Rescuing compounds for Lesch-Nyhan disease identified using stem cell-based phenotypic screening.

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.