GNE myopathy, caused by biallelic mutations in the GNE gene, is characterized by initial ankle dorsiflexor weakness and rimmed vacuoles in the muscle histopathology, resulting in reduced sialic acid production. Sialyllactose is a source of sialic acid. We performed a pilot clinical trial to analyze the pharmacokinetic properties of 6'-sialyllactose (6SL) and evaluated the safety, and efficacy of oral 6SL in patients with GNE myopathy. Ten participants were in the pharmacokinetic study, and 20 in the subsequent clinical trial. For the pharmacokinetic study, participants were administered either 3 g (low-dose) or 6 g (high-dose) of 6SL in a single dose. Plasma concentrations of 6SL, sialic acid, and sialic acid levels on the surface of red blood cells were periodically assessed in blood samples. Patients were randomly allocated to test (low- and high-dose groups) or placebo groups for the trial. Motor function, ambulation, plasma 6SL and sialic acid concentrations, GNE myopathy-functional activity scale scores, and MRI findings were assessed. 6SL was well tolerated, except for self-limited gastrointestinal discomfort. Free sialic acid in both low- and high-dose groups significantly increased at 6 and 12 weeks, but not in the placebo group. In the high-dose group, proximal limb powers improved with daily 6SL. Considering the fat fraction on muscle MRI, results in the high-dose group were superior to those in the low-dose group. 6SL may be a good candidate for GNE myopathy therapeutics as it induces an increase or reduces the decrease in limb muscle power, attenuates muscle degeneration, and improves the biochemical properties of sialic acid.

2022-09-01·Archives of pharmacal research

Inhibitory effects of 6′-sialyllactose on angiotensin II-induced proliferation, migration, and osteogenic switching in vascular smooth muscle cells

Article

作者: Nguyen, Thuy Le Lam ; Heo, Kyung-Sun ; Kim, Lila ; Jin, Yujin

Excessive production and migration of vascular smooth muscle cells (VSMCs) are associated with vascular remodeling that causes vascular diseases, such as restenosis and hypertension. Angiotensin II (Ang II) stimulation is a key factor in inducing abnormal VSMC function. This study aimed to investigate the effects of 6'-sialyllactose (6'SL), a human milk oligosaccharide, on Ang II-stimulated cell proliferation, migration and osteogenic switching in rat aortic smooth muscle cells (RASMCs) and human aortic smooth muscle cells (HASMCs). Compared with the control group, Ang II increased cell proliferation by activating MAPKs, including ERK1/2/p90RSK/Akt/mTOR and JNK pathways. However, 6'SL reversed Ang II-stimulated cell proliferation and the ERK1/2/p90RSK/Akt/mTOR pathways in RASMCs and HASMCs. Moreover, 6'SL suppressed Ang II-stimulated cell cycle progression from G0/G1 to S and G2/M phases in RASMCs. Furthermore, 6'SL effectively inhibited cell migration by downregulating NF-κB-mediated MMP2/9 and VCAM-1 expression levels. Interestingly, in RASMCs, 6'SL attenuated Ang II-induced osteogenic switching by reducing the production of p90RSK-mediated c-fos and JNK-mediated c-jun, leading to the downregulation of AP-1-mediated osteopontin production. Taken together, our data suggest that 6'SL inhibits Ang II-induced VSMC proliferation and migration by abolishing the ERK1/2/p90RSK-mediated Akt and NF-κB signaling pathways, respectively, and osteogenic switching by suppressing p90RSK- and JNK-mediated AP-1 activity.

2021-02-01·Journal of pharmaceutical and biomedical analysis3区 · 医学

Development and validation of a bioanalytical method of analyzing 3′- and 6′-sialyllactose using liquid chromatography–tandem mass spectrometry in minipig plasma and its application in a pharmacokinetic study

3区 · 医学

Article

作者: Jang, Seok-In ; Kang, Jong Seong ; Lee, Jong-Hwa ; Kim, Lila ; Eom, Han Young ; Hwang, Jeong Ho

Sialyllactose (SL) is an acidic oligosaccharide, consisting of a combination of sialic acid and lactose. It is found in human milk. It has immune-protective effects against pathogens in newborns and helps with the development of the immune system and intestinal microorganisms. We developed and validated a method by which 3'-SL and 6'-SL levels were simultaneously analyzed via liquid chromatography-tandem mass spectrometry (LC-MS/MS), and evaluated the pharmacokinetics of the materials after systemic delivery to minipigs. To improve chromatographic selectivity, several types of columns (C18, amide, and HILIC phase) were used to separate the peaks of 3'-SL and 6'-SL. Ultimately the HILIC phase column was selected, as it had a good peak shape and quick resolution. The mobile phase comprised ammonium acetate buffer and acetonitrile with gradient elution. MS was performed in the negative ion and multiple reaction monitoring modes. Plasma samples were prepared using the protein precipitation method with methanol. A surrogate matrix was used for quantification because SLs are endogenous plasma compounds. The method developed was validated according to U.S. Food and Drug Administration guidance. A pharmacokinetic study was performed with intravenous administration of 3'-SL and 6'-SL in minipigs (Sus scrofa/Yucatan). The concentrations of 3'-SL and 6'-SL were readily measurable in the plasma samples, which suggests that the method adequately determined systemic exposure in minipigs.

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2021-04-06

·BioSpace

Shanghai Genchem Co., Ltd. (Genechem) Announces Global Collaboration on Bispecific Antibodies

SHANGHAI, April 6,, 2021 /PRNewswire/ -- Shanghai Genechem Co., Ltd. (Genechem), a discovery company dedicated to novel drug target discovery and development of novel therapeutics, today announced the execution of a global collaboration with I-Mab (Nasdaq: IMAB), a Nasdaq-listed global biopharmaceutical company, to develop and commercialize multiple bi-specific antibodies (BsAb) based on monoclonal antibody developed by Genechem and antibodies selected by I-MAB. "This collaboration is the first of many that will leverage Genechem's Good Research Practice (GRP) and CHAMP antibody discovery platform, strong bioinformatic database, as well as strong development expertise of synergistic partners, to deliver globally competitive assets based on innovative targets. We are excited to collaborate with I-Mab, a global leader in Oncology and antibody development, to bring more products to address clinical unmet needs for patients in China and globally", commented Yueqiong Cao, Founder and CEO of Genechem. About Shanghai Genchem Co., Ltd. (Genechem) Genechem is a leading innovation research company focused on target discovery/validation, development of antibody and cell therapy products against novel targets, and partnership globally to maximize its portfolio. Founded in 2002, now with over 500 employees, Genechem works closely with Research Oncologists to translate clinical research into therapeutics addressing high clinical unmet needs, leveraging its strong network of Research Oncologists in over 300 hospitals and Good Research Practice (GRP platform) which includes comprehensive RNAi library, tools including genetic typing, bioinformatic analysis, genetic manipulation, as well as SOP and project management systems. For more information, visit . Contact: Dr. Tong Zhang Chief Business Officer Shanghai Genechem Co., Ltd Tong.zhang@genechem.com.cn +86-18501607878

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