Research Programs
Neuro-genetics and functional restoration therapeutics for neurological disorders
Genetic defects play a critical role in the pathogenesis of both developmental and degenerative disorders of the nervous system. For example, intellectual disability (ID), a major clinical manifestation of neurodevelopmental disorders (NDDs), is caused by pathogenic genetic changes in approximately two-thirds of cases. Despite advances in exome and genome sequencing in routine clinical practice, a molecular diagnosis (identifying the disease-causing variants) remains elusive in nearly half of NDD patients with a suspected genetic cause. Furthermore, approximately 90% of NDDs currently lack approved treatments.
At GCNI, we address the pressing challenges of genetic NDDs and neurodegenerative diseases (NGDs) by integrating basic research with translational approaches. Our efforts span from the discovery of novel disease-causing genes and variants to the development of preclinical models that elucidate pathogenic mechanisms, culminating in the creation of gene therapies and personalized treatment strategies based on each patient’s genetic profile. Our two main research directions are as follows:
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From molecular diagnosis to “pathogenicity diagnosis”
Bridging the gap between molecular diagnosis and effective patient treatment requires moving beyond identifying genetic variants to achieving an accurate “pathogenicity diagnosis.” We have identified multiple novel genes implicated in NDDs and NGDs and developed a range of preclinical models to study their pathogenicity. These models include neuronal stem cells, brain organoids, and animal models such as mice and zebrafish, all of which recapitulate patients’ genotypes and phenotypes. Using these tools, we comprehensively investigate the molecular, neuropathological, and behavioral abnormalities to uncover the mechanisms underlying these disorders.
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Precision gene therapy and personalized treatment
Building on insights into the specific pathogenic mechanisms of each gene and variant, we are developing targeted therapies to correct or mitigate the abnormal phenotypes observed in our preclinical models. These therapeutic approaches include CRISPR-based genome editing to correct DNA mutations, RNA interference (RNAi) and antisense oligonucleotides (ASOs) to modulate gene expression, and gene replacement therapies to restore normal function. Additionally, we are functionally characterizing variants of uncertain significance (VUS) identified in epilepsy patients. This work could guide clinicians in selecting appropriate anti-epileptic drugs tailored to specific genetic changes.
We collaborate with clinical geneticists worldwide to identify novel genes associated with NDDs and NGDs, conduct genotype-phenotype correlation analyses, and develop innovative treatments. Our goal is to achieve not only accurate molecular diagnoses but also a deeper understanding of the corresponding pathogenic mechanisms. This knowledge will enable us to deliver personalized gene therapies and targeted drug treatments, ultimately improving outcomes for patients with neurological disorders.
