Research Lab

Pathogenicity mechanism and gene therapy of neurodegenerative disorder

Hereditary spastic paraplegia (HSP) are a group of neurological disorders characterized by upper motor neuron (UMN) degeneration, leading to spasticity and weakness in the lower extremities. Currently, there is no cure for this degenerative condition. Our research group, along with others, identified an autosomal dominant HSP subtype associated with the UBAP1 (ubiquitin-associated protein 1) gene. Using CRISPR/Cas9, we established in vitro human embryonic stem cells (hESCs) and in vivo mouse models harboring the recurrent variant in UBAP1. We are investigating the molecular, neuropathological, and behavioral abnormalities in these preclinical models. We are also evaluating the therapeutic approaches to specifically silence the expression of the mutant UBAP1 and rescue the HSP phenotype.

Pathogenicity mechanism and gene therapy of neurodevelopmental disorder

Neurodevelopmental disorders (NDDs) affect brain function and development, with 90% lacking approved treatments. Understanding their pathogenic mechanisms is critical for developing precision gene therapies. We previously reported an autosomal recessive NDD associated with the Mediator complex subunit 27 (MED27) gene. Mediator is essential for transcription initiation by linking enhancers to RNA polymerase II at promoters. All MED27 patients exhibited cerebellar hypoplasia or atrophy, indicating the vulnerability of the cerebellum to MED27 alterations. Using CRISPR/Cas9, we established hESCs harboring the most recurrent variant in MED27 and generated several mouse models of the gene. We are investigating the molecular, neuropathological, and behavioral abnormalities in these preclinical models and searching candidate genes as therapeutic targets.

Functional characterization of variants of uncertain significance and antiepileptic drug selection

Epilepsy is a common neurological disease and often has a monogenic etiology, particularly involving channelopathy genes encoding voltage-gated ion channels. The pathogenic mechanisms in channelopathy epilepsies can involve either gain-of-function (GoF) or loss-of-function (LoF), which require different sets of antiepileptic drugs (AEDs) for treatment. Improper AED selection may lead to ineffective therapy or even exacerbation of seizures. Therefore, accurate molecular diagnosis and understanding the pathogenicity mechanisms of variants of uncertain significance (VUS) are crucial for effective treatment. Among early-life onset epilepsy patients underwent epilepsy gene panel testing at local hospitals, we identified VUS in sodium, potassium, and calcium channel genes. Comprehensive electrophysiological recordings were performed to assess the ion channel functional changes caused by these variants. Mutant ion channels with abnormal properties were rescued using selected AEDs, and the recorded GoF or LoF defects were compared with the patients’ AED histories. This study established a robust platform for channelopathy variant curation and AED selection, enabling effective patient management. This platform holds the potential to not only examine existing approved AEDs but also explore experimental drugs targeting ion channel genes, paving the way for personalized medicine.

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