Molecular genetics and metabolism最新文献

{"title":"Characterisation of infantile cardiomyopathy in Alström syndrome using ALMS1 knockout induced pluripotent stem cell derived cardiomyocyte model","authors":"Leena Patel ,&nbsp;Ashwin Roy ,&nbsp;Jonathan Barlow ,&nbsp;Christopher O'Shea ,&nbsp;Daniel Nieves ,&nbsp;Amar J. Azad ,&nbsp;Caitlin Hall ,&nbsp;Ben Davies ,&nbsp;Phalguni Rath ,&nbsp;Davor Pavlovic ,&nbsp;Ashish Chikermane ,&nbsp;Tarekegn Geberhiwot ,&nbsp;Richard P. Steeds ,&nbsp;Katja Gehmlich","doi":"10.1016/j.ymgme.2024.108575","DOIUrl":"10.1016/j.ymgme.2024.108575","url":null,"abstract":"<div><p>Alström syndrome (AS) is an inherited rare ciliopathy characterised by multi-organ dysfunction and premature cardiovascular disease. This may manifest as an infantile-onset dilated cardiomyopathy with significant associated mortality. An adult-onset restrictive cardiomyopathy may also feature later in life. Loss of function pathogenic variants in <em>ALMS1</em> have been identified in AS patients, leading to a lack of ALMS1 protein. The biological role of <em>ALMS1</em> is unknown, particularly in a cardiovascular context. To understand the role of <em>ALMS1</em> in infantile cardiomyopathy, the reduction of ALMS1 protein seen in AS patients was modelled using human induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs), in which <em>ALMS1</em> was knocked out. MuscleMotion analysis and calcium optical mapping experiments suggest that <em>ALMS1</em> knockout (KO) cells have increased contractility, with altered calcium extrusion and impaired calcium handling dynamics compared to wildtype (WT) counterparts. Seahorse metabolic assays showed <em>ALMS1</em> knockout iPSC-CMs had increased glycolytic and mitochondrial respiration rates, with <em>ALMS1</em> knockout cells portraying increased energetic demand and respiratory capacity than WT counterparts. Using senescence associated β-galactosidase (SA-β gal) staining assay, we identified increased senescence of <em>ALMS1</em> knockout iPSC-CMs. Overall, this study provides insights into the molecular mechanisms in AS, particularly the role of <em>ALMS1</em> in infantile cardiomyopathy in AS, using iPSC-CMs as a ‘disease in a dish’ model to provide insights into multiple aspects of this complex disease.</p></div>","PeriodicalId":18937,"journal":{"name":"Molecular genetics and metabolism","volume":"143 1","pages":"Article 108575"},"PeriodicalIF":3.7,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S1096719224004591/pdfft?md5=73579819ff6ee142177ea42d49285583&pid=1-s2.0-S1096719224004591-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142145988","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Elevated cerebrospinal fluid glial fibrillary acidic protein levels in Smith-Lemli-Opitz syndrome","authors":"Rachel A. Luke ,&nbsp;Niamh X. Cawley ,&nbsp;Samar Rahhal ,&nbsp;Aishwarya Selvaraman ,&nbsp;Audrey Thurm ,&nbsp;Christopher A. Wassif ,&nbsp;Forbes D. Porter","doi":"10.1016/j.ymgme.2024.108570","DOIUrl":"10.1016/j.ymgme.2024.108570","url":null,"abstract":"<div><p>Smith-Lemli-Opitz syndrome (SLOS) is a rare, multiple malformation/intellectual disability disorder caused by pathogenic variants of <em>DHCR7.</em> DHCR7 catalyzes the reduction of 7-dehydrocholesterol (7DHC) to cholesterol in the final step of cholesterol biosynthesis. This results in accumulation of 7DHC and a cholesterol deficiency. Although the biochemical defect is well delineated and multiple mechanisms underlying developmental defects have been explored, the post developmental neuropathological consequences of altered central nervous system sterol composition have not been studied. Preclinical studies suggest that astroglial activation may occur in SLOS. To determine if astroglial activation is present in individuals with SLOS, we quantified cerebrospinal fluid (CSF) glial fibrillary acidic protein using a Quanterix Simoa® GFAP Discovery Kit for SR-X™. Relative to an age-appropriate comparison group, we found that CSF GFAP levels were elevated 3.9-fold in SLOS (3980 ± 3732 <em>versus</em> 1010 ± 577 pg/ml, <em>p</em> = 0.0184). Simvastatin, a 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitor, has previously been shown to increase expression of hypomorphic <em>DHCR7</em> alleles and in a placebo-controlled trial improved serum sterol levels and decreased irritability. Using archived CSF samples from that prior study, we observed a significant decrease (<em>p</em> = 0.0119) in CSF GFAP levels in response to treatment with simvastatin. Although further work needs to be done to understand the potential contribution of neuroinflammation to SLOS neuropathology and cognitive dysfunction, these data confirm astroglial activation in SLOS and suggest that CSF GFAP may be a useful biomarker to monitor therapeutic responses.