Journal of Inherited Metabolic Disease最新文献

{"title":"Therapeutic liver cell transplantation to treat murine PKU","authors":"Melanie Willimann,&nbsp;Hiu Man Grisch-Chan,&nbsp;Nicole Rimann,&nbsp;Tanja Rothgangl,&nbsp;Martina Hruzova,&nbsp;Gerald Schwank,&nbsp;Beat Thöny","doi":"10.1002/jimd.12802","DOIUrl":"10.1002/jimd.12802","url":null,"abstract":"<p>For gene therapy of the liver, in vivo applications based on adeno-associated virus are the most advanced vectors despite limitations, including low efficacy and episomal loss, potential integration and safety issues, and high production costs. Alternative vectors and/or delivery routes are of high interest. The regenerative ability of the liver bears the potential for ex vivo therapy using liver cell transplantation for disease correction if provided with a selective advantage to expand and replace the existing cell mass. Here we present such treatment of a mouse model of human phenylketonuria (PKU). Primary hepatocytes from wild-type mice were gene modified in vitro (with a lentiviral vector) that carries a gene editing system (CRISPR) to inhibit <i>Cypor</i>. <i>Cypor</i> inactivation confers paracetamol (or acetaminophen) resistance to hepatocytes and thus a growth advantage to eliminate the pre-existing liver cells upon grafting (via the spleen) and exposure to repeated treatment with paracetamol. Grafting <i>Cypor</i>-inactivated wild-type hepatocytes into inbred young adult <i>enu2</i> (PKU) mice, followed by selective expansion by paracetamol dosing, resulted in replacing up to 5% of cell mass, normalization of blood phenylalanine, and permanent correction of PKU. Hepatocyte transplantation offers thus an armamentarium of novel therapy options for genetic liver defects.</p>","PeriodicalId":16281,"journal":{"name":"Journal of Inherited Metabolic Disease","volume":"47 6","pages":"1322-1335"},"PeriodicalIF":4.2,"publicationDate":"2024-10-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jimd.12802","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142502178","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Exploring RNA therapeutics for urea cycle disorders","authors":"Eva Richard,&nbsp;Ainhoa Martínez-Pizarro,&nbsp;Lourdes R. Desviat","doi":"10.1002/jimd.12807","DOIUrl":"10.1002/jimd.12807","url":null,"abstract":"<p>RNA has triggered a significant shift in modern medicine, providing a promising way to revolutionize disease treatment methods. Different therapeutic RNA modalities have shown promise to replace, supplement, correct, suppress, or eliminate the expression of a targeted gene. Currently, there are 22 RNA-based drugs approved for clinical use, including the COVID-19 mRNA vaccines, whose unprecedented worldwide success has meant a definitive boost in the RNA research field. Urea cycle disorders (UCD), liver diseases with high mortality and morbidity, may benefit from the progress achieved, as different genetic payloads have been successfully targeted to liver using viral vectors, N-acetylgalactosamine (GalNAc) conjugations or lipid nanoparticles (LNP). This review explores the potential of RNA-based medicines for UCD and the ongoing development of applications targeting specific gene defects, enzymes, or transporters taking part in the urea cycle. Notably, LNP-formulated mRNA therapy has been assayed preclinically for citrullinemia type I (CTLN1), adolescent and adult citrin deficiency, argininosuccinic aciduria, arginase deficiency and ornithine transcarbamylase deficiency, in the latter case has progressed to the clinical trials phase.