Small Molecule Modulators of Lithium for Treatment of Fragile X Syndrome

With a $219,500 grant from FRAXA Research Foundation, Dr. Stephen Haggarty from Havard/MIT developed a high-throughput drug screen to find compounds that inhibit GSK3, a critical enzyme in Fragile X. He looked for compounds that can accomplish this either alone or in combination with lithium, offering the possibility of enhancing the effectiveness of lithium as a treatment. His drug screen used patient-specific neural progenitor (NP) cells derived from human induced pluripotent stem cells (iPSCs) – which are created from cells in a skin biopsy from people with Fragile X syndrome (FXS) and other autism spectrum disorders.

Stephen Haggarty, PhD, Harvard/MIT, Principal Investigator, FRAXA research grant
$219,500 Grant
Stephen Haggarty, PhD
Principal Investigator
Havard/MIT
2008-2010 FRAXA Research Grant
$219,500 over 3 Years

Chemical genomics is a translational research strategy that aims to develop small-molecule therapeutics for human genetic disorders based upon a molecular understanding of disease etiology and pathophysiology. One limitation for the development of new mechanism of action therapeutics has been access to cell models that capture the complexity of human genetic variation associated with disease. However, recent advances in the field of stem cell biology enabled the generation of genetically accurate cellular models of human diseases and the differentiation of these stem cells into defined cell types of the human body, including neurons and glia.

To take advantage of these advances for the study of FXS, we established and were validating a process for the generation of self-renewing, patient-specific neural progenitor (NP) cells derived from human induced pluripotent stem cells (iPSCs) created from fibroblasts from patients with Fragile X syndrome (FXS) and other autism spectrum disorders. The ability to derive genetically accurate iPSC-NP cells lines from readily accessible patient cells available through existing cell repositories and collected from fresh patient skin biopsies facilitated the elucidation of potential inter-patient variability and the influence of factors such as CGG repeat length and other genetic modifiers of FXS.

The overall goal of our project was to develop, characterize, and use a panel of iPSC-NP cells as a platform for chemical genomic characterization of small molecules targeting pathways implicated in FXS pathology. Based upon recent studies from the labs of Jope, Bauchwitz, as well as others, our particular interest was in the role that dysregulation of the kinase glycogen synthase kinase 3 (GSK-3) may play in FXS and other disorders with neuropsychiatric symptoms. On the basis of these findings, we proposed to pilot the use of iPSC-NP cells to study FXS by testing the effects of small molecules targeting the GSK-3/b-catenin pathway. We implemented a miniaturized culture system using iPSC-NP cells and are developing image-based assays measuring neural cell morphology, differentiation, and GSK-3/b-catenin signaling as well as transcriptional reporters to measure GSK-3 signaling. We used these assays to look for disease-associated phenotypic differences.

Upon completion of these studies we expected to have identified small molecules that can be tested in other models of FXS for their ability to ameliorate molecular and behavioral symptoms of FXS. These studies may help identify novel targets for the development of therapeutics for the treatment and cure of FXS.

Results published: Full Text of article

Surya Reis, PhD
FRAXA Postdoctoral Fellow

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