Granted Patent
B2
US 12,703,864 · App. 17/587,999 · Granted Aug 11, 2026
Vectors and compositions for treating hemoglobinopathies
Assignee:
Children's Medical Center Corporation
C12N15/113A61K9/0019A61K31/7088C12N15/86C12N2310/11C12N2320/32C12N2330/51C12N2740/15043C12N2740/15045C12N2740/15071C12N2830/008
View Patent ↗
Loading inventors, assignments & file history…
Abstract
The invention provides improved gene therapy vectors, compositions, and methods.
Claims (11)
1 . A lentiviral vector genomic RNA comprising: (a) an HIV-1 strain NL4-3 5′ long terminal repeat (LTR) comprising an R region and a U5 region; (b) a Ψ packaging signal; (c) an HIV-1 strain NL4-3 central polypurine tract (cPPT)/FLAP element; (d) an HIV-1 strain HXB3 RRE RNA export element; (e) an HIV-1 strain NL4-3 env splice acceptor sequence; a human β-globin promoter operably linked to a polynucleotide encoding a shmiR that comprises an antisense sequence that hybridizes to a human BCL11A mRNA, wherein the shmiR comprises the sequence set forth in SEQ ID NO: 1; (g) a human β-globin LCR comprising a HS2 DNAse I hypersensitive site comprising about 638 nucleotides, and a HS3 DNAse I hypersensitive site comprising about 847 nucleotides; and (h) an HIV-1 strain NL4-3 3′ SIN LTR comprising a U3 region comprising a deletion and an R region.
2 . The lentiviral vector genomic RNA of claim 1 , wherein the lentiviral vector genomic RNA does not comprise an HS4 DNAse I hypersensitivity site.
3 . The lentiviral vector genomic RNA of claim 1 , further comprising: (a) a polynucleotide of about 459 nucleotides that encodes a gag protein; comprising one or more mutated ATG start codons and/or (b) a synthetic poly(A) sequence.
4 . The lentiviral vector genomic RNA of claim 1 , wherein the HIV-1 env splice acceptor sequence comprises about 176 nucleotides; and/or (b) the cPPT/FLAP element comprises about 381 nucleotides.
5 . The lentiviral vector genomic RNA of claim 1 , wherein the lentiviral vector genomic RNA comprises an expression cassette comprising the erythroid specific promoter and the polynucleotide encoding the shmiR are in the reverse orientation compared to the transcription of the lentiviral vector genomic RNA.
6 . A lentiviral transfer vector comprising a polynucleotide sequence encoding the lentiviral vector genomic RNA of claim 1 .
7 . A lentiviral vector particle comprising the lentiviral vector genomic RNA of claim 1 .
8 . A composition comprising the lentiviral vector particle of claim 7 .
9 . The composition of claim 8 , further comprising a pharmaceutically acceptable carrier.
10 . The composition of claim 9 , wherein the pharmaceutically acceptable carrier is a physiologically acceptable solution.
11 . A method of treating a hemoglobinopathy in a subject comprising administering the subject an effective amount of a composition according to claim 10 .
Assignments (3)
ASSIGNMENT OF ASSIGNOR'S INTEREST
Recorded Feb 16, 2023
From: BLUEBIRD BIO, INC.
To: THE CHILDREN'S MEDICAL CENTER CORPORATION
Reel/Frame 062722/0034 →
ASSIGNMENT OF ASSIGNOR'S INTEREST
Recorded Jul 26, 2022
From: VERES, GABOR
To: BLUEBIRD BIO, INC.
Reel/Frame 060624/0980 →
ASSIGNMENT OF ASSIGNOR'S INTEREST
Recorded Jul 26, 2022
From: WILLIAMS, DAVID A.
To: CHILDREN'S MEDICAL CENTER CORPORATION
Reel/Frame 060625/0001 →
Continuity (4)
Provisional Application
62489149
· Apr 24, 2017
Provisional Application
62478375
· Mar 29, 2017
Related Publication
20220259594A1
· Aug 18, 2022
References Cited (163)
US 5460964A
· McGlave et al.
· 1995
[cited by applicant]
US 5635387A
· Fei et al.
