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NIH grant 1K08NS146682-01A1: Examining the impact of cobalamin C deficiency in human brain development
Institute: {'code': 'NS', 'abbreviation': 'NINDS', 'name': 'National Institute of Neurological Disorders and Stroke', 'admin_org_id': '12500053', 'admin_funding_url': ''}. PI: Yue Huang. Award: $236115.
Start: 2026-08-28T00:00:00.
PROJECT SUMMARY/ABSTRACT
Inborn errors of metabolism (IEMs) are a group of genetic disorders resulting from defects in cellular metabolism.
While individually rare, IEMs collectively affect approximately 1 in 1000 newborns, with 85% of them exhibiting
neurodevelopmental symptoms. Cobalamin C deficiency, one of the most common IEMs, interrupts the
remethylation of methionine from homocysteine. Affected individuals typically present with neonatal-onset
encephalopathy, hypotonia, microcephaly, and neurodevelopmental delay. Current treatment regimens for
cobalamin C deficiency are ineffective for neurological manifestations. Most patients continue to experience
severe developmental delays and intellectual disability despite early diagnosis through newborn screening and
prompt initiation of treatment during the neonatal period.
Dr. Huang is a clinical geneticist specializing in inherited metabolic disorders. He has a long-term scientific
aspiration to investigate pathophysiology and develop novel therapeutics for neurodevelopmental phenotypes
associated with IEMs. In the short term, his research focuses on understanding the role of cobalamin C deficiency
in human brain development and developing a gene-editing approach to correct common mutations in this
disorder. Based on preliminary data obtained from a human brain organoid model of cobalamin C deficiency, he
hypothesizes that cobalamin C deficiency-induced metabolic derangements disrupt oligodendroglial
differentiation during human brain development. To test this hypothesis, Dr. Huang proposes a research program
to investigate the timing and stage of differentiation blockage during oligodendrogenesis in Aim 1. He takes a
step further in Aim 2 to explore the molecular mechanism underlying cobalamin C deficiency by examining the
impact of disrupted methionine remethylation on the creatine synthesis pathway. In Aim 3, Dr. Huang proposes
an innovative approach to overcome the barriers to deliver gene-editing machinery to restore the missing gene
product in cobalamin C deficiency.
This research program, along with an individualized career development plan, is developed by Dr. Huang and
his mentors Dr. Alysson Muotri, Dr. Bruce Barshop, and Dr. Stephanie Cherqui, who are experts with
complementary expertise in brain organoid modeling, metabolomics, and gene therapy. Utilizing this research
program, Dr. Huang will be able to pursue his learning objectives outlined in his career development plan,
allowing him to broaden his knowledge in the molecular mechanism of neurometabolic disorders, gain proficiency
in new experimental techniques, and improve his biostatistical and bioinformatic skills for data analysis. Dr.
Huang is committed to a career as a physician-scientist and determined to advance the field of metabolic
genetics. This career development award will prepare him to pursue his career goal and facilitate his transition
to become an independent investigator.document fetched 2026-09-06 02:47