Browsing by Author "Liu, Liang"

Now showing 1 - 4 of 4
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    Mouse γ-Synuclein Promoter-Mediated Gene Expression and Editing in Mammalian Retinal Ganglion Cells
    (SfN, 2020-05-13) Wang, Qizhao; Zhuang, Pei; Huang, Haoliang; Li, Liang; Liu, Liang; Webber, Hannah C.; Dalal, Roopa; Siew, Leonard; Fligor, Clarisse M.; Chang, Kun-Che; Nahmou, Michael; Kreymerman, Alexander; Sun, Yang; Meyer, Jason S.; Goldberg, Jeffrey Louis; Hu, Yang; Biology, School of Science
    Optic neuropathies are a group of optic nerve (ON) diseases caused by various insults including glaucoma, inflammation, ischemia, trauma, and genetic deficits, which are characterized by retinal ganglion cell (RGC) death and ON degeneration. An increasing number of genes involved in RGC intrinsic signaling have been found to be promising neural repair targets that can potentially be modulated directly by gene therapy, if we can achieve RGC specific gene targeting. To address this challenge, we first used adeno-associated virus (AAV)-mediated gene transfer to perform a low-throughput in vivo screening in both male and female mouse eyes and identified the mouse γ-synuclein (mSncg) promoter, which specifically and potently sustained transgene expression in mouse RGCs and also works in human RGCs. We further demonstrated that gene therapy that combines AAV-mSncg promoter with clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 gene editing can knock down pro-degenerative genes in RGCs and provide effective neuroprotection in optic neuropathies.SIGNIFICANCE STATEMENT Here, we present an RGC-specific promoter, mouse γ-synuclein (mSncg) promoter, and perform extensive characterization and proof-of-concept studies of mSncg promoter-mediated gene expression and clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 gene editing in RGCs in vivo To our knowledge, this is the first report demonstrating in vivo neuroprotection of injured RGCs and optic nerve (ON) by AAV-mediated CRISPR/Cas9 inhibition of genes that are critical for neurodegeneration. It represents a powerful tool to achieve RGC-specific gene modulation, and also opens up a promising gene therapy strategy for optic neuropathies, the most common form of eye diseases that cause irreversible blindness.
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    The fatty acid elongase ELOVL6 regulates bortezomib resistance in multiple myeloma
    (American Society of Hematology, 2021) Lipchick, Brittany C.; Utley, Adam; Han, Zhannan; Moparthy, Sudha; Yun, Dong Hyun; Bianchi-Smiraglia, Anna; Wolff, David W.; Fink, Emily; Liu, Liang; Furdui, Cristina M.; Lee, Jingyun; Lee, Kelvin P.; Nikiforov, Mikhail A.; Medicine, School of Medicine
    Resistance to the proteasome inhibitor bortezomib (BTZ) represents a major obstacle in the treatment of multiple myeloma (MM). The contribution of lipid metabolism in the resistance of MM cells to BTZ is mostly unknown. Here we report that levels of fatty acid elongase 6 (ELOVL6) were lower in MM cells from BTZ-nonresponsive vs BTZ-responsive patients and in cultured MM cells selected for BTZ resistance compared with parental counterparts. Accordingly, depletion of ELOVL6 in parental MM cells suppressed BTZ-induced endoplasmic reticulum (ER) stress and cytotoxicity, whereas restoration of ELOVL6 levels in BTZ-resistant MM cells sensitized them to BTZ in tissue culture settings and, as xenografts, in a plasmacytoma mouse model. Furthermore, for the first time, we identified changes in the BTZ-induced lipidome between parental and BTZ-resistant MM cell lines underlying a functional difference in their response to BTZ. We demonstrated that restoration of ELOVL6 levels in BTZ-resistant MM cells resensitized them to BTZ largely via upregulation of ELOVL6-dependent ceramide species, which was a prerequisite for BTZ-induced ER stress and cell death in these cells. Our data characterize ELOVL6 as a major clinically relevant regulator of MM cell resistance to BTZ, which can emerge from the impaired ability of these cells to alter ceramide composition in response to BTZ.
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    Treatment patterns and outcomes in elderly patients with newly diagnosed multiple myeloma: results from the Connect® MM Registry
    (Springer Nature, 2021-07-23) Lee, Hans C.; Ailawadhi, Sikander; Gasparetto, Cristina J.; Jagannath, Sundar; Rifkin, Robert M.; Durie, Brian G. M.; Narang, Mohit; Terebelo, Howard R.; Toomey, Kathleen; Hardin, James W.; Wagner, Lynne; Omel, James L.; Dhalla, Mazaher; Liu, Liang; Joshi, Prashant; Abonour, Rafat; Connect® MM Registry; Medicine, School of Medicine
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    Treatment Patterns, Survival, Quality of Life, and Healthcare Resource Use Among Patients With Triple-Class Refractory Multiple Myeloma in US Clinical Practice: Findings From the Connect MM Disease Registry
    (Elsevier, 2023) Lee, Hans C.; Ramasamy, Karthik; Weisel, Katja; Abonour, Rafat; Hardin, James W.; Rifkin, Robert M.; Ailawadhi, Sikander; Terebelo, Howard R.; Durie, Brian G. M.; Tang, Derek; Joshi, Prashant; Liu, Liang; Jou, Ying-Ming; Che, Min; Hernandez, Gabriela; Narang, Mohit; Toomey, Kathleen; Gasparetto, Cristina; Wagner, Lynne I.; Jagannath, Sundar; Medicine, School of Medicine
    Background: Adults with triple-class refractory (TCR) multiple myeloma (MM) have limited treatment options and poor prognosis, but the burden of TCR MM has not been well characterized. This study evaluated treatment patterns, overall survival (OS), health-related quality of life (HRQoL), and healthcare resource use (HCRU) among patients with TCR MM in US clinical practice. Patients and methods: Patients with TCR MM in the Connect MM Registry (NCT01081028; a large, US, multicenter, prospective observational cohort study of patients with newly diagnosed MM) were included. Patient characteristics, treatment patterns, HRQoL, and HCRU were analyzed using descriptive statistics. OS was calculated using Kaplan-Meier methodology for the overall cohort and for patients with/without ≥1 post-TCR line of therapy (LOT). Results: A total of 232 patients with TCR MM were included; 155 (67%) had ≥1 post-TCR LOT (post-TCR-Treated subgroup; median 9.9 months of follow-up). Most common post-TCR treatments were carfilzomib (47%), pomalidomide (40%), and daratumumab (26%); median treatment duration was 3.3 months. Median OS was 9.9 months in the overall population, 10.8 months in post-TCR-Treated patients, and 2.6 months for those with no new post-TCR LOT. HRQoL deteriorated and pain increased over 1 year of follow-up, with clinically meaningfully changes in EQ-5D (mean, -0.06 points) and FACT-G (mean, -9.9 points). 124 (53%) patients had ≥1 all-cause hospitalization and 58 (25%) had ≥1 MM-related hospitalization; median annualized length of stay was 35.3 and 42.9 days, respectively. Conclusion: The burden of TCR MM is substantial, emphasizing the need for more effective treatment options in the TCR setting.