</p></div>","PeriodicalId":18937,"journal":{"name":"Molecular genetics and metabolism","volume":"143 1","pages":"Article 108570"},"PeriodicalIF":3.7,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142149513","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Assessment of combined α-GAL enzyme activity and lyso-GL3 for Fabry disease screening in women with chronic kidney disease","authors":"Cassiano Augusto Braga Silva ,&nbsp;Fellype de Carvalho Barreto ,&nbsp;Osvaldo Merege Vieira Neto ,&nbsp;Leandro Junior Lucca ,&nbsp;Fernando A. Vieira ,&nbsp;Ana Paula Santana Gueiros ,&nbsp;Marta V. Boger ,&nbsp;Artur Quintiliano Silva ,&nbsp;Felipe Leite Guedes ,&nbsp;Karla Cristina P. Israel ,&nbsp;Gina Elizabeth Moreno Gordon ,&nbsp;Valeria S.P. Veloso ,&nbsp;Gabriela Sevignani ,&nbsp;Carolina Teles Barretto ,&nbsp;Maria Gabriela Rosa ,&nbsp;Roberta C. Pascotto ,&nbsp;Gelzie S. Ennes ,&nbsp;Eduarda Morgana da Silva Montenegro Malaguti Souza ,&nbsp;Marcia Goncalves Ribeiro ,&nbsp;Luis Gustavo Modelli de Andrade","doi":"10.1016/j.ymgme.2024.108565","DOIUrl":"10.1016/j.ymgme.2024.108565","url":null,"abstract":"<div><h3>Introduction</h3><p>The spectrum of clinical presentation of Fabry disease (FD) in women is broad and challenging<strong>.</strong> The aim is to evaluate the effectiveness of an alternative screening method for FD in women.</p></div><div><h3>Methods</h3><p>A collaborative multicenter cross-sectional study to evaluate the sensitivity and specificity of the combination of two tests (α-GAL enzyme activity assay and lyso-GL3 assay) for the diagnosis of FD in women. We included women with chronic kidney disease (CKD) stages 3 to 5, receiving conservative treatment or on dialysis programs, from different nephrology services in Brazil.</p></div><div><h3>Results</h3><p>We evaluated 1874 patients that underwent blood collection for α-GAL and lyso-GL3 assays. Isolated decreased α-GAL enzyme activity was found in 64 patients (3.5%), while isolated increased lyso-GL3 levels were found in 67 patients (3.6%), with one patient presenting alterations in both tests. All cases with low α-GAL enzyme activity and/or increased lyso-GL3 levels underwent genetic analysis for FD variants (132 performed <em>GLA</em> genetic test). Low α-GAL enzyme activity had higher sensitivity and specificity to detect FD compared to the other measures (elevated lyso-GL3 alone or both altered). The negative predictive value (NPV) of α-GAL activity was 99%, and the positive predictive value (PPV) was 9.2%. For lyso-GL3 assay, the specificity was 99.7% and the PPV was 2.9%, therefore considered inferior to α-GAL assay. Both assays altered, had higher PPV (100%) and higher NPV (99.7%) considered the best method. We found 7 cases of <em>GLA</em> gene variants found, resulting in an initial prevalence of 0.37% for FD in this sample female population.</p></div><div><h3>Conclusion</h3><p>This study contributes to the diagnostic value of the biomarkers α-GAL and lyso-GL3 in the context of FD in women with CKD. The combination of these biomarkers was an effective approach for the diagnosis of the disease, with high PPV and NPV.</p></div>","PeriodicalId":18937,"journal":{"name":"Molecular genetics and metabolism","volume":"143 1","pages":"Article 108565"},"PeriodicalIF":3.7,"publicationDate":"2024-08-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S1096719224004499/pdfft?md5=e5071ac76c7f1111db4ec20e142892cd&pid=1-s2.0-S1096719224004499-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142050089","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Pharmacodynamic profiling in three patients with molybdenum cofactor deficiency type A reveals prolonged biological effects after withdrawal of cyclic pyranopterin monophosphate","authors":"B.C. Schwahn ,&nbsp;K. Barvíková ,&nbsp;H.T. Wu ,&nbsp;A. Horman ,&nbsp;E. Emmett ,&nbsp;V. Kožich","doi":"10.1016/j.ymgme.2024.108563","DOIUrl":"10.1016/j.ymgme.2024.108563","url":null,"abstract":"<div><p>Molybdenum cofactor deficiency type A has successfully been treated in a small number of children with daily intravenous administration of cyclic pyranopterin