· 1997
[cited by applicant]
US 5677136A
· Simmons et al.
· 1997
[cited by applicant]
US 5716827A
· Tsukamoto et al.
· 1998
[cited by applicant]
US 5750397A
· Tsukamoto et al.
· 1998
[cited by applicant]
US 5759793A
· Schwartz et al.
· 1998
[cited by applicant]
US 5928638A
· Uchida et al.
· 1999
[cited by applicant]
US 6682907B1
· Charneau et al.
· 2004
[cited by applicant]
US 8383604B2
· Orkin
· 2013
[cited by examiner]
US 9228185B2
· Orkin et al.
· 2016
[cited by applicant]
US 9885041B2
· Orkin et al.
· 2018
[cited by applicant]
US 20040259247A1
· Tuschl et al.
· 2004
[cited by applicant]
US 20080051431A1
· Verhelle et al.
· 2008
[cited by applicant]
US 20110294114A1
· Van Der Loo et al.
· 2011
[cited by applicant]
US 20110294144A1
· Noguchi et al.
· 2011
[cited by applicant]
EP 1752536A1
· 2007
[cited by applicant]
EP 2334794B1
· 2016
[cited by applicant]
EP 2334794B8
· 2017
[cited by applicant]
JP 2006507841A
· 2006
[cited by applicant]
WO 2004054512A2
· 2004
[cited by applicant]
WO 2009007685A2
· 2009
[cited by applicant]
WO 2011072086A1
· 2011
[cited by applicant]
WO 2012073047A2
· 2012
[cited by applicant]
WO 2013049615A1
· 2013
[cited by applicant]
WO 2014085593A1
· 2014
[cited by applicant]
WO 2014093965A1
· 2014
[cited by applicant]
WO 2015065964A1
· 2015
[cited by applicant]
WO 2015164730A1
· 2015
[cited by applicant]
WO 2015164739A1
· 2015
[cited by applicant]
WO 2015164750A2
· 2015
[cited by applicant]
WO 2015164759A2
· 2015
[cited by applicant]
WO 2016037138A1
· 2016
[cited by applicant]
WO 2016094304A2
· 2016
[cited by applicant]
WO 2016156404A1
· 2016
[cited by applicant]
WO 2016182893A1
· 2016
[cited by applicant]
WO 2017040529A1
· 2017
[cited by applicant]
WO 2017139576A1
· 2017
[cited by applicant]
Adachi et al., “Production of acquired immunodeficiency syndrome-associated retrovirus in human and nonhuman cells transfected with an infectious molecular clone.” Journal of virology 59.2: 284-291 (1986).
[cited by applicant]
Akinsheye et al., “Fetal hemoglobin in sickle cell anemia.” Blood 118(1):19-27 (2011).
[cited by applicant]
Amaya et al., “Mi2JI-mediated silencing of the fetal y-globin gene in adult erythroid cells.” Blood 121(17):3493-501 (2013).
[cited by applicant]
Amendah et al., “Sickle cell disease-related pediatric medical expenditures in the U.S.” American Journal of preventive Medicine 38(4 Suool):S550-S556 (2010).
[cited by applicant]
Atweh et al., “Pharmacological induction of fetal hemoglobin in sickle cell disease and beta-thalassemia.” Seminars in Hematology 38(4):367-73 (2001).
[cited by applicant]
Bauer et al., “An erythroid enhancer of BCL 11A subject to genetic variation determines fetal hemoglobin level,” Science. Oct. 11, 2013 ;342(6155):253-7.
[cited by applicant]
Bauer et al., “HbF-Associated Genetic Variation Marks an Erythroid Regulatory Element Essential for BCL 11A transcription and Subsequent Staqe-Specific Globin Expression.” Blood 120:828 (2012).
[cited by applicant]
Bauer et al., “Hemoglobin switching's surprise: the versatile transcription factor BCL 11A is a master repressor of fetal hemoglobin” Current Opinion in Genetics & Development 33:62-70 (2015).
[cited by applicant]
Bauer et al., “Reawakening fetal hemoglobin: prospects for new therapies for the B-globin disorders.” Blood 120 [15):2945-2953 (2012).
