GNE myopathy is a rare genetic muscle disease characterized by progressive muscle atrophy and weakness. The disease is caused by mutations in the gene that encodes the enzyme that initiates and regulates N-acetylneuraminic acid (Neu5Ac) biosynthesis and glycan sialylation. Currently, there is no therapy available for this disease. N-Acetylmannosamine (ManNAc), an orphan drug in development for GNE myopathy, is an uncharged monosaccharide and the first committed precursor in Neu5Ac biosynthesis. In this randomized, double-blind, placebo-controlled trial the efficacy and long-term safety of ManNAc will be evaluated in subjects with GNE myopathy.

开始日期2022-04-05

申办/合作机构

Leadiant Biosciences, Inc.

[+4]

ACTRN12619000101189 / Completed临床1期

A Phase 1, Single Center, Open-Label, Randomized, Two-Period, Two- Arm Crossover Study Of The Bioavailability Of A Single Dose Of N- Acetyl-D-Mannosamine Monohydrate (ManNAc) In A Fasted Condition and A Fed Condition In Healthy Adults

开始日期2019-01-24

申办/合作机构

Leadiant Biosciences, Inc.

NCT02639260 / Completed临床1期IIT

A Phase 1 Multiple Ascending Dose Study to Evaluate the Safety, Tolerability, and Pharmacokinetics of ManNAc in Subjects With Primary Podocyte Diseases

Three kidney diseases that affect both children and adults are minimal change disease (MCD), focal segmental glomerulosclerosis (FSGS) and membranous nephropathy (MN). These diseases are characterized by proteinuria (protein in the urine) and in the cases of FSGS and membranous nephropathy, a tendency to progressive scarring of the glomerulus (the filtering units of the kidneys) that leads to end-stage kidney disease. Several therapies are available for these diseases, but these therapies do not provide lasting reduction in proteinuria for many subjects. In the current study, carried out at the NIH Clinical Center, we are testing a new therapy, ManNAc. ManNAc is a naturally occurring uncharged sugar that cells use to produce negatively charged sialic acid. Kidney cells attach sugars such as sialic acids to proteins and lipids (resulting in glycans), and these assist in cell function. Mouse models of the inherited muscle disease GNE myopathy, which is due to sialic acid deficiency on muscle glycans, responded favorably to oral ManNAc therapy and a clinical trial of ManNAc is ongoing in GNE myopathy subjects. There is evidence that some subjects with MCD, FSGS or MN do not put enough sialic acids on glomerular proteins and so ManNAc therapy may increase sialic acid production and sialylation of glomerular proteins in these subjects. For the present study, we will recruit 12 subjects who have MCD, FSGS or MN. Each subject will stay at the NIH Clinical Center for 11 days to receive oral ManNAc. The primary purposes of the study are to determine: 1) the safety of ManNAc in subject s with kidney disease; and 2) the ManNAc and sialic acid metabolism related to ManNAc in subjects with kidney disease. Concentrations of ManNAc and sialic acid will be measured in plasma at various times before and after dosing. If this study suggests that ManNAc is safe in subject with kidney disease, the results will be used to plan a longer-term study to determine whether it is effective at reducing proteinuria....

开始日期2016-07-07

申办/合作机构

National Institute of Diabetes & Digestive & Kidney Diseases

100 项与 N-acetyl-D-mannosamine 相关的临床结果

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100 项与 N-acetyl-D-mannosamine 相关的专利（医药）

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154

项与 N-acetyl-D-mannosamine 相关的文献（医药）

2024-01-15·Glycobiology

GNE deficiency impairs Myogenesis in C2C12 cells and cannot be rescued by ManNAc supplementation.

Article

作者: Carolin T Neu ; Linus Weilepp ; Kaya Bork ; Astrid Gesper ; Rüdiger Horstkorte

GNE myopathy (GNEM) is a late-onset muscle atrophy, caused by mutations in the gene for the key enzyme of sialic acid biosynthesis, UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase (GNE). With an incidence of one to nine cases per million it is an ultra-rare, so far untreatable, autosomal recessive disease. Several attempts have been made to treat GNEM patients by oral supplementation with sialic acid precursors (e.g. N-acetylmannosamine, ManNAc) to restore sarcolemmal sialylation and muscle strength. In most studies, however, no significant improvement was observed. The lack of a suitable mouse model makes it difficult to understand the exact pathomechanism of GNEM and many years of research have failed to identify the role of GNE in skeletal muscle due to the lack of appropriate tools. We established a CRISPR/Cas9-mediated Gne-knockout cell line using murine C2C12 cells to gain insight into the actual role of the GNE enzyme and sialylation in a muscular context. The main aspect of this study was to evaluate the therapeutic potential of ManNAc and N-acetylneuraminic acid (Neu5Ac). Treatment of Gne-deficient C2C12 cells with Neu5Ac, but not with ManNAc, showed a restoration of the sialylation level back to wild type levels-albeit only with long-term treatment, which could explain the rather low therapeutic potential. We furthermore highlight the importance of sialic acids on myogenesis, for C2C12 Gne-knockout myoblasts lack the ability to differentiate into mature myotubes.