monophosphate. Pharmacodynamic data for this novel treatment have not been published and alternative dosing intervals have not been explored. We monitored pharmacodynamic biomarkers of sulfite oxidase and xanthine oxidoreductase activity in three patients with MoCD-A for a period of 2 to 9 months after discontinuation of cPMP substitution. We found that the clinical and metabolic effects were sustained for longer than expected, over 7 days at least. Our data implicate a biological half-life of the molybdenum cofactor dependent enzyme activities of approximately 3 days and suggest the possibility that less frequent than once daily dosing intervals could be a safe alternative to current practice.</p></div>","PeriodicalId":18937,"journal":{"name":"Molecular genetics and metabolism","volume":"143 1","pages":"Article 108563"},"PeriodicalIF":3.7,"publicationDate":"2024-08-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142012743","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Improved therapeutic efficacy in two mouse models of methylmalonic acidemia (MMA) using a second-generation mRNA therapy","authors":"Kimberly A. Coughlan,&nbsp;Marianne Eybye,&nbsp;Nicholas Henderson,&nbsp;Christine M. DeAntonis,&nbsp;Andrea Frassetto,&nbsp;Erin Hanahoe,&nbsp;Tatiana Ketova,&nbsp;Eric Jacquinet,&nbsp;Vladimir Presnyak,&nbsp;Ruchi Jain,&nbsp;John Marshall,&nbsp;Paolo G.V. Martini","doi":"10.1016/j.ymgme.2024.108560","DOIUrl":"10.1016/j.ymgme.2024.108560","url":null,"abstract":"<div><p>Isolated methylmalonic acidemia/aciduria (MMA) due to MMUT enzyme deficiency is an ultra-rare pediatric disease with high morbidity and mortality, with no approved disease-altering therapies. Previous publications showed that systemic treatment with a codon-optimized mRNA encoding wild-type human MMUT (MMUT) is a promising strategy for treatment of MMA. We developed a second-generation drug product, mRNA-3705, comprised of an mRNA encoding the MMUT enzyme formulated in a lipid nanoparticle (LNP) with incorporation of enhancements over the previous clinical candidate mRNA-3704. Both drug products produced functional MMUT in rat livers when dosed IV, and showed long-term safety and efficacy in two mouse models of MMA. mRNA-3705 produced 2.1–3.4-fold higher levels of hepatic MMUT protein expression than the first-generation drug product mRNA-3704 when given at an identical dose level, which resulted in greater and more sustained reductions in plasma methylmalonic acid. The data presented herein provide comprehensive preclinical pharmacology to support the clinical development of mRNA-3705.</p></div>","PeriodicalId":18937,"journal":{"name":"Molecular genetics and metabolism","volume":"143 1","pages":"Article 108560"},"PeriodicalIF":3.7,"publicationDate":"2024-08-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141913318","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Clinical outcomes in elderly patients receiving agalsidase alfa treatment in the Fabry Outcome Survey","authors":"Albina Nowak ,&nbsp;Jaco Botha ,&nbsp;Christina Anagnostopoulou ,&nbsp;Derralynn A. Hughes","doi":"10.1016/j.ymgme.2024.108561","DOIUrl":"10.1016/j.ymgme.2024.108561","url":null,"abstract":"<div><h3>Background and objectives</h3><p>Treatment with agalsidase alfa in patients with Fabry disease is most effective when initiated early in the disease course; however, the clinical benefits in elderly patients are less well established. This analysis assesses outcomes in patients aged 65 years or older from the Fabry Outcome Survey (FOS) who were treated with agalsidase alfa.</p></div><div><h3>Methods</h3><p>FOS data were extracted for adult patients aged 65 years or older who received agalsidase alfa, had baseline data and at least 3 years of post-baseline data, and had undergone no renal transplantation and/or dialysis before treatment. The data of patients who had undergone renal transplantation and/or dialysis during follow-up were excluded from estimated glomerular filtration rate (eGFR) analysis after the date of the renal transplantation and/or dialysis. Adult patients were stratified into two groups: those who started treatment before 65 years of age and who were still being treated when aged 65 years or older (group A), and those who started treatment when aged 65 years or older (group B). Mean annual changes in left ventricular mass index (LVMI), eGFR and proteinuria were assessed in group A (before and after the age of 65 years to understand if there was an age-related effect once patients turned 65 years of age) and in group B.