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Comparison of RT-qPCR With Branched DNA to Quantify a Lipid Nanoparticle-Encapsulated mRNA Therapeutic in Serum and Liver Tissue Samples From Nonclinical PK Studies

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AAPS JOURNAL 2025年第1期27卷 1-10页

作者： Ortiz, Jessica Brunner, Laura Ci, Lei baek, rena Jani, Darshana Marshall, Jean-Claude Pennucci, Jason Moderna Inc Cambridge MA 02142 USA

While the branched DNA (bDNA) assay is an established bioanalytical method for measurement of lipid nanoparticle (LNP)-encapsulated messenger RNA (mRNA) pharmacokinetic parameters, reverse transcription-quantitative polymerase chain reaction (RT-qPCR) has been considered as an alternative platform. RT-qPCR and bDNA platforms were compared for sensitivity, specificity, correlation, and overall assay performance using serum and tissue samples from 2 nonclinical mouse studies of a therapeutic mRNA candidate, LNP-PAH-mRNA, which encodes for human phenylalanine hydroxylase enzyme. Pharmacokinetic parameter noncompartmental analysis was completed using Phoenix WinNonlin. The assays were compared using simple linear regression and Bland-Altman analyses. Sensitivity ranged from 0.05 to 6.40 ng/mL for the bDNA assays, from 0.00000761 to 7.61 ng/mL in serum, and from 0.000179 to 179 ng/g in tissue for the RT-qPCR assay. Inter-assay accuracy was within +/- 10%, inter-assay precision was <= 10%, and the total error for both assays was <= 20%. RT-qPCR serum mRNA concentrations were 2- to fourfold lower compared with the bDNA assay, whereas tissue samples were comparable between assays. A linear relationship with - 0.37 to - 0.02 systematic bias demonstrated acceptable concordance. Bland-Altman plots demonstrated close equivalence, with a negative bias of < 0.5, and >= 95% of the data points were within the 95% limits of agreement. The comparison of the RT-qPCR with bDNA assay platforms for quantification of pharmacokinetic properties of an mRNA-LNP therapeutic has demonstrated acceptable concordance. This comparison reinforces the use of the RT-qPCR, a widely accessible strategy, as an alternative platform for the quantification of subsequent mRNA-LNP therapeutics.

关键词： bDNA bioanalytical mRNA therapeutics pharmacokinetics RT-qPCR

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Therapeutic strategies for the ganglioside storage diseases

Therapeutic strategies for the ganglioside storage diseases

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作者： baek, rena C. Boston College

学位级别：Ph.D.

The Gangliosidoses, to include GM1 gangliosidosis and Sandhoff disease are a class of incurable lysosomal storage disorders characterized by an abnormal accumulation of gangliosides leading to progressive neurodegeneration and eventually death. GM1 gangliosidosis is caused by a genetic defect in the lysosomal-specific acid β-galactosidase, which results in the massive accumulation of ganglioside GM1 primarily in the central nervous system (CNS). Sandhoff disease (SD) results from a defect in the β-subunit of β-Hexosaminidase A and leads to the accumulation of ganglioside GM2 and its asialo derivative (GA2). As there are no effective therapies for these glycosphingolipid (GSL) storage disorders, I studied substrate reduction therapy (SRT), stem cell therapy, and adeno-associated viral (AAV) gene therapy in neonatal mice as early intervention therapies and were effective in reducing CNS GSL storage. In addition, AAV gene therapy was also evaluated in the adult GM1 gangliosidosis mice. Furthermore, analysis of the brain lipids in mice, cats, and humans with Sandhoff disease revealed that the SD cat model is intermediate between the SD mouse and the SD patient with respect to GM2 and GA2 accumulation. These findings are the first to compare the different therapies and provide valuable information for the translation of mouse studies to clinical trials in patients.