</p>","PeriodicalId":16281,"journal":{"name":"Journal of Inherited Metabolic Disease","volume":"47 6","pages":"1269-1277"},"PeriodicalIF":4.2,"publicationDate":"2024-10-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jimd.12807","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142502135","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Natural history of valve disease in patients with mucopolysaccharidosis II and the impact of enzyme replacement therapy","authors":"Christoph Kampmann,&nbsp;Christina Lampe,&nbsp;Christiane M. Wiethoff,&nbsp;Laila Arash-Kaps,&nbsp;Eugen Mengel,&nbsp;Joerg Reinke,&nbsp;Michael Beck,&nbsp;Julia B. Hennermann,&nbsp;Tariq Abu-Tair","doi":"10.1002/jimd.12808","DOIUrl":"10.1002/jimd.12808","url":null,"abstract":"<p>Mucopolysaccharidosis II (MPS II, Hunter syndrome) is a rare, X-linked lysosomal storage disease caused by reduced activity of iduronate-2-sulfatase (I2S), with subsequent cellular accumulation of the glycosaminoglycans (GAGs), heparan sulfate, and dermatan sulfate (DS). DS is a major component of the extracellular matrix of heart valves, which can be affected in MPS II. We investigated the natural history of valve disease in MPS II and the impact of long-term intravenous enzyme replacement therapy (ERT) with recombinant I2S (idursulfase). In total, 604 cardiac examinations were assessed from serial follow-up of 80 male patients (49 neuronopathic). Valve disease was classified according to standard practice from hemodynamic features evident from echocardiography. The natural history group comprised 48 patients (up to 14.8 years of follow-up; median, 2.6 years; 24 patients started ERT during the study); 56 patients were treated (up to 14.2 years of follow-up; median, 6.2 years). Lifetime GAG burden (calculated from urinary GAG measurements) correlated significantly with the degree of valve disease. Onset of moderate-to-severe valve disease was significantly delayed in treated (median age at onset, 29.1 ± 2 [95% CI: 25.2–32.9] years; Kaplan–Meier estimation) versus untreated patients (17.6 ± 1 [95% Cl: 15.8–19.4] years; <i>p</i> &lt; 0.0001). Cox regression modeling found that long-term ERT reduced the probability of developing severe valve disease (<i>χ</i>², 32.736; significant after 5 years of ERT). Overall, this study found that valve disease severity in MPS II correlates with GAG burden and that progression is delayed by long-term ERT.</p>","PeriodicalId":16281,"journal":{"name":"Journal of Inherited Metabolic Disease","volume":"48 1","pages":""},"PeriodicalIF":4.2,"publicationDate":"2024-10-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11670151/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142502136","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"An update on autophagy disorders","authors":"Hormos Salimi Dafsari,&nbsp;Diego Martinelli,&nbsp;Afshin Saffari,&nbsp;Darius Ebrahimi-Fakhari,&nbsp;Manolis Fanto,&nbsp;Carlo Dionisi-Vici,&nbsp;Heinz Jungbluth","doi":"10.1002/jimd.12798","DOIUrl":"10.1002/jimd.12798","url":null,"abstract":"<p>Macroautophagy is a highly conserved cellular pathway for the degradation and recycling of defective cargo including proteins, organelles, and macromolecular complexes. As autophagy is particularly relevant for cellular homeostasis in post-mitotic tissues, congenital disorders of autophagy, due to monogenic defects in key autophagy genes, share a common “clinical signature” including neurodevelopmental, neurodegenerative, and neuromuscular features, as well as variable abnormalities of the eyes, skin, heart, bones, immune cells, and other organ systems, depending on the expression pattern and the specific function of the defective proteins. Since the clinical and genetic resolution of <i>EPG5</i>-related Vici syndrome, the paradigmatic congenital disorder of autophagy, the widespread use of massively parallel sequencing has resulted in the identification of a growing number of autophagy-associated disease genes, encoding members of the core autophagy machinery as well as related proteins. Recently identified monogenic disorders linking selective autophagy, vesicular trafficking, and other pathways have further expanded the molecular and phenotypical spectrum of congenital disorders of autophagy as a clinical disease spectrum. Moreover, significant advances in basic research have enhanced the understanding of the underlying pathophysiology as a basis for therapy development. Here, we review (i) autophagy in the context of other intracellular trafficking pathways; (ii) the main congenital disorders of autophagy and their typical clinico-pathological signatures; and (iii) the recommended primary health surveillance in monogenic disorders of autophagy based on available evidence. We further discuss recently identified molecular mechanisms that inform the current understanding of autophagy in health and disease, as well as perspectives on future therapeutic approaches.