</p></div><div><h3>Results</h3><p>Estimated mean (standard error [SE]) annual changes in LVMI were 0.46 (0.26) g/m^2.7 and 0.21 (0.42) g/m^2.7 in patients in group A when they were younger than 65 years and when they were aged 65 years or older, respectively, and 0.12 (0.65) g/m^2.7 in patients in group B. For eGFR, mean (SE) annual changes were 0.83 (2.12) mL/min/1.73 m² and 2.64 (2.18) mL/min/1.73 m² in patients in group A when they were younger than 65 years and when they were aged 65 years or older, respectively, and 2.31 (1.44) mL/min/1.73 m² in patients in group B. Proteinuria remained relatively stable in both subgroups of group A (before and after the age of 65 years) and group B.</p></div><div><h3>Conclusions</h3><p>Continuation and initiation of agalsidase alfa treatment in patients aged 65 years or older with Fabry disease were associated with stabilization of proteinuria and minimal increases in cardiac (LVMI) and renal (eGFR) outcomes.</p></div>","PeriodicalId":18937,"journal":{"name":"Molecular genetics and metabolism","volume":"143 1","pages":"Article 108561"},"PeriodicalIF":3.7,"publicationDate":"2024-08-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142002472","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Clinical insight meets scientific innovation to develop a next generation ERT for Pompe disease","authors":"Priya S. Kishnani ,&nbsp;Yin-Hsiu Chien ,&nbsp;Kenneth I. Berger ,&nbsp;Nate Thibault ,&nbsp;Susan Sparks","doi":"10.1016/j.ymgme.2024.108559","DOIUrl":"10.1016/j.ymgme.2024.108559","url":null,"abstract":"<div><p>Years of research into the structure, processing, and function of acid alpha-glucosidase led to the development and 2006 approval of alglucosidase alfa (recombinant human acid alpha-glucosidase, Myozyme®/Lumizyme®), an enzyme replacement therapy and the first approved treatment for Pompe disease. Alglucosidase alfa has been a lifesaving treatment for patients with infantile-onset Pompe disease and radically improved daily life for patients with late-onset Pompe disease; however, long-term experience with alglucosidase alfa unraveled key unmet needs in these populations.</p><p>Despite treatment, Pompe disease continues to progress, especially from a skeletal muscle perspective, resulting in a multitude of functional limitations. Strong collaboration between the scientific and patient communities led to increased awareness of Pompe disease, a better understanding of disease pathophysiology, knowledge of the clinical course of the disease as patients surpassed the first decade of life, and the strengths and limitations of enzyme replacement therapy. Taken together, these advancements spurred the need for development of a next generation of enzyme replacement therapy and provided a framework for progress toward other novel treatments. This review provides an overview of the development of avalglucosidase alfa as a model to highlight the interaction between clinical experience with existing treatments, the role of the clinician scientist, translational research at both system and cellular levels, and the iterative and collaborative process that optimizes the development of therapeutics.</p></div>","PeriodicalId":18937,"journal":{"name":"Molecular genetics and metabolism","volume":"143 1","pages":"Article 108559"},"PeriodicalIF":3.7,"publicationDate":"2024-08-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141998295","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Patient-reported outcomes and functional assessments of patients with Alkaptonuria in a 3-year Nitisinone treatment trial","authors":"Kathryn R. Spears ,&nbsp;Francis Rossignol ,&nbsp;Monique B. Perry ,&nbsp;Michael A. Kayser ,&nbsp;Pim Suwannarat ,&nbsp;Kevin E. O'Brien ,&nbsp;Joy C. Bryant ,&nbsp;Wendy F. Greenwood ,&nbsp;Steve Fuller ,&nbsp;William A. Gahl ,&nbsp;Wendy J. Introne","doi":"10.1016/j.ymgme.2024.108562","DOIUrl":"10.1016/j.ymgme.2024.108562","url":null,"abstract":"<div><p>Alkaptonuria is a rare disorder of tyrosine catabolism caused by deficiency of homogentisate 1,2-dioxygenase that leads to accumulation of homogentisic acid (HGA). Deposition of HGA-derived polymers in connective tissue causes progressive arthropathy of the spine and large joints, cardiac valvular disease, and genitourinary stones beginning in the fourth decade of life. Nitisinone, a potent inhibitor of the upstream enzyme, 4-hydroxyphenylpyruvate