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N-butyldeoxygalactonojirimycin reduces brain ganglioside and GM2 content in neonatal Sandhoff disease mice

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NEUROCHEMISTRY INTERNATIONAL 2008年第6期52卷 1125-1133页

作者： baek, rena C. Kasperzyk, Julie L. Platt, Frances A. Seyfried, Thomas N. Boston Coll Dept Biol Chestnut Hill MA 02467 USA Univ Oxford Dept Pharmacol Oxford England

Sandhoff disease involves the CNS accumulation of ganglioside GM2 and asialo-GM2 (GA2) due to inherited defects in the beta-subunit gene of beta-hexosammidase A and B (Hexb gene). Accumulation of these glycosphingolipids (GSLs) produces progressive neurodegeneration, ultimately leading to death. Substrate reduction therapy (SRT) aims to decrease the rate of glycosphingolipid (GSL) biosynthesis to compensate for the impaired rate of catabolism. The imino sugar, N-butyldeoxygalactonojirimycin (NB-DGJ) inhibits the first committed step in GSL biosynthesis. NB-DGJ treatment, administered from postnatal day 2 (p-2) to p-5 (600 mg/kg/day)), significantly reduced total brain ganglioside and GM2 content in the Sandhoff disease (Hexb(-/-)) mice, but did not reduce the content of GA2. We also found that NB-DGJ treatment caused a slight, but significant elevation in brain sialidase activity. The drug had no adverse effects on viability, body weight, brain weight, or brain water content in the mice. No significant alterations in neutral lipids or acidic phospholipids were observed in the NB-DGJ-treated Hexb(-/-) mice. Our results show that NB-DGJ is effective in reducing total brain ganglioside and GM2 content at early neonatal ages. (C) 2007 Elsevier Ltd. All rights reserved.

关键词： beta-hexosaminidase gangliosidosis glycosphingolipids GM2 neurodegenerative disease substrate reduction therapy (SRT)

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Comparative Analysis of Brain Lipids in Mice, Cats, and Humans with Sandhoff Disease

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LIPIDS 2009年第3期44卷 197-205页

作者： baek, rena C. Martin, Douglas R. Cox, Nancy R. Seyfried, Thomas N. Boston Coll Dept Biol Chestnut Hill MA 02467 USA Auburn Univ Coll Vet Med Scott Ritchey Res Ctr Auburn AL 36849 USA Auburn Univ Coll Vet Med Dept Pathobiol Auburn AL 36849 USA

Sandhoff disease (SD) is a glycosphingolipid (GSL) storage disease that arises from an autosomal recessive mutation in the gene for the beta-subunit of beta-Hexosaminidase A (Hexb gene), which catabolizes ganglioside GM2 within lysosomes. Accumulation of GM2 and asialo-GM2 (GA2) occurs primarily in the CNS, leading to neurodegeneration and brain dysfunction. We analyzed the total lipids in the brains of SD mice, cats, and humans. GM2 and GA2 were mostly undetectable in the normal mouse, cat, and human brain. The lipid abnormalities in the SD cat brain were generally intermediate to those observed in the SD mouse and the SD human brains. GM2 comprised 38, 67, and 87% of the total brain ganglioside distribution in the SD mice, cats, and humans, respectively. The ratio of GA2-GM2 was 0.93, 0.13, and 0.27 in the SD mice, cats, and humans, respectively, suggesting that the relative storage of GA2 is greater in the SD mouse than in the SD cat or human. Finally, the myelin-enriched lipids, cerebrosides and sulfatides, were significantly lower in the SD brains than in the control brains. This study is the first comparative analysis of brain lipids in mice, cats, and humans with SD and will be important for designing therapies for Sandhoff disease patients.

关键词： Sandhoff disease beta-Hexosaminidase Gangliosides Glycosphingolipids GM2 GA2 Cerebrosides Sulfatides Myelin

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The influence of a polymorphism in the gene encoding angiotensin converting enzyme (ACE) on treatment outcomes in late-onset Pompe patients receiving alglucosidase alfa

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MOLECULAR GENETICS AND METABOLISM REPORTS 2016年 8卷 48-50页

作者： baek, rena C. Palmer, Rachel Pomponio, Robert J. Lu, Yuefeng Ma, Xiwen McVie-Wylie, Alison J. Sanofi 5 Mt Rd Framingham MA 01701 USA

Correlations between angiotensin-converting enzyme (ACE) genotype (I/I, I/D, D/D), disease severity at baseline and response to enzyme replacement therapy (ERT) were assessed in the Pompe disease Late-Onset Treatment Study (LOTS). No correlations were observed between ACE genotype and disease severity at baseline. However, D/D patients appeared to have a reduced response to alglucosidase alfa treatment than I/I or I/D patients, suggesting that ACE polymorphisms may influence the response to alglucosidase alfa treatment and warrants further investigation. (C) 2016 The Authors. Published by Elsevier Inc.

