that could be used to screen for drugs and therapeutics that can rescue the cellular and molecular readouts.
Grant Application Details
- A drug-screening platform for autism spectrum disorders using human astrocytes
Autism spectrum disorders (ASD) are complex neurodevelopmental diseases that affect about 1% of 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. The causes and best treatments remain uncertain. One of the major impediments to ASD research is the lack of relevant human disease models. 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. The main goal of this project is to accelerate drug discovery to treat ASD using astrocytes generated from human iPSC. 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 astrocytes, we can begin to unravel how genetic variation in ASD dictates responses to different drugs. Insights that emerge from our studies may drive the development of new therapeutic interventions for ASD. They may also illuminate possible differences in drug responsiveness in different patients and potentially define a molecular signature resulting from ASD variants, which could predict the onset of disease before symptoms are seen.
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 brain cells 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.
- 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)
- Transl Psychiatry (2017) Modeling anorexia nervosa: transcriptional insights from human iPSC-derived neurons. (PubMed: 28291261)
- Neurogenesis (Austin) (2017) Modeling Williams syndrome with induced pluripotent stem cells. (PubMed: 28229087)
- Proc Natl Acad Sci U S A (2016) KCC2 rescues functional deficits in human neurons derived from patients with Rett syndrome. (PubMed: 26733678)
- 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)
- Brain Res (2016) Modeling autism spectrum disorders with human neurons. (PubMed: 26854137)
- 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)
- J Cell Sci (2016) Bradykinin promotes neuron-generating division of neural progenitor cells through ERK activation. (PubMed: 27528403)
- 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)