</p>","PeriodicalId":16281,"journal":{"name":"Journal of Inherited Metabolic Disease","volume":"48 1","pages":""},"PeriodicalIF":4.2,"publicationDate":"2024-10-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11669743/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142467662","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Protein requirements in adults with phenylketonuria and bioavailability of glycomacropeptide compared to an l-amino acid-based product","authors":"Abrar Turki,&nbsp;Sylvia Stockler-Ipsiroglu,&nbsp;Sandra Sirrs,&nbsp;Jennifer Branov,&nbsp;Taryn Bosdet,&nbsp;Rajavel Elango","doi":"10.1002/jimd.12806","DOIUrl":"10.1002/jimd.12806","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Phenylketonuria (PKU) is caused by phenylalanine hydroxylase deficiency. Treatment is primarily a low-Phe diet combined with <span>l</span>-amino acid-based products (<span>l</span>-AA). Protein requirements in adults with PKU have not been directly determined. A formula with glycomacropeptide (GMP) and low phenylalanine is available, yet untested for optimal protein synthesis.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Objectives</h3>\u0000 \u0000 <p>To determine the protein requirements in adults with PKU and the bioavailability of GMP-AA in the same patients using the indicator amino acid oxidation (IAAO) technique.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Each participant was allocated to 7 separate <span>l</span>-AA intakes (range: 0.1–1.8 g/kg/day) in Experiment 1. In Experiment 2, the same patients participated in 4 GMP-AA intakes (range: 0.1–0.9 g/kg/day). The IAAO method with <span>l</span>-[1-¹³C]-lysine as the indicator amino acid and its oxidation to ¹³CO₂ was used as the primary indicator of protein synthesis. Protein requirements were identified with a breakpoint, and bioavailability was determined by comparing ¹³CO₂ slope from GMP-AA versus <span>l</span>-AA.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Six adults with PKU (4 M: 2F) completed a total of 54 study days over the 2 experiments. The estimated average requirement (EAR) for protein was determined to be 1.11 g/kg/day (<i>R</i>² = 0.20). The bioavailability of protein from GMP-AA was determined to be 99.98%, which was high and near to 100% comparable to <span>l</span>-AA; although, the results apply only to the tested GMP-AA blend.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>To our knowledge, this is the first study to directly define a quantitative protein requirement and indicates that current PKU protein recommendations for adults with PKU may be underestimated. The bioavailability of protein in the GMP-AA blend was high and optimal for protein synthesis in adults with PKU.</p>\u0000 </section>\u0000 </div>","PeriodicalId":16281,"journal":{"name":"Journal of Inherited Metabolic Disease","volume":"48 1","pages":""},"PeriodicalIF":4.2,"publicationDate":"2024-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11670041/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142467663","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Disease models of Leigh syndrome: From yeast to organoids","authors":"Marie-Thérèse Henke,&nbsp;Alessandro Prigione,&nbsp;Markus Schuelke","doi":"10.1002/jimd.12804","DOIUrl":"10.1002/jimd.12804","url":null,"abstract":"<p>Leigh syndrome (LS) is a severe mitochondrial disease that results from mutations in the nuclear or mitochondrial DNA that impairs cellular respiration and ATP production. Mutations in more than 100 genes have been demonstrated to cause LS. The disease most commonly affects brain development and function, resulting in cognitive and motor impairment. The underlying pathogenesis is challenging to ascertain due to the diverse range of symptoms exhibited by affected individuals and the variability in prognosis. To understand the disease mechanisms of different LS-causing mutations and to find a suitable treatment, several different model systems have been developed