2023-12-15·Journal of chromatography. A

Surface multi-walled carbon nanotube modified quaternary amine-functionalized polymers for purification and determination of glyphosate and its four metabolites in plasma samples.

Article

作者: Shengdong Pan ; Meijun Ye ; Peng Yan ; Yanbo Guo ; Dandan Zhang ; Qian He

The present study focused on the pretreatment and detection of GLY and its four metabolites AMPA, N-acetyl AMPA, N-methyl GLY and N-acetyl GLY in plasma samples. Multi-walled carbon nanotube-modified quaternary amine-functionalized polymers (QA-PDNV@MWCNTs) were synthesized in a controlled manner by self-assembly, and its morphology and composition were extensively characterized. The QA-PDNV@MWCNTs microspheres were then used as an SPE adsorbent for the preparation and rapid determination of GLY and its four metabolites in plasma samples combined with ultra-performance liquid chromatography-high resolution mass spectrometry (UPLCHRMS). The SPE conditions based on QA-PDNV@MWCNTs were optimized for GLY and its metabolites to obtain the best purification efficiency. The experimental results show that when the adsorbent contains 8% MWCNTs, it can balance the adsorption of target analytes and the purification performance of the adsorbent for impurities. In addition, this study compared the QA-PDNV@MWCNTs based SPE method with the commercial Waters Oasis MAX SPE cartridge and the results showed that the developed method in this study has better resistance to matrix interference. Under optimal conditions, the recoveries of GLY and its metabolites spiked in plasma were 82.6-99.4 % with relative standard deviations (RSDs) of 1.0-7.8 %. The limits of detection (LODs, S/N ≥ 3) and limits of quantification (LOQs, S/N ≥ 9) of the method were 0.05-0.33 μg/L and 0.15-1.00 μg/L, respectively. Finally, the developed QA-PDNV@MWCNTs based SPE-UPLCHRMS method was used to confirm GLY poisoning not only on the basis of the detection of the GLY prototype, but also on the basis of its four metabolites.

2023-11-24·Frontiers in bioscience (Landmark edition)

Evaluation of N-Acetylmannosamine Administration to Restore Sialylation in GNE-Deficient Human Embryonal Kidney Cells.

Article

作者: Emilia Peters ; Philipp Selke ; Kaya Bork ; Rüdiger Horstkorte ; Astrid Gesper

BACKGROUND:

A key mechanism in the neuromuscular disease GNE myopathy (GNEM) is believed to be that point mutations in the GNE gene impair sialic acid synthesis - maybe due to UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase (GNE) activity restrictions - and resulting in muscle tissue loss. N-acetylmannosamine (ManNAc) is the first product of the bifunctional GNE enzyme and can therefore be regarded as a precursor of sialic acids. This study investigates whether this is also a suitable substance for restoring the sialic acid content in GNE-deficient cells.

METHODS:

A HEK-293 GNE-knockout cell line was generated using CRISPR-Cas9 and analyzed for its ability to synthesize sialic acids. The cells were then supplemented with ManNAc to compensate for possible GNE inactivity and thereby restore sialic acid synthesis. Sialic acid levels were monitored by immunoblot and high performance liquid chromatography (HPLC).

RESULTS:

The HEK-293 GNE-knockout cells showed almost no polysialylation signal (immunoblot) and a reduced overall (-71%) N-acetylneuraminic acid (Neu5Ac) level (HPLC) relative to total protein and normalized to wild type level. Supplementation of GNE-deficient HEK-293 cells with 2 mM ManNAc can restore polysialylation and free intracellular sialic acid levels to wild type levels. The addition of 1 mM ManNAc is sufficient to restore the membrane-bound sialic acid level.

CONCLUSIONS:

Although the mechanism behind this needs further investigation and although it remains unclear why adding ManNAc to GNE-deficient cells is sufficient to elevate polysialylation back to wild type levels - since this substance is also converted by the GNE, all of this might yet prove helpful in the development of an appropriate therapy for GNEM.