[cited by applicant]
Bauer et al., “Supplementary Material: An Erythroid Enhancer of BCL 11A Subject to Genetic Variation Determines Fetal Hemoglobin Level.” Science 342(6155):253-257 (2013).
[cited by applicant]
Bjurstrom et al. “Reactivating fetal hemoglobin expression in human adult erythroblasts through BCL 11A knockdown using targeted endonucleases.” Molecular Therapy-Nucleic Acids 5:e351 (2016).
[cited by applicant]
Boettcher et al., “Choosing the right tool for the job: RNAi, TALEN, or CRISPR.” Molecular Cell 58(4):575-585 (2015).
[cited by applicant]
Bohmer et al., “Identification of fetal nucleated red cells in co-cultures from fetal and adult peripheral blood: differential effects of serum on fetal and adult erythropoiesis.” Prenatal Diagnosis 19(7):628-636 (1999).
[cited by applicant]
Brendel et al., “Lineage-specific BCL11A knockdown circumvents toxicities and reverses sickle phenotype.” The Journal of clinical investigation 126.10: 3868-3878 (2016).
[cited by applicant]
Bunn “Reversing ontoqenv.” New Enql. J Med. 328(2):129-131 (1993).
[cited by applicant]
Cante-Barret et al. “Lentiviral gene transfer into human and murine hematopoietic stem cells: size matters.” BMC research notes 9: 1-6 (2016).
[cited by applicant]
Canver et al., “BCL 11A enhancer dissection by Cas9-mediated in situ saturating mutagenesis.” Nature 527 (7577):192-197 (2015).
[cited by applicant]
Cao et al., “Recent advances in B-thalassemias.” Pediatric Reports 3(2):65-71 (2011).
[cited by applicant]
Cavazzana-Calvo, M. et al., “Transfusion independence and HMGA2 activation after gene therapy of human S-thalassaemia”, Nature (2010), 467(7313): 318-322.
[cited by applicant]
Chabchoub et al., “The facial dysmorphy in the newly recognised microdeletion 2p15-p16.1 refined to a 570 kb region in 2p15.” Journal of Medical Genetics 45(3):189-192 (2008).
[cited by applicant]
Clever, J. et al., “RNA Secondary Structure and Binding Sites for gag Gene Products in the 59 Packaging Signal of Human Immunodeficiency Virus Type 1”, J. of Virology (1995), 69(4): 2101-2109.
[cited by applicant]
Coleman et al., “Sickle cell anemia: targeting the role of fetal hemoglobin in therapy.” Clinical Pediatrics 46 (5):386-391 (2007).
[cited by applicant]
Cox et al., “Therapeutic genome editing: prospects and challenges” Nature Medicine 21 (2): 121-131 (2015).
[cited by applicant]
Cullen et al., “Requlatorv Pathways Governing HIV-1 Replication”, Cell (1989); 58: 423-426.
[cited by applicant]
Cullen, B.R., “Human Immunodeficiency Virus as a Prototypic Complex Retrovirus”, Journal of Virology (1991); 65 (3): 1053-1056.
[cited by applicant]
Dixit et al., “Hydroxyurea in thalassemia intermedia—a promising therapy.” Annals of Hematology 84(7) :441-446 [2005).
[cited by applicant]
Doench et al., “Rational design of highly active sgRNAs for CRISPR-Cas9-mediated gene inactivation.” Nature Biotechnology 32(12): 1262-1267 (2014).
[cited by applicant]
Doench et al., “Supplementary Material: Rational design of highly active sgRNAs for CRISPR-Cas9-mediated gene inactivation.” Nature Biotechnology 32(12):1262-1267 (2014).
[cited by applicant]
Fenaux “Inhibitors of DNA methylation: beyond myelodysplastic syndromes.” Nature Reviews Clinical Oncology 2 (S21):S36-S44 (2005).
[cited by applicant]
Fischer et al., “Pulmonary Passage is a Major Obstacle for Intravenous Stem Cell Delivery: The Pulmonary First Pass Effect” Stem Cells and Development 18(5):683-91 (2009).
