ArticleJCI insight2020
Rescuing compounds for Lesch-Nyhan disease identified using stem cell-based phenotypic screening.
Article in JCI insight, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 15 papers.
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Who cites it
15 citing papers in PubMed, 29 citations in OpenAlex.
- Changes in Purine Metabolism During Differentiation of Dopamine Neurons from Human Induced Pluripotent Stem Cells.Cellular and molecular neurobiology · 2026Article
- Umbilical Cord Blood Transplantation in Lesch-Nyhan Syndrome: A Case Report and Literature Review.Cureus · 2025Article
- Gene Expression Analysis of HPRT-Deficient Cells Maintained with Physiological Levels of Folic Acid.Cells · 2025Article
- Current Applications of Human Pluripotent Stem Cells in Neuroscience Research and Cell Transplantation Therapy for Neurological Disorders.Stem cell reviews and reports · 2025Review
- The Role of Purine Metabolism and Uric Acid in Postnatal Neurologic Development.Molecules (Basel, Switzerland) · 2025Review
- Case report: Whole exome sequencing identifies a novel variant in theFrontiers in genetics · 2025Article
- Article
- Trichostatin A for Efficient CRISPR-Cas9 Gene Editing of Human Pluripotent Stem Cells.The CRISPR journal · 2023Article
- Identification of signaling pathways modifying human dopaminergic neuron development using a pluripotent stem cell-based high-throughput screening automated system: purinergic pathways as a proof-of-principle.Frontiers in pharmacology · 2023Article
- Functional genomics in stem cell models: considerations and applications.Frontiers in cell and developmental biology · 2023Review
- Inborn errors of metabolism: Lessons from iPSC models.Reviews in endocrine & metabolic disorders · 2021Review
- Contribution of Human Pluripotent Stem Cell-Based Models to Drug Discovery for Neurological Disorders.Cells · 2021Review
- Induced pluripotent stem cells from subjects with Lesch-Nyhan disease.Scientific reports · 2021Article
- Human Embryo Models and Drug Discovery.International journal of molecular sciences · 2021Review
- Application of CRISPR/Cas9 to human-induced pluripotent stem cells: from gene editing to drug discovery.Human genomics · 2020Review
Corrections and comments
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Authors and funding
9 authors at 2 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
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.
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Registered trials
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