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Updated: Dec 29, 2025
Using Human Induced Pluripotent Stem Cell-derived Hepatocyte-like Cells for Drug Discovery
Published on: May 19, 2018
Rescuing compounds for Lesch-Nyhan disease identified using stem cell-based phenotypic screening
Valentin Ruillier1,2,3, Johana Tournois1, Claire Boissart1
1CECS.
Abstract:
Lesch-Nyhan disease (LND) is a rare monogenic disease caused by deficiency of the salvage pathway enzyme hypoxanthine-guanine phosphoribosyltransferase (HGPRT). LND is characterized by severe neuropsychiatric symptoms that currently cannot be treated. Predictive in vivo models are lacking for screening and evaluating candidate drugs because LND-associated neurological symptoms are not recapitulated in HGPRT-deficient animals. Here, we used human neural stem cells and neurons derived from induced pluripotent stem cells (iPSCs) of children affected with LND to identify neural phenotypes of interest associated with HGPRT deficiency to develop a target-agnostic-based drug screening system. We screened more than 3000 molecules and identified 6 pharmacological compounds, all possessing an adenosine moiety, that corrected HGPRT deficiency-associated neuronal phenotypes by promoting metabolism compensations in an HGPRT-independent manner. This included S-adenosylmethionine, a compound that had already been used as a compassionate approach to ease the neuropsychiatric symptoms in LND. Interestingly, these compounds compensate abnormal metabolism in a manner complementary to the gold standard allopurinol and can be provided to patients with LND via simple food supplementation. This experimental paradigm can be easily adapted to other metabolic disorders affecting normal brain development and functioning in the absence of a relevant animal model.
Insights
Lesch-Nyhan disease (LND) drug discovery is advanced by a new screening system using patient-derived neurons. Six compounds, including S-adenosylmethionine, show promise for treating LND
Area of Science:
- Neuroscience
- Genetics
- Biochemistry
Background:
- Lesch-Nyhan disease (LND) is a rare genetic disorder caused by hypoxanthine-guanine phosphoribosyltransferase (HGPRT) deficiency.
- LND presents severe, untreatable neuropsychiatric symptoms, and lacks predictive animal models for drug development.
Purpose of the Study:
- To develop a target-agnostic drug screening system for LND using patient-derived neural cells.
- To identify novel therapeutic compounds that can correct HGPRT deficiency-associated neuronal phenotypes.
Main Methods:
- Utilized human neural stem cells and induced pluripotent stem cell (iPSC)-derived neurons from LND patients.
- Screened over 3000 molecules to identify compounds that ameliorate HGPRT deficiency-related neural phenotypes.
- Assessed compounds for their ability to compensate for abnormal metabolism independently of HGPRT activity.
Main Results:
- Identified 6 pharmacological compounds, all containing an adenosine moiety, that corrected LND-associated neuronal phenotypes.
- S-adenosylmethionine was among the identified compounds, known for compassionate use in LND symptom management.
- The identified compounds demonstrated complementary metabolic compensation to allopurinol and can be administered via food supplementation.
Conclusions:
- Developed a novel in vitro screening platform for LND using patient-derived iPSC neurons.
- Discovered adenosine-based compounds that offer a potential therapeutic strategy for LND by promoting compensatory metabolism.
- The established experimental paradigm is adaptable for studying other metabolic disorders impacting brain development and function.