over the last 30 years. This review summarizes the established disease models of LS and their key findings. Smaller organisms such as yeast have been used to study the biochemical properties of causative mutations. <i>Drosophila melanogaster</i>, <i>Danio rerio</i>, and <i>Caenorhabditis elegans</i> have been used to dissect the pathophysiology of the neurological and motor symptoms of LS. Mammalian models, including the widely used <i>Ndufs4</i> knockout mouse model of complex I deficiency, have been used to study the developmental, cognitive, and motor functions associated with the disease. Finally, cellular models of LS range from immortalized cell lines and trans-mitochondrial cybrids to more recent model systems such as patient-derived induced pluripotent stem cells (iPSCs). In particular, iPSCs now allow studying the effects of LS mutations in specialized human cells, including neurons, cardiomyocytes, and even three-dimensional organoids. These latter models open the possibility of developing high-throughput drug screens and personalized treatments based on defined disease characteristics captured in the context of a defined cell type. By analyzing all these different model systems, this review aims to provide an overview of past and present means to elucidate the complex pathology of LS. We conclude that each approach is valid for answering specific research questions regarding LS, and that their complementary use could be instrumental in finding treatment solutions for this severe and currently untreatable disease.</p>","PeriodicalId":16281,"journal":{"name":"Journal of Inherited Metabolic Disease","volume":"47 6","pages":"1292-1321"},"PeriodicalIF":4.2,"publicationDate":"2024-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jimd.12804","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142391115","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Extended long-term efficacy and safety of velmanase alfa treatment up to 12 years in patients with alpha-mannosidosis","authors":"Nathalie Guffon,&nbsp;Line Borgwardt,&nbsp;Anna Tylki-Szymańska,&nbsp;Andrea Ballabeni,&nbsp;Francesca Donà,&nbsp;Amer Joseph,&nbsp;Henriët Nienhuis,&nbsp;Caterina Maugeri,&nbsp;Allan Lund","doi":"10.1002/jimd.12799","DOIUrl":"10.1002/jimd.12799","url":null,"abstract":"<p>Enzyme replacement therapy (ERT) using velmanase alfa previously showed promising efficacy and safety outcomes for up to 4 years of therapy in patients with alpha-mannosidosis. This pooled analysis from two multicenter, open-label phase IIIb extension trials rhLAMAN-07 (<i>N</i> = 13; NCT01908712) and rhLAMAN-09 (<i>N</i> = 8; NCT01908725) evaluated the long-term effects of velmanase alfa. Sixteen patients who previously completed phase I–III rhLAMAN-02/-03/-04/-05/-08 trials and five ERT-naïve patients were enrolled. Patients received 1 mg/kg velmanase alfa once weekly. Endpoints included changes from treatment baseline (before initial dose of velmanase alfa in any trial) in serum oligosaccharides, 6-minute walk test (6MWT), 3-minute stair climb test (3MSCT), pulmonary function (forced vital capacity [FVC], % predicted), serum immunoglobulin G (IgG) levels, and adverse events. The overall cohort comprised 21 patients, divided by age at treatment baseline into pediatric (<i>n</i> = 14) and adult subgroups (<i>n</i> = 7). Distance walked according to 6MWT increased or stabilized in pediatric patients, while in adults either stabilization or slight decline was observed. Similarly, pediatric patients performed better in the 3MSCT. Changes in FVC, % predicted, were comparable in both subgroups up to ~6 years of observation, diverging thereafter. Overall, sustained serum oligosaccharide clearance and serum IgG level increase was observed upon treatment initiation and persisted until last common observation. Velmanase alfa treatment was generally well tolerated, with the majority of reported adverse events being of mild-to-moderate intensity. With follow-up of up to 12 years, long-term efficacy and safety outcomes indicate continued benefits of velmanase alfa in patients with alpha-mannosidosis.