[cited by applicant]
Flanagan et al., “Hydroxycarbamide alters erythroid gene expression in children with sickle cell anaemia.” BritishJournal of Haematology 157(2):240-248 (2012).
[cited by applicant]
Gen Bank Accession No. NM_022893.4. “
[cited by applicant]
GeneCard for BCL 11A, retrieved from http://www.genecards.org/cgi-bin/carddisp.pl?gene=BCL 11A on Jun. 22, 2012.
[cited by applicant]
Ginn, et al., “Gene therapy clinical trials worldwide to 2012—an update.” The Journal of Gene Medicine (2013); 15 (2): 65-77.
[cited by applicant]
Goffin et al., “DNA methyltransferase inhibitors-state of the art.” Annals of Oncology 13(11):1699-716 (2002).
[cited by applicant]
Goldberg et al., “Treatment of sickle cell anemia with hydroxyurea and erythropoietin.” New England Journal of Medicine 323(6):366-372 (1990).
[cited by applicant]
Hackam “Translating animal research into clinical benefit” BMJ 334:163-68 (2007).
[cited by applicant]
Hancarova et al. “A patient with de nova 0.45 Mb deletion of 2p16. 1: The role of BCL 11A, PAPOLG, REL, and FLJ16341 in the 2p15-p16. 1 microdeletion syndrome.” American Journal of Medical Genetics Part A 161(4):865-870…
[cited by applicant]
Harding et al., “Large animal models for stem cell therapy”, Stem Cell Research & Therapy 4(23):1-9(2013).
[cited by applicant]
Hebbel et al., “The HDAC inhibitors trichostatin A and suberoylanilide hydroxamic acid exhibit multiple modalities of benefit for the vascular pathobiology of sickle transgenic mice.” Blood 115(12):2483-2490 (2010).
[cited by applicant]
Hendel et al., “Chemically modified guide RNAs enhance CRISPR-Cas genome editing in human primary cells.” Nature Biotechnology 33(9):985-989 (2015).
[cited by applicant]
Higgs et al., “Genetic complexity in sickle cell disease.” PNAS 105(33): 11595-11596 (2008).
[cited by applicant]
Ho et al., “In vitro induction of fetal hemoglobin in human erythroid progenitor cells.” Experimental Hematology 31 (7):586-591 (2003).
[cited by applicant]
Hsieh et al., “Allogeneic hematopoietic stem-cell transplantation for sickle cell disease.” New England Journal of Medicine 361(24):2309-2317 (2009).
[cited by applicant]
Huang et al., “Role of the hepatitis B virus posttranscriptional regulatory element in export of intronless transcripts,” Molecular and Cellular Biology (1995); 15(7): 3864-3869.
[cited by applicant]
Imren, S. et al., “Permanent and panerythroid correction of murine ? thalassemia by multiple lentiviral integration in hematopoietic stem cells”, Proc Natl Acad Sci US A (2002), 99(22): 14380-14385.
[cited by applicant]
Jane et al., “Understanding fetal globin gene expression: a step towards effective HbF reactivation in haemoglobinopathies.” British Journal of Haematology 102(2):415-423 ( 1998).
[cited by applicant]
Kauf et al., “The cost of health care for children and adults with sickle cell disease.” American Journal of Hematology 84(6):323-327 (2009).
[cited by applicant]
Kitowski et al., A lentiviral vector conferring coregulated, erythroid-specific expression of γ-globin and shRNA sequences to BCL11A for the treatment of sickle cell disease. Southern Illinois University at Carbondale (…
[cited by applicant]
Kirschner et al., “Genomic mapping of chromosomal region 2p15-p21 {D2S378-D2S391): integration of Genemap'98 within a framework of yeast and bacterial artificial chromosomes” Genomics 62(1):21-33 (1999).
[cited by applicant]
Thein et al., “Discovering the genetics underlying foetal haemoglobin production in adults.” British Journal of aematology 145(4):455-467 (2009).
[cited by applicant]
Thompson “Structure, Function, and Molecular Defects of Factor IX.” Blood 67(3):565-72 (1986).