关键词： Pompe disease Angiotensin-converting enzyme Gene polymorphism Enzyme replacement therapy Alglucosidase alfa

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The influence of a polymorphism in the gene encoding angiotensin converting enzyme (ACE) on treatment outcomes in late onset Pompe patients receiving alglucosidase alfa

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MOLECULAR GENETICS AND METABOLISM 2013年第2期108卷 S64-S64页

作者： McVie-Wylie, Alison baek, rena Palmer, Rachel Pomponio, Robert Genzyme Corp Framingham MA 01701 USA

150

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Restricted ketogenic diet enhances the therapeutic action of N-butyldeoxynojirimycin towards brain GM2 accumulation in adult Sandhoff disease mice

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JOURNAL OF NEUROCHEMISTRY 2010年第6期113卷 1525-1535页

作者： Denny, Christine A. Heinecke, Karie A. Kim, Youngho P. baek, rena C. Loh, Katrina S. Butters, Terry D. Bronson, Roderick T. Platt, Frances M. Seyfried, Thomas N. Boston Coll Dept Biol Chestnut Hill MA 02467 USA Univ Oxford Dept Biochem Glycobiol Inst Oxford OX1 3QU England Dana Farber Harvard Comprehens Canc Ctr Boston MA USA Univ Oxford Dept Pharmacol Oxford OX1 3QT England

P>Sandhoff disease is an autosomal recessive, neurodegenerative disease involving the storage of brain ganglioside GM2 and asialo-GM2. Previous studies showed that caloric restriction, which augments longevity, and N-butyldeoxynojirimycin (NB-DNJ, Miglustat), an imino sugar that hinders the glucosyltransferase catalyzing the first step in glycosphingolipid biosynthesis, both increase longevity and improve motor behavior in the beta-hexosaminidase (Hexb) knockout (-/-) murine model of Sandhoff disease. In this study, we used a restricted ketogenic diet (KD-R) and NB-DNJ to combat ganglioside accumulation. Adult Hexb-/- mice were placed into one of the following groups: (i) a standard diet (SD), (ii) a SD with NB-DNJ (SD + NB-DNJ), (iii) a KD-R, and (iv) a KD-R with NB-DNJ (KD-R + NB-DNJ). Forebrain GM2 content (mu g sialic acid/100 mg dry wt) in the four groups was 375 +/- 15, 312 +/- 8, 340 +/- 28, and 279 +/- 26, respectively, indicating an additive interaction between NB-DNJ and the KD-R. Most interestingly, brain NB-DNJ content was 3.5-fold greater in the KD-R + NB-DNJ mice than in the SD + NB-DNJ mice. These data suggest that the KD-R and NB-DNJ may be a potential combinatorial therapy for Sandhoff disease by enhancing NB-DNJ delivery to the brain and may allow lower dosing to achieve the same degree of efficacy as high dose monotherapy.

关键词： GA2 ganglioside GM2 ketogenic diet lysosomal storage disease Sandhoff disease

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Preclinical studies in support of phase I/II clinical trials to treat GUCY2D-associated Leber congenital amaurosis

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MOLECULAR THERAPY-METHODS & CLINICAL DEVELOPMENT 2023年 28卷 129-145页

作者： Boye, Sanford L. O'Riordan, Catherine Morris, James Lukason, Michael Compton, David baek, rena Elmore, Dana M. Peterson, James. J. Fajardo, Diego Mccullough, K. Tyler Scaria, Abraham McVie-Wylie, Alison Boye, Shannon E. Univ Florida Powell Gene Therapy Ctr Dept Pediat Gainesville FL 32610 USA Sanofi Framingham MA 01701 USA Atsena Therapeut Durham NC 27701 USA Univ Florida Dept Pediat Div Cellular & Mol Therapy POB 100296 Gainesville FL 32610 USA