dioxygenase, dramatically reduces HGA production. As such, nitisinone is a proposed treatment for alkaptonuria. A randomized clinical trial of nitisinone in alkaptonuria confirmed the biochemical efficacy and tolerability of nitisinone for patients with alkaptonuria but the selected primary outcome did not demonstrate significant clinical benefit. Given that alkaptonuria is a rare disease with slow progression and variable presentation, identifying outcome parameters that can detect significant change during a time-limited clinical trial is challenging. To gain insight into patient-perceived improvements in quality of life and corresponding changes in physical function associated with nitisinone use, we conducted a <em>post-hoc</em> per protocol analysis of patient-reported outcomes and a functional assessment. Analysis revealed that nitisinone-treated patients showed significant improvements in complementary domains of the 36-Item Short-Form Survey (SF-36) and 6-min walk test (6MWT). Together, these findings suggest that nitisinone improves both quality of life and function of patients with alkaptonuria. The observed trends support nitisinone as a therapy for alkaptonuria.</p></div>","PeriodicalId":18937,"journal":{"name":"Molecular genetics and metabolism","volume":"143 1","pages":"Article 108562"},"PeriodicalIF":3.7,"publicationDate":"2024-08-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141913319","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cover 2 / Ed. Board","authors":"","doi":"10.1016/S1096-7192(24)00431-1","DOIUrl":"10.1016/S1096-7192(24)00431-1","url":null,"abstract":"","PeriodicalId":18937,"journal":{"name":"Molecular genetics and metabolism","volume":"142 4","pages":"Article 108547"},"PeriodicalIF":3.7,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S1096719224004311/pdfft?md5=1f50ff631a085552509d76be9e4d67bb&pid=1-s2.0-S1096719224004311-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141961112","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Clinical and preclinical insights into high-dose ambroxol therapy for Gaucher disease type 2 and 3: A comprehensive systematic review","authors":"Bibiche den Hollander ,&nbsp;Hoang Lan Le ,&nbsp;Eleonora L. Swart ,&nbsp;Hennie Bikker ,&nbsp;Carla E.M. Hollak ,&nbsp;Marion M. Brands","doi":"10.1016/j.ymgme.2024.108556","DOIUrl":"10.1016/j.ymgme.2024.108556","url":null,"abstract":"<div><h3>Rationale</h3><p>Gaucher disease (GD), an autosomal recessive lysosomal storage disease, results from <em>GBA1</em> variants causing glucocerebrosidase (GCase) deficiency. While enzyme replacement therapy (ERT) helps with systemic symptoms, neurological complications in GD2 and GD3 persist due to the blood-brain-barrier (BBB) limiting ERT efficacy. Ambroxol, a BBB-permeable chaperone, enhances GCase activity. Our review explores high-dose ambroxol's therapeutic potential, both preclinical and clinical, in GD2 and GD3.</p></div><div><h3>Methods</h3><p>PubMed was searched for studies published before March 2023, including clinical, animal, and in vitro studies focusing on the effect of high-dose ambroxol in GD2 and GD3. A narrative synthesis was performed.</p></div><div><h3>Results</h3><p>Nine in vitro, three animal, and eight clinical studies were included, demonstrating varied responses to ambroxol across diverse outcome measures. In vitro and animal studies demonstrated reduced endoplasmatic reticulum stress due to the relocation of GCase from the ER to the lysosomes. In vitro cell lines exhibited varying degrees of increased GCase activity. Clinical trials observed reduced lyso-GL1 levels in plasma (41–89%) and cerebrospinal fluid (CSF) (26–97%), alongside increased GCase activity in GD3 patients. Ambroxol exhibited varying effects on neurological outcomes and development. No severe adverse events were reported.</p></div><div><h3>Conclusion</h3><p>High-dose ambroxol shows promise in managing neurological manifestations in GD3, albeit with uncertainties resulting from genetic heterogeneity and variable response. Further clinical trials, are essential for elucidating dosage-response relationships and refining treatment outcomes and strategies for neuronopathic GD.</p></div>","PeriodicalId":18937,"journal":{"name":"Molecular genetics and metabolism","volume":"143 1","pages":"Article 108556"},"PeriodicalIF":3.7,"publicationDate":"2024-07-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141907086","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}