[cited by applicant]
Uda et al., “Genome-wide association study shows BCL 11A associated with persistent fetal hemoglobin and amelioration of the phenotype of thalassemia.” PNAS 105(5): 1620-1625 (2008).
[cited by applicant]
Wang et al. “Genetic screens in human cells using the CRISPR/Cas9 system.” Science 343(6166):80-84 (2013).
[cited by applicant]
Wang et al. “Supplementary Material: Genetic screens in human cells using the CRISPR/Cas9 system.” Science 343 (6166):80-84 (2013).
[cited by applicant]
Wang et al., “In Vivo Delivery Systems for Therapeutic Genome Editing” International Journal of Molecular Sciences 17(5):1-19 (2016).
[cited by applicant]
Wang et al., “Selection of hyperfunctional siRNAs with improved potency and specificity.” Nucleic Acids Research 37 (22):e152 (2009).
[cited by applicant]
White et al., “Factor VIII Gene and Hemophili A.” Blood 73(1):1-12 (1989).
[cited by applicant]
World Health Organization. “Sickle-cell anaemia. Report A59/9. Provisional agenda item 11 .4.” 59th World Health Assembly. www.who.inUqb/ebwha/pdf files/WHA59/A59 9-en.pdf (2006).
[cited by applicant]
Xu et al., “Correction of sickle cell disease in adult mice by interference with fetal hemoglobin silencing”, Science 334 (6058):993-996 (2011).
[cited by applicant]
Xu et al., “Reactivation of silenced human HbF in adult mice by inactivation of BCL 11A.” Blood 116: Abstract 643 (2010).
[cited by applicant]
Xu et al., “Transcriptional silencing of beta-globin by BCL 11A involvs long-range interactions and cooperation with SOX6.” Genes and Development 24(8):783-798 (2010).
[cited by applicant]
Yin et al., “Bel 11 a Causes p21 Cip1 Down-Regulation and Transplantable Leukemia in Nf 1-Deficient Mice.” Blood 110 (11):2657-2657 (2007) fabstract Onlyi.
[cited by applicant]
Yu et al., “Bcl11 a is essential for lymphoid development and negatively regulates p53,” J. Exp. Med. 2012 vol. 209 No. 13 2467-2483.
[cited by applicant]
Zennou, V. et al., “HIV-1 genome nuclear import is mediated by a central DNA flap”, Cell (2000), 101(2): 173-185.
[cited by applicant]
Zufferey, R. et al., “Woodchuck hepatitis virus posttranscriptional regulatory element enhances expression of transqenes delivered by retroviral vectors.” J Virol. ( 1999); 73( 4): 2886-2892.
[cited by applicant]
Koshy et al., “2-deoxy 5-azacytidine and fetal hemoglobin induction in sickle cell anemia.” Blood 96(7):2379-2384 (2000).
[cited by applicant]
Kutner, et al., “Simplified production andconcentration of HIV-1-based lentiviral vectors using HYPERFlask vessels and anion exchange membrane chromatography”, BMC Biotechnol. (2009); 9:10. p. 1-7.
[cited by applicant]
Kutner et al., “Production, concentration and titration of pseudotyped HIV-1-based lentiviral vectors”, Nature Protocols (2009); 4: 495-505.
[cited by applicant]
Labie “Le controle en trans de la production d'hemoglobine fretale: une recherche qui dure depuis 20 ans.” Hematologie 14(2):165-166 (2008).
[cited by applicant]
Landau et al., “Packaging system for rapid production of murine leukemia virus vectors with variable tropism.” Journal of Viroloqy (1992); 66.8: 5110-5113.
[cited by applicant]
Lettre et al., “DNA polymorphisms at the BCL 11A, HBS1 L-MYB, and beta-globin loci associate with fetal hemoqlobin levels and pain crises in sickle cell disease.” PNAS 105{33):11869-11874 (2008).
[cited by applicant]
Liu et al., “HnRNP L binds a cis-acting RNA sequence element that enables intron-dependent gene expression,” Genes & Dev. (1995); 9: 1766-1780.
[cited by applicant]
Liu et al., “Bcl11 a is essential for normal lymphoid development.” Nature Immunology 4(6):525-532 (2003).
