Global Collaboration Shared with Love Never Sinks
Current Worldwide Lesch-Nyhan Research
Around the world, researchers are working tirelessly to better understand Lesch-Nyhan disease and its variants. This page highlights current projects that have been brought to the attention of Love Never Sinks and shared directly by the researchers themselves. Our goal is to connect families, clinicians, and scientists, fostering a collaborative environment where discoveries are openly shared. Below you’ll find ongoing studies, project summaries, and contact information for researchers leading efforts to advance knowledge, treatment options, and hope for those living with Lesch-Nyhan.
Join or Share a Project
If you are a researcher or clinician currently studying Lesch-Nyhan disease or related HPRT1 variants, Love Never Sinks welcomes your collaboration. Please reach out through our Contact Form or email OutreachLNS@gmail.com to share your project details.
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Lead Researcher: Dr. Hyder A. Jinnah
Institution: Emory University, USA
Contact: hjinnah@emory.edu
Summary: The pathogenesis of neurodevelopmental disorders is challenging to address for many reasons. The human brain is relatively inaccessible for direct evaluation, human autopsy and imaging studies provide limited opportunities to study molecular or cellular mechanisms, animal models sometimes do not replicate important disease features, and immortalized neuron-like cell lines cannot be used to model normal development. Induced pluripotent stem cells (iPSCs) provide a powerful new experimental tool to address these limitations. They can be created from patients with known developmental disorders caused by defined mutations, they provide a renewable resource, and they can be differentiated into specific cell lineages to provide species-specific and lineage-specific experimental models to study developmental mechanisms at the cellular and molecular levels. In the current proposal we address several fundamental questions that are broadly relevant to iPSC modeling for neurodevelopmental disorders. We focus on Lesch-Nyhan disease (LND) as a prototype disorder, because it has numerous features that make it an unusually tractable Mendelian disorder for iPSC modeling. LND and its milder variants are caused by mutations in the HPRT1gene, resulting in deficiency of the purine salvage enzyme, hypoxanthine-guanine phosphoribosyltransferase (HGprt). The neurobehavioral abnormalities in this disorder have been linked with developmental dysfunction of brain dopamine neurons. Aim 1 focuses on establishing a well-characterized bank of iPSCs across the spectrum of disease severity, to address issues related to how specific mutations causing different disease severity are reflected in iPSC models. Aim 2 focuses on establishing a well-characterized bank of isogenic iPSCs in which specific mutations have been introduced via gene editing methods, to address issues related to the genetic background of individuals from which iPSC models are derived. In Aim 3 we differentiate these lines into dopamine neurons, to address how iPSC models can reveal the timing and mechanisms of pathogenesis related to LND. Overall, this project will address fundamental questions that are broadly relevant for iPSC modeling of neurodevelopmental disorders, as well as more specific insights into the pathogenesis of the neurobehavioral abnormalities of LND.
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Lead Researcher: Dr. Hyder A. Jinnah
Institution: Emory University, USA
Contact: hjinnah@emory.edu
Summary: Lesch-Nyhan disease (LND) is a neurodevelopmental disorder with a characteristic clinical phenotype that includes motor impairment resembling cerebral palsy, intellectual disability (mental retardation), difficult behaviors (severe self-injury and impulsivity), and overproduction of uric acid (leading to kidney stones and gout). LND is caused by pathological genetic variants in the HPRT1 gene, which encodes the purine salvage enzyme hypoxanthine-guanine phosphoribosyltransferase (HGprt). Over the past 20 years, great progress has been made in understanding the pathogenesis of the disease using cell models, animal models, and studies of human patients. These studies have indicated that the neurobehavioral abnormalities result in large part from dysfunction of midbrain dopamine neurons. These neurons do not die or show degenerative changes; they develop abnormally. The many preclinical advances have not been translated into clinical trials for LND for one major reason. This reason is that there is insufficient information regarding the developmental age at which interventions, such as restoration of HGprt, must be made. It is possible that intervention at any age could have a therapeutic effect by reversing functional metabolic defects responsible for arrested development or neuronal dysfunction. Alternatively, if HGprt deficiency causes irreversible defects during early development, then the intervention may have to occur at an early age to have any therapeutic value. The current proposal addresses this crucial question regarding the developmental window for intervention and rescue. We plan a three-tiered approach involving a novel cell model based on induced pluripotent stem cells (iPSCs), a novel Hprt1 conditional knockout mouse, and a unique bank of human LND brains collected at autopsy. The results will provide answers that address a major roadblock in translational efforts to rescue the phenotype of LND.