项与 N-acetyl-D-mannosamine 相关的新闻（医药）

2021-04-27

·BioSpace

LogicBio Therapeutics Announces Research Collaboration with Daiichi Sankyo

LEXINGTON, Mass., April 27, 2021 /PRNewswire/ -- LogicBio Therapeutics, Inc. (LogicBio - Nasdaq: LOGC), a clinical-stage genetic medicine company pioneering gene delivery and gene editing platforms to address rare and serious diseases from infancy through adulthood, today announced the signing of a research collaboration and exclusive option agreement with Daiichi Sankyo Company, Limited (Daiichi Sankyo). Under the terms of the agreement, the companies will collaborate on the development of treatments for two undisclosed indications based on GeneRide™, LogicBio's proprietary gene insertion platform. The agreement also grants Daiichi Sankyo an option to negotiate and acquire worldwide licenses for LogicBio's development programs in these two indications. Financial terms of the collaboration are not disclosed. "I am very pleased to announce this collaboration as a new milestone in the validation of our GeneRide platform. In 2020, we cleared our first Investigational New Drug (IND) application for GeneRide for the treatment of pediatric methylmalonic acidemia (MMA) patients and initiated the Phase 1/2 SUNRISE clinical trial. We also formed our first research agreement with another major pharmaceutical company to develop a drug candidate for Crigler-Najjar syndrome," said Frederic Chereau, president and chief executive officer of LogicBio. "By partnering with Daiichi Sankyo, a global leader in developing innovative medicines, we are reinforcing our commitment to bring innovative therapeutics to people living with serious genetic conditions including many that can present symptoms as early as infancy." The GeneRide platform harnesses a cell's natural DNA repair process leading to durable therapeutic protein expression levels. GeneRide supports the development of a new generation of genetic medicine able to insert a DNA segment into the human genome while potentially avoiding certain risks associated with other gene editing technologies. The therapy uses a viral vector to deliver the therapeutic gene, known as a transgene, to the nuclei of a patient's cells via one-time infusion. LogicBio's two lead development programs based on the GeneRide platform are focused on rare pediatric conditions. The company is currently evaluating LB-001 in the Phase 1/2 SUNRISE trial in MMA and LB-301 in Crigler-Najjar syndrome through another research collaboration. LogicBio is also advancing the development of sAAVyTM, its next-generation AAV capsid platform, designed to overcome limitations with the current generation of AAV-based gene therapies. About LogicBio Therapeutics, Inc. LogicBio Therapeutics is a clinical-stage genetic medicine company pioneering gene delivery and gene editing platforms to address rare and serious diseases from infancy through adulthood. The company's proprietary GeneRide™ platform is a new approach to precise gene insertion that harnesses a cell's natural DNA repair process leading to durable therapeutic protein expression levels. LogicBio's cutting-edge sAAVyTM capsid development platform is designed to support development of treatments in a broad range of indications and tissues. The company is based in Lexington, MA. For more information, visit . Bill Berry Berry & Company Public Relations W: 212-253-8881 C: 917-846-3862 bberry@berrypr.com Jenna Urban Berry & Company Public Relations W: 212-253-8881 C: 203-218-9180 jurban@berrypr.com Company Codes: NASDAQ-NMS:LOGC

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远端性肌病	临床3期	-	Leadiant Biosciences, Inc. 更多
遗传性包涵体肌病	临床2期	美国更多	Leadiant Biosciences, Inc. 更多

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研究	分期	人群特征	评价人数	分组	结果	评价	发布日期


NCT02346461 (CTgov)	临床2期	遗传性包涵体肌病	12	ManNAc (ManNAc: Cohort A)	衊網憲簾遞積遞鹹築繭(鹽構鹹獵構鹽觸顧獵範) = 衊構鬱鏇淵廠繭觸醖積顧餘鑰獵鬱製鹽願積鑰 (獵網襯範遞鏇範簾蓋衊, 鏇製獵夢淵壓蓋廠蓋簾 ~ 夢憲艱鑰餘築鏇憲衊選) 更多	-	2019-04-16
NCT02346461 (CTgov)	临床2期	遗传性包涵体肌病	12	ManNAc (ManNAc: Cohort B)	衊網憲簾遞積遞鹹築繭(鹽構鹹獵構鹽觸顧獵範) = 糧鏇衊鏇鏇製鏇觸鬱獵顧餘鑰獵鬱製鹽願積鑰 (獵網襯範遞鏇範簾蓋衊, 夢繭製襯鏇窪齋遞繭簾 ~ 選襯憲艱範餘積鏇膚襯) 更多	-	2019-04-16
NCT02346461 (Pubmed \| Genet Med) 人工标引	临床2期	遗传性包涵体肌病	12	ManNAc	鑰蓋齋鹹蓋蓋壓鹽糧鹹(餘餘醖網餘窪簾選網廠) = 積膚衊構選鬱淵壓鑰觸鏇繭製壓艱鬱夢積廠願 (衊遞築衊顧顧範願網齋 )	积极	2021-11-01