[cited by applicant]
Liu et al., “Functional studies of BCL 11A: characterization of the conserved BCL 11A-XL splice variant and its interaction with BCL6 in nuclear paraspeckles of germinal center B cells.” Molecular Cancer 5(18):1-6 (2006…
[cited by applicant]
Luc et al., “Bcl11 a-deficiency leads to hematopoietic stem cell defects with an aging-like phenotype,” Cell Rep. Sep. 20, 2016; 16(12): 3181-3194.
[cited by applicant]
Lulli et al., “MicroRNA-486-3p regulates y-globin expression in human erythroid cells by directly modulatinq BCL 11A.” PLoS One 8(4):e60436 (2013).
[cited by applicant]
Mahajan et al. “Control of beta globin genes.” Journal of cellular biochemistry 102.4: 801-810 (2007).
[cited by applicant]
Makala et al., “Fetal Hemoglobin Induction to Treat b-Hemoglobinopathies: From Bench to Bedside” J Hematol Transfus 2(2):1-2 (2014).
[cited by applicant]
Malik et al., “Successful Correction of the Human Cooley's Anemia—Thalassemia Major Phenotype Using a Lentiviral Vector Flanked by the Chicken Hypersensitive Site 4 Chromatin Insulator”, Annals of the New York Academy o…
[cited by applicant]
Martin-Su Bero et al., “Recurrent involvement of the REL and BCL 11Aloci in classical Hodgkin lymphoma.” Blood 99(4):1474-1477 (2002).
[cited by applicant]
Matsuda et al., “Transcription factors LRF and BCL 11 A independently repress expression of fetal hemoglobin” Science 351 (6270):285-289 (2016).
[cited by applicant]
May et al., “Therapeutic haemoglobin synthesis in ?-thalassaemic mice expressing lentivirus-encoded human beta-qlobin”, Nature (2000), 406(6791): 82-86.
[cited by applicant]
Menzel et al., “A QTL influencing F cell production maps to a gene encoding a zinc-finger protein on chromosome p15.” Nature Genetics 39(10): 1197-1199 (2007).
[cited by applicant]
Migliaccio et al., “Influence of recombinant hematopoietins and of fetal bovine serum on the globin synthetic pattern pf human BFUe.” Blood 76(6): 1150-1157 ( 1990).
[cited by applicant]
Moffat et al., “A lentiviral RNAi library for human and mouse genes applied to an arrayed viral hiqh-content screen.” 124(6):1283-1298 (2006).
[cited by applicant]
Naldini, L., “Gene therapy returns to centre stage.” Nature (2015); 526(7573): 351-360.
[cited by applicant]
Nemudryi et al., “TALEN and CRISPR/Cas Genome Editing Systems: Tools of Discovery” Acta Naturae, 6(3):19-40 (2014).
[cited by applicant]
Neven et al., “A Mendelian predisposition to B-cell lymphoma caused by IL-10R deficiency,” Blood 3713-3722 (2013).
[cited by applicant]
Orkin et al., “Recent advances in globin research using genome-wide association studies and gene editing.” Annals of the New York Academy of Sciences 1368 (1):5-10 (2016).
[cited by applicant]
Papayannopoulou et al., “Erythroid progenitors circulating in the blood of adult individuals produce fetal hemoqlobin in culture.” Science 199{4335): 1349-1350 (1978).
[cited by applicant]
Pauling et al., “Sickle cell anemia a molecular disease.” Science 110(2865):543-548 (1949).
[cited by applicant]
Pawliuk, R. et al., “Correction of sickle cell disease in transgenic mouse models by gene therapy”, Science (2001), 294(5550): 2368-2371 (and Supplementary Material).
[cited by applicant]
Pembrey et al., “Fetal haemoglobin production and the sickle gene in the oases of Eastern Saudi Arabia.” British Journal of haematoloqy 40(3):415-429 (1978).
[cited by applicant]
Perrine “Fetal globin induction—can it cure beta thalassemia?” American Society of Hematology Education Program Book pp. 38-44 (2005).
