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.
The goal of this Development Candidate Feasibility (DCF) Award project is to use pluripotent stem cells derived from Rett Syndrome (RTT) and patients with idiopathic autism to identify novel small molecule drugs to treat autism spectrum disorders (ASD). This project is based on the hypothesis that astrocytes, one of the main support cells in the central nervous system, play an important role in the formation and function of neural connections. Astrocytes will be obtained by in vitro differentiation of iPS cells derived from patients with ASD. The goal is to identify novel small molecule therapeutics for autism spectrum disorders based on screening for the correction of dysfunction in cultured astrocytes.
Objective and Milestones
- The proposed DCF award should lead to a Development Candidate if good hits are seen in the screen.
- The proposal has achievable and clearly laid out milestones. It was, however, noted that the success of the rest of the project is dependent on a successful completion of milestones in Aim 1, therefore making the project somewhat higher risk.
- The Target Product Profile is not well developed.
Rationale and Significance
- There is a significant unmet medical need to identify drugs that could be used to treat autism.
- The approach of targeting astrocytes as a means of altering neuronal behavior in ASD is logical.
- There was some concern expressed that drugs identified based on screening with Rett syndrome will not translate more broadly to ASD, since Rett Syndrome is no longer classified as ASD.
Feasibility and Design
- The research plan is well developed. This work represents a logical extension of the PI’s pioneering work developing in vitro model systems for neurologic disease.
- Preliminary data were viewed as strong, but not compelling.
- Reviewers were not clear on the selection of the particular cell characteristic being used for the primary screen, which was not drawn directly from the abnormal cellular properties described in the preliminary data and may not be clinically meaningful. This point combined with the fact that the primary screen could take two years to validate led reviewers to suggest the screening design might need to be reconsidered.
Qualification of the PI (Co-PI, Partner PI, if applicable) and Research Team
- The PI was praised for his/her excellent track record and prior success and published work in disease modeling.
- The Partner PI has a clear track record of therapeutic drug discovery.
- There was some concern expressed by reviewers regarding productivity on a current CIRM award.
Collaborations, Assets, Resources and Environment
- The collaboration between the PI and a Partner PI at a translational research center was praised as well conceived with complementary areas of expertise.
- The resources for the project are outstanding with appropriate institutional support for the project.
Responsiveness to the RFA
- This proposal is highly responsive to the RFA. It depends on disease-specific iPS cells from a disease affecting a pediatric population for which there is limited therapeutic options.