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CRISPR-Cas9 Gene Editing for Sickle Cell Disease and β-Thalassemia

四川生理科学杂志 2020年第4期42卷 506-506页

作者： haydar frangoul From the Sarah Cannon Center for Blood Cancer at the Children’s Hospital at TriStar Centennial Nashville (H.F. J.D.) and St. Jude Children’s Research Hospital Memphis (A.S.) — both in Tennessee Vertex Pharmaceuticals (D.A. B.K.E. J.L.-H. A.Y.) and Boston University School of Medicine (M.H.S.) Boston and CRISPR Therapeutics Cambridge (Y.-S.C. T.W.H. A. Kernytsky S. Soni) — both in Massachusetts the University of Milan Milan (M.D.C.) and Ospedale Pediatrico Bambino Gesù Rome Sapienza University of Rome Rome (F.L.) the University of Regensburg Regensburg (J. Foell S.C.) and Children’s University Hospital University of Tübingen Tübingen (R.H.) — both in Germany Imperial College Healthcare NHS Trust St. Mary’s Hospital London (J. de la Fuente) Children’s Hospital of Philadelphia Perelman School of Medicine at the University of Pennsylvania Philadelphia (S.G.) the University of Athens Athens (A. Kattamis) BC Children’s Hospital University of British Columbia Vancouver (A.M.L.) and the Hospital for Sick Children–University of Toronto Toronto (D.W.) — both in Canada Columbia University (M.Y.M.) and the Joan and Sanford I. Weill Medical College of Cornell University (S. Sheth) New York Necker–Enfants Malades Hospital Assistance Publique–Hôpitaux de Paris University of Paris Paris (M.M.) and the University of Illinois at Chicago Chicago (D.R.).

Transfusion-dependent β-thalassemia(TDT)and sickle cell disease(SCD)are severe monogenic diseases with severe and potentially life-threatening ***11A is a transcription factor that represses γ-globin expression and fetal hemoglobin in erythroid *** performed electroporation of CD34+hematopoietic stem and progenitor cells obtained from healthy donors,with CRISPR-Cas9 targeting the BCL11A erythroid-specific *** 80% of the alleles at this locus were modified,with no evidence of off-target *** undergoing myeloablation,two patients-one with TDT and the other with SCD-received autologous CD34+cells edited with CRISPR-Cas9 targeting the same BCL11A *** than a year later,both patients had high levels of allelic editing in bone marrow and blood,increases in fetal hemoglobin that were distributed pancellularly,transfusion independence,and(in the patient with SCD)elimination of vaso-occlusive episodes.

关键词： fetal transfusion patients

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Molecular and epidemiologic characterization of Wilms tumor from Baghdad, Iraq

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World Journal of Pediatrics 2018年第6期14卷 585-593页

作者： Hannah M.Phelps Mazin F.Al-Jadiry Natasha M.Corbitt Janene M.Pierce Bingshan Li Qiang Wei Raina R.Flores Hernan Correa Stefania Uccini haydar frangoul Adel R.Alsaadawi Safaa A.F.Al-Badri Amir F.Al-Darraji Raghad M.Al-Saeed Salma A.Al-Hadad Harold N.LovvornⅢ Vanderbilt University School of Medicine 2215 Garland AvenueNashvilleTN 37232-9780USA Oncology Unit Children’s Welfare Teaching HospitalBaghdad University Medical CityBaghdadIraq Department of P ediatric Surgery Vanderbilt University Medical CenterNashvilleUSA Department of Molecular Physiology and Bioph ysics Vanderbilt University School of MedicineNashvilleUSA Division of P ediatric Pathology Vanderbilt University Medical CenterNashvilleUSA Department of Clinical and Molecular Medicine Sapienza UniversityRomeItaly Division of P ediatric Hematology and Oncology Vanderbilt University Medical CenterNashvilleUSA Department of P athology Baghdad University Medical CityBaghdadIraq Oncology Unit Children’s Welfare Teaching HospitalWasit University College of MedicineWasitIraq

Background Wilms tumor (WT) is the most common childhood kidney cancer worldwide, yet its incidence and clinical behavior vary according to race and access to adequate healthcare resources. To guide and streamline therapy in the war-torn and resource-constrained city of Baghdad, Iraq, we conducted a first-ever molecular analysis of 20 WT specimens to characterize the biological features of this lethal disease within this challenged population. Methods Next-generation sequencing of ten target genes associated with WT development and treatment resistance (WT1, CTNNB1, WTX, IGF2, CITED1, SIX2, p53, N-MYC, CRABP2, and TOP2A) was completed. Immunohistochemistry was performed for 6 marker proteins of WT (WT1, CTNNB1, NCAM, CITED1, SIX2, and p53). Patient outcomes were compiled. Results Mutations were detected in previously described WT 'hot spots' (e.g., WT1 and CTNNB1) as well as novel loci that may be unique to the Iraqi population. Immunohistochemistry showed expression domains most typical of blastemal-predominant WT. Remarkably, despite the challenges facing families and care providers, only one child, with combined WT1 and CTNNB1 mutations, was confirmed dead from disease. Median clinical follow-up was 40.5 months (range 6–78 months). Conclusions These data suggest that WT biology within a population of Iraqi children manifests features both similar to and unique from disease variants in other regions of the world. These observations will help to risk stratify WT patients living in this difficult environment to more or less intensive therapies and to focus treatment on cell-specific targets.

关键词： Iraq Low- and middle-income countries Next-generation sequencing Pediatric cancer Wilms tumor

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