</p>","PeriodicalId":16281,"journal":{"name":"Journal of Inherited Metabolic Disease","volume":"48 1","pages":""},"PeriodicalIF":4.2,"publicationDate":"2024-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11667663/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142391116","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A phase III, open-label clinical trial evaluating pegunigalsidase alfa administered every 4 weeks in adults with Fabry disease previously treated with other enzyme replacement therapies","authors":"Myrl Holida,&nbsp;Aleš Linhart,&nbsp;Antonio Pisani,&nbsp;Nicola Longo,&nbsp;François Eyskens,&nbsp;Ozlem Goker-Alpan,&nbsp;Eric Wallace,&nbsp;Patrick Deegan,&nbsp;Camilla Tøndel,&nbsp;Ulla Feldt-Rasmussen,&nbsp;Derralynn Hughes,&nbsp;Anat Sakov,&nbsp;Rossana Rocco,&nbsp;Einat Brill Almon,&nbsp;Sari Alon,&nbsp;Raul Chertkoff,&nbsp;David G. Warnock,&nbsp;Stephen Waldek,&nbsp;William R. Wilcox,&nbsp;John A. Bernat","doi":"10.1002/jimd.12795","DOIUrl":"10.1002/jimd.12795","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <p>Pegunigalsidase alfa, a PEGylated α-galactosidase A enzyme replacement therapy (ERT) for Fabry disease, has a longer plasma half-life than other ERTs administered intravenously every 2 weeks (E2W). BRIGHT (NCT03180840) was a phase III, open-label study in adults with Fabry disease, previously treated with agalsidase alfa or beta E2W for ≥3 years, who switched to 2 mg/kg pegunigalsidase alfa every 4 weeks (E4W) for 52 weeks. Primary objective assessed safety, including number of treatment-emergent adverse events (TEAEs). Thirty patients were enrolled (24 males); 23 previously received agalsidase beta. Pegunigalsidase alfa plasma concentrations remained above the lower limit of quantification throughout the 4-week dosing interval. Thirty-three of 182 TEAEs (in 9 patients) were considered treatment-related; all were mild/moderate. No patients developed de novo anti-drug antibodies (ADAs). In the efficacy analysis (<i>n</i> = 29), median (inter-quartile range) eGFR change from baseline over 52 weeks was −1.9 (−5.9; 1.8) mL/min/1.73 m² (<i>n</i> = 28; males [<i>n</i> = 22]: –2.4 [−5.2; 3.2]; females [<i>n</i> = 6]: −0.7 [−9.2; 2.0]). Overall, median eGFR slope was –1.9 (−8.3; 1.9) mL/min/1.73 m²/year (ADA-negative [<i>n</i> = 20]: −1.2 [−6.4; 2.6]; ADA-positive [<i>n</i> = 9]: −8.4 [−11.6; –1.0]). Lyso-Gb3 concentrations were low and stable in females, with a slight increase in males (9/24 ADA-positive). The BRIGHT study results suggest that 2 mg/kg pegunigalsidase alfa E4W is tolerated well in stable adult patients with Fabry disease. Due to the low number of patients in this study, more research is needed to demonstrate the effects of pegunigalsidase alfa given E4W. Further evidence, outside of this clinical trial, should be factored in for physicians to prolong the biweekly ERT intervals to E4W.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Take-home message</h3>\u0000 \u0000 <p>Treatment with 2 mg/kg pegunigalsidase alfa every 4 weeks could offer a new treatment option for patients with Fabry disease.</p>\u0000 </section>\u0000 </div>","PeriodicalId":16281,"journal":{"name":"Journal of Inherited Metabolic Disease","volume":"48 1","pages":""},"PeriodicalIF":4.2,"publicationDate":"2024-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11667655/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142391114","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Genetically humanized phenylketonuria mouse model as a testing tool for human genome editing in fertilized eggs","authors":"Atsumi Tsuji-Hosokawa,&nbsp;Iku Tsuchiya,&nbsp;Kie Shimizu,&nbsp;Miho Terao,&nbsp;Mito Yasuhara,&nbsp;Natsuho Miyamoto,&nbsp;Saki Kikuchi,&nbsp;Yuya Ogawa,&nbsp;Kazuaki Nakamura,&nbsp;Yoichi Matsubara,&nbsp;Shuji Takada","doi":"10.1002/jimd.12803","DOIUrl":"10.1002/jimd.12803","url":null,"abstract":"<p>Targeted genome editing has made significant advancements; however, safety and ethical issues have not been fully elucidated, resulting in strict control of the technique. We tested genome editing tools on gametes from a genetically humanized mouse model using a phenylketonuria (PKU) mouse model to gain insights into genome