Stanford Advisors

  • Yang Sun, Postdoctoral Faculty Sponsor

All Publications

  • Base editing correction of OCRL in Lowe syndrome: ABE-mediated functional rescue in patient-derived fibroblasts. Human molecular genetics Chen, S., Lo, C. H., Liu, Z., Wang, Q., Ning, K., Li, T., Sun, Y. 2024


    Lowe syndrome, a rare X-linked multisystem disorder presenting with major abnormalities in the eyes, kidneys, and central nervous system, is caused by mutations in OCRL gene (NG_008638.1). Encoding an inositol polyphosphate 5-phosphatase, OCRL catalyzes the hydrolysis of PI(4,5)P2 into PI4P. There are no effective targeted treatments for Lowe syndrome. Here, we demonstrate a novel gene therapy for Lowe syndrome in patient fibroblasts using an adenine base editor (ABE) that can efficiently correct pathogenic point mutations. We show that ABE8e-NG-based correction of a disease-causing mutation in a Lowe patient-derived fibroblast line containing R844X mutation in OCRL gene, restores OCRL expression at mRNA and protein levels. It also restores cellular abnormalities that are hallmarks of OCRL dysfunction, including defects in ciliogenesis, microtubule anchoring, α-actinin distribution, and F-actin network. The study indicates that ABE-mediated gene therapy is a feasible treatment for Lowe syndrome, laying the foundation for therapeutic application of ABE in the currently incurable disease.

    View details for DOI 10.1093/hmg/ddae045

    View details for PubMedID 38557732

  • Compartmentalized ciliation changes of oligodendrocytes in aged mouse optic nerve. Journal of neuroscience research Ning, K., Tran, M., Kowal, T. J., Mesentier-Louro, L. A., Sendayen, B. E., Wang, Q., Lo, C. H., Li, T., Majumder, R., Luo, J., Hu, Y., Liao, Y. J., Sun, Y. 2024; 102 (1): e25273


    Primary cilia are microtubule-based sensory organelles that project from the apical surface of most mammalian cells, including oligodendrocytes, which are myelinating cells of the central nervous system (CNS) that support critical axonal function. Dysfunction of CNS glia is associated with aging-related white matter diseases and neurodegeneration, and ciliopathies are known to affect CNS white matter. To investigate age-related changes in ciliary profile, we examined ciliary length and frequency in the retinogeniculate pathway, a white matter tract commonly affected by diseases of aging but in which expression of cilia has not been characterized. We found expression of Arl13b, a marker of primary cilia, in a small group of Olig2-positive oligodendrocytes in the optic nerve, optic chiasm, and optic tract in young and aged C57BL/6 wild-type mice. While the ciliary length and ciliated oligodendrocyte cells were constant in young mice in the retinogeniculate pathway, there was a significant increase in ciliary length in the anterior optic nerve as compared to the aged animals. Morphometric analysis confirmed a specific increase in the ciliation rate of CC1+ /Olig2+ oligodendrocytes in aged mice compared with young mice. Thus, the prevalence of primary cilia in oligodendrocytes in the visual pathway and the age-related changes in ciliation suggest that they may play important roles in white matter and age-associated optic neuropathies.

    View details for DOI 10.1002/jnr.25273

    View details for PubMedID 38284846

  • Effect of Brimonidine on Retinal Ganglion Cell Function by in vivo Calcium Imaging in Glaucoma Mice Model Li, T., Wang, Q., Lo, C., Ning, K., Majumder, R., Sun, Y. ASSOC RESEARCH VISION OPHTHALMOLOGY INC. 2023
  • Cilia-associated wound repair mediated by IFT88 in retinal pigment epithelium. Scientific reports Ning, K., Bhuckory, M. B., Lo, C. H., Sendayen, B. E., Kowal, T. J., Chen, M., Bansal, R., Chang, K. C., Vollrath, D., Berbari, N. F., Mahajan, V. B., Hu, Y., Sun, Y. 2023; 13 (1): 8205


    Primary cilia are conserved organelles that integrate extracellular cues into intracellular signals and are critical for diverse processes, including cellular development and repair responses. Deficits in ciliary function cause multisystemic human diseases known as ciliopathies. In the eye, atrophy of the retinal pigment epithelium (RPE) is a common feature of many ciliopathies. However, the roles of RPE cilia in vivo remain poorly understood. In this study, we first found that mouse RPE cells only transiently form primary cilia. We then examined the RPE in the mouse model of Bardet-Biedl Syndrome 4 (BBS4), a ciliopathy associated with retinal degeneration in humans, and found that ciliation in BBS4 mutant RPE cells is disrupted early during development. Next, using a laser-induced injury model in vivo, we found that primary cilia in RPE reassemble in response to laser injury during RPE wound healing and then rapidly disassemble after the repair is completed. Finally, we demonstrated that RPE-specific depletion of primary cilia in a conditional mouse model of cilia loss promoted wound healing and enhanced cell proliferation. In summary, our data suggest that RPE cilia contribute to both retinal development and repair and provide insights into potential therapeutic targets for more common RPE degenerative diseases.

    View details for DOI 10.1038/s41598-023-35099-3

    View details for PubMedID 37211572

    View details for PubMedCentralID 6513937