Mutations in GUCY2D are associated with severe early-onset retinal dystrophy, Leber congenital amaurosis type 1 (LCA1), a leading cause of blindness in children. Despite a high degree of visual disturbance stemming from photoreceptor dysfunc-tion, patients with LCA1 largely retain normal photoreceptor structure, suggesting that they are good candidates for gene replacement therapy. The purpose of this study was to conduct the preclinical and IND-enabling experiments required to sup-port clinical application of AAV5-hGRK1-GUCY2D in patients harboring biallelic recessive mutations in GUCY2D. Preclinical studies were conducted in mice to evaluate the effect of vector manufacturing platforms and transgene species on the thera-peutic response. Dose-ranging studies were conducted in cyno-molgus monkeys to establish the minimum dose required for efficient photoreceptor transduction. Good laboratory practice (GLP) studies evaluated systemic biodistribution in rats and toxicology in non-human primates (NHPs). These results expanded our knowledge of dose response for an AAV5-vectored transgene under control of the human rhodopsin ki-nase (hGRK1) promoter in NHPs with respect to photore-ceptor transduction and safety and, in combination with the rat biodistribution and mouse efficacy studies, informed the design of a first-in-human clinical study in patients with LCA1.

关键词： AAV adeno-associated virus GUCY2D Leber congenital amaurosis LCA LCA1 retGC1 retinal guanylate cyclase gene therapy inherited retinal disease

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Biomarker and pathway analysis in Pompe disease

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MOLECULAR GENETICS AND METABOLISM 2019年第2期126卷 S59-S59页

作者： George, Kelly baek, rena Lane, Monica Oliva, Petra Zhang, Kate McVie-Wylie, Alison Sanofi Genzyme Framingham MA USA

120

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Quantitative Systems Pharmacology Modeling of Acid Sphingomyelinase Deficiency and the Enzyme Replacement Therapy Olipudase Alfa Is an Innovative Tool for Linking Pathophysiology and Pharmacology

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CPT-PHARMACOMETRICS & SYSTEMS PHARMACOLOGY 2018年第7期7卷 442-452页

作者： Kaddi, Chanchala D. Niesner, Bradley baek, rena Jasper, Paul Pappas, John Tolsma, John Li, Jing van Rijn, Zachary Tao, Mengdi Ortemann-Renon, Catherine Easton, Rachael Tan, Sharon Puga, Ana Cristina Schuchman, Edward H. Barrett, Jeffrey S. Azer, Karim Sanofi TMED Translat Informat Bridgewater MA 02139 USA Sanofi Genzyme Cambridge MA USA RES Grp Inc Needham MA USA Icahn Sch Med Mt Sinai Genet & Genom Sci New York NY USA

Acid sphingomyelinase deficiency (ASMD) is a rare lysosomal storage disorder with heterogeneous clinical manifestations, including hepatosplenomegaly and infiltrative pulmonary disease, and is associated with significant morbidity and mortality. Olipudase alfa (recombinant human acid sphingomyelinase) is an enzyme replacement therapy under development for the non-neurological manifestations of ASMD. We present a quantitative systems pharmacology (QSP) model supporting the clinical development of olipudase alfa. The model is multiscale and mechanistic, linking the enzymatic deficiency driving the disease to molecular-level, cellular-level, and organ-level effects. Model development was informed by natural history, and preclinical and clinical studies. By considering patient-specific pharmacokinetic (PK) profiles and indicators of disease severity, the model describes pharmacodynamic (PD) and clinical end points for individual patients. The ASMD QSP model provides a platform for quantitatively assessing systemic pharmacological effects in adult and pediatric patients, and explaining variability within and across these patient populations, thereby supporting the extrapolation of treatment response from adults to pediatrics.

关键词： NIEMANN-Pick diseases LUNG diseases ENZYMES PHARMACOLOGY MOLECULAR structure

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