editing in human embryos. The human PKU mouse model <i>Pah</i>^hR111X mice was generated. The junctional region between exon 3 and intron 3 of <i>Pah</i> was replaced with a 120 bp corresponding human <i>PAH</i> sequence, including the pathogenic common variant c.331C &gt; T in <i>Pah</i>^hR111X mice. <i>Pah</i>^{<i>hR111X</i>} mice successfully recapitulated the PKU phenotype and showed cognitive dysfunction and depressive-like behavior, which are observed in human patients with PKU. Genome editing was applied to fertilized eggs of <i>Pah</i>^{<i>hR111X</i>} mice utilizing sgRNA that targets the human sequence. Mice with the corrected allele exhibited normal serum phenylalanine levels. Through genome editing, we validated the utility of sgRNA. The genetically humanized mouse model suggested that germ-line genome editing of the pathogenic variant may be feasible for monogenic disorders by revealing the recovery of the phenotype; however, there are remaining issues with the tool, including its efficiency and accuracy. This genome editing protocol using a genetically humanized mouse model will provide insights for improving current issues and contribute to the establishment of heritable human genome editing protocols.</p>","PeriodicalId":16281,"journal":{"name":"Journal of Inherited Metabolic Disease","volume":"48 1","pages":""},"PeriodicalIF":4.2,"publicationDate":"2024-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11729594/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142391117","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Newborn screening algorithm distinguishing potential symptomatic isovaleric acidemia from asymptomatic newborns","authors":"Rachel Rock,&nbsp;Oded Rock,&nbsp;Suha Daas,&nbsp;Vered Biton-Regev,&nbsp;Nadav Sagiv,&nbsp;Nasser Abu Salah,&nbsp;Yair Anikster,&nbsp;Ortal Barel,&nbsp;Ronen Hady Cohen,&nbsp;Elena Dumin,&nbsp;Aviva Fattal-Valevski,&nbsp;Tzipora Falik-Zaccai,&nbsp;Eli Herskovitz,&nbsp;Sagi Josefsberg,&nbsp;Hatem Khammash,&nbsp;Katya Kneller,&nbsp;Stanley H. Korman,&nbsp;Yuval E. Landau,&nbsp;Tally Lerman-Sagie,&nbsp;Hanna Mandel,&nbsp;Elon Pras,&nbsp;Haike Reznik-Wolf,&nbsp;Avraham Shaag,&nbsp;Nava Shaul Lotan,&nbsp;Ronen Spiegel,&nbsp;Galit Tal,&nbsp;Orna Staretz-Chacham,&nbsp;Yael Wilnai,&nbsp;Shlomo Almashanu","doi":"10.1002/jimd.12800","DOIUrl":"10.1002/jimd.12800","url":null,"abstract":"<p>Newborn screening (NBS) for isovaleric acidemia (IVA) reduces mortality and morbidity; however, it has also resulted in the detection of individuals with an asymptomatic or mild presentation for which early detection via newborn screening has not been proven to alter neurological outcome. We reevaluated biochemical and molecular data for newborns flagged positive for IVA in aim of developing a new screening algorithm to exclude the latter from positive screening. Among 2 794 365 newborns underwent routine newborn screening in Israel, 412 flagged positive for IVA, of which, 371 were false positives on recall sample testing and 41 positive newborns were referred to the clinic. 38/41 have biochemical and molecular confirmation in keeping with IVA. Among the 38 patients, 32% (12/38) were classified as symptomatic while, 68% (26/38) were classified as asymptomatic. 69% of the latter group harbor the known variant associated with mild potentially asymptomatic phenotype, c.932C&gt;T; p. Ala311Val. Among asymptomatic patients, only 46% (12/26) are currently treated. Two novel variants have been detected in the IVD gene: c.487G&gt;A; p. Ala163Thr and c.985A&gt;G; p. Met329Val. Cut-off recalculation, of referred newborns' initial biochemical results, after classifying the referred patients to two binary groups of symptomatic and asymptomatic, resulted in an improved NBS algorithm comprising of C5 &gt;5 μM and C5/C2&gt;0.2 and C5/C3&gt;4 flagging only those likely to have the classic symptomatic phenotype.</p>","PeriodicalId":16281,"journal":{"name":"Journal of Inherited Metabolic Disease","volume":"48 1","pages":""},"PeriodicalIF":4.2,"publicationDate":"2024-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142348357","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}