[cited by applicant]
Platt et al., “Mortality in sickle cell disease. Life expectancy and risk factors for early death.” New Enqland Journal of Medicine 330(23):1639-1644 (1994).
[cited by applicant]
Purton et al., “All-trans retinoic acid enhances the long-term repopulating activity of cultured hematopoietic stem cells.” Blood 95(2):470-477 (2000).
[cited by applicant]
Pusch et al., “Enhanced gene silencing of HIV-1 speci® c siRNA using microRNA designed hairpins,” Nucleic Acids Research, 2004, vol. 32, No. 3, 1154-1158.
[cited by applicant]
Ren Ella et al. “Hematopoietic SIN lentiviral micro RNA-mediated silencing of BCL 11A: pre-clinical evidence for a sickle cell disease qene-therapy trial.” 120(21):Abstract 753 (2012).
[cited by applicant]
Ridley et al., “Ervthropoietin: A Review” J Natl Med Assoc., 86(2):129-135 (1994).
[cited by applicant]
Rodriguez et al., “A bioavailability and pharmacokinetic study of oral and intravenous hydroxyurea.” Blood 9 (5):1533-1541 (1998).
[cited by applicant]
Rosenblum et al., “Peripheral blood erythroid progenitors from patients with sickle cell anemia: HPLC separation of hemoglobins and the effect of a HbF switching factor.” Progress in Clinical and Bioloqical Research 191…
[cited by applicant]
Saiki et al., “Human EVI9, a homologue of the mouse myeloid leukemia gene, is expressed in the hematopoietic progenitors and down-regulated during myeloid differentiation of HL60 cells.” Genomics 70(3):387-391 (2000).
[cited by applicant]
Sankaran et al., “Developmental and species-divergent globin switching are driven by BCL 11A.” Nature 460 (7259):1093-1097 (2009).
[cited by applicant]
Sankaran et al., “Human fetal hemoglobin expression is regulated by the developmental stage-specific repressor BCL 11A.” Science 322(5909): 1839-1843 (2008).
[cited by applicant]
Sankaran et al., “Targeted therapeutic strategies for fetal hemoglobin induction.” American Society of Hematoloqy Education Proqram Book 2011(1):459-465 (2011).
[cited by applicant]
Satterwhite et al., “The BCL 11 gene family: involvement of BCL 11A in lymphoid malignancies.” Blood, 98 (12):3413-3420 (2001).
[cited by applicant]
Schopman et al. “Optimization of sh RNA inhibitors by variation of the terminal loop sequence.” Antiviral Research 86 (2):204-211 (2010).
[cited by applicant]
Sebastiani et al., “BCL 11A enhancer haplotypes and fetal hemoglobin in sickle cell anemia.” Blood Cells, Molecules, and Diseases 54(3):224-230 (2015).
[cited by applicant]
Sedgewick et al., “BCL 11A is a major HbF quantitative trail locus in three different populations with 13 hemoqlobinopathies.” Blood Cells, Molecules, and Diseases 41(3):255-258 (2008).
[cited by applicant]
Shen et al., “Modifcation of globin gene expression by RNA targeting strategies.” Experimental Hematology, 35 fB): 1209-1218 (2007).
[cited by applicant]
Soneoka, Yuko, et al. “A transient three-plasmid expression system for the production of high titer retroviral vectors.” Nucleic Acids Research ( 1995); 23.4: 628-633.
[cited by applicant]
Takeuchi et al., “Redesign of extensive protein-DNA interfaces of meganucleases using iterative cycles of in vitro compartmentalization.” PNAS 111(11):4061-4066 (2014).
[cited by applicant]
Taymans et al., “Radiation hybrid mapping of chromosomal region 2p15-p16: integration of expressed and polymorphic sequences maps at the Carney complex (CNC) and Doyne honeycomb retinal dystrophy (DHRD) loci.” Genomics …
[cited by applicant]
Terasawa et al., “Synthetic pre-miRNA-based shRNA as potent RNAi triggers.” Journal of Nucleic Acids (2011).
[cited by applicant]
Thein “Genetic modifiers of the beta-haemoglobinopathies.” British Journal of Hematology, 141(3):357-366 (2008).
[cited by applicant]