ES2641840T3 - Composiciones y métodos para el tratamiento de hemoglobinopatías - Google Patents
Composiciones y métodos para el tratamiento de hemoglobinopatías Download PDFInfo
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- ES2641840T3 ES2641840T3 ES13751886.6T ES13751886T ES2641840T3 ES 2641840 T3 ES2641840 T3 ES 2641840T3 ES 13751886 T ES13751886 T ES 13751886T ES 2641840 T3 ES2641840 T3 ES 2641840T3
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- 208000034737 hemoglobinopathy Diseases 0.000 title description 2
- 208000018337 inherited hemoglobinopathy Diseases 0.000 title description 2
- 238000000034 method Methods 0.000 title description 2
- 239000000203 mixture Substances 0.000 title description 2
- 108020005004 Guide RNA Proteins 0.000 description 15
- 108091033409 CRISPR Proteins 0.000 description 14
- 230000030279 gene silencing Effects 0.000 description 11
- 108010042407 Endonucleases Proteins 0.000 description 7
- 102100031690 Erythroid transcription factor Human genes 0.000 description 6
- 101710100588 Erythroid transcription factor Proteins 0.000 description 6
- 102100031780 Endonuclease Human genes 0.000 description 5
- 108010073062 Transcription Activator-Like Effectors Proteins 0.000 description 4
- 108090000623 proteins and genes Proteins 0.000 description 4
- 108010044495 Fetal Hemoglobin Proteins 0.000 description 3
- 238000003776 cleavage reaction Methods 0.000 description 3
- 108010038853 gamma-Globins Proteins 0.000 description 3
- 230000035772 mutation Effects 0.000 description 3
- 239000002773 nucleotide Substances 0.000 description 3
- 125000003729 nucleotide group Chemical group 0.000 description 3
- 230000007017 scission Effects 0.000 description 3
- FWMNVWWHGCHHJJ-SKKKGAJSSA-N 4-amino-1-[(2r)-6-amino-2-[[(2r)-2-[[(2r)-2-[[(2r)-2-amino-3-phenylpropanoyl]amino]-3-phenylpropanoyl]amino]-4-methylpentanoyl]amino]hexanoyl]piperidine-4-carboxylic acid Chemical compound C([C@H](C(=O)N[C@H](CC(C)C)C(=O)N[C@H](CCCCN)C(=O)N1CCC(N)(CC1)C(O)=O)NC(=O)[C@H](N)CC=1C=CC=CC=1)C1=CC=CC=C1 FWMNVWWHGCHHJJ-SKKKGAJSSA-N 0.000 description 2
- 238000010354 CRISPR gene editing Methods 0.000 description 2
- 102000004533 Endonucleases Human genes 0.000 description 2
- 108091005903 Hemoglobin subunit delta Proteins 0.000 description 2
- 230000003197 catalytic effect Effects 0.000 description 2
- 210000004027 cell Anatomy 0.000 description 2
- 230000004186 co-expression Effects 0.000 description 2
- 230000014509 gene expression Effects 0.000 description 2
- 102000004169 proteins and genes Human genes 0.000 description 2
- 230000001105 regulatory effect Effects 0.000 description 2
- 230000001629 suppression Effects 0.000 description 2
- 238000011144 upstream manufacturing Methods 0.000 description 2
- 108091032973 (ribonucleotides)n+m Proteins 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- 108091026890 Coding region Proteins 0.000 description 1
- 108020004705 Codon Proteins 0.000 description 1
- 108020004414 DNA Proteins 0.000 description 1
- 102100031573 Hematopoietic progenitor cell antigen CD34 Human genes 0.000 description 1
- 108091005904 Hemoglobin subunit beta Proteins 0.000 description 1
- 108091005886 Hemoglobin subunit gamma Proteins 0.000 description 1
- 101000777663 Homo sapiens Hematopoietic progenitor cell antigen CD34 Proteins 0.000 description 1
- 101710163270 Nuclease Proteins 0.000 description 1
- 108091028043 Nucleic acid sequence Proteins 0.000 description 1
- 238000010459 TALEN Methods 0.000 description 1
- 208000002903 Thalassemia Diseases 0.000 description 1
- 108010043645 Transcription Activator-Like Effector Nucleases Proteins 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 230000004721 adaptive immunity Effects 0.000 description 1
- 230000001580 bacterial effect Effects 0.000 description 1
- 230000033228 biological regulation Effects 0.000 description 1
- 230000002759 chromosomal effect Effects 0.000 description 1
- 238000010367 cloning Methods 0.000 description 1
- 238000012217 deletion Methods 0.000 description 1
- 230000037430 deletion Effects 0.000 description 1
- 210000000267 erythroid cell Anatomy 0.000 description 1
- 230000006870 function Effects 0.000 description 1
- 230000004927 fusion Effects 0.000 description 1
- 101150034785 gamma gene Proteins 0.000 description 1
- 238000010353 genetic engineering Methods 0.000 description 1
- 108060003196 globin Proteins 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 210000004962 mammalian cell Anatomy 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- 238000010172 mouse model Methods 0.000 description 1
- 230000032965 negative regulation of cell volume Effects 0.000 description 1
- 230000003584 silencer Effects 0.000 description 1
- 230000008685 targeting Effects 0.000 description 1
Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/43—Enzymes; Proenzymes; Derivatives thereof
- A61K38/46—Hydrolases (3)
- A61K38/465—Hydrolases (3) acting on ester bonds (3.1), e.g. lipases, ribonucleases
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K48/00—Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/06—Antianaemics
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N9/00—Enzymes; Proenzymes; Compositions thereof; Processes for preparing, activating, inhibiting, separating or purifying enzymes
- C12N9/14—Hydrolases (3)
- C12N9/16—Hydrolases (3) acting on ester bonds (3.1)
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N9/00—Enzymes; Proenzymes; Compositions thereof; Processes for preparing, activating, inhibiting, separating or purifying enzymes
- C12N9/14—Hydrolases (3)
- C12N9/16—Hydrolases (3) acting on ester bonds (3.1)
- C12N9/22—Ribonucleases RNAses, DNAses
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2319/00—Fusion polypeptide
- C07K2319/80—Fusion polypeptide containing a DNA binding domain, e.g. Lacl or Tet-repressor
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- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Organic Chemistry (AREA)
- Genetics & Genomics (AREA)
- Wood Science & Technology (AREA)
- Zoology (AREA)
- Medicinal Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Molecular Biology (AREA)
- Biotechnology (AREA)
- Biomedical Technology (AREA)
- Microbiology (AREA)
- General Engineering & Computer Science (AREA)
- Biochemistry (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Immunology (AREA)
- Gastroenterology & Hepatology (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Hematology (AREA)
- Diabetes (AREA)
- Micro-Organisms Or Cultivation Processes Thereof (AREA)
- Medicines Containing Material From Animals Or Micro-Organisms (AREA)
- Enzymes And Modification Thereof (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
Ejemplo 5
Selección de la región de silenciamiento de la hemoglobina fetal dirigida a las endonucleasas basadas en I-OnuI utilizando compartimentación in vitro
[0133] En la Tabla 4 se presentan ejemplos de secuencias diana de endonucleasa homing (HE), que están distribuidas uniformemente a lo largo de la región de 350 pb (SEQ ID NO: 2) que incluye la región de ocupación de Bcl 11a dentro de la región de silenciamiento HbF en células eritroides adultas que se interrumpe en la supresión HPFH francesa. Estas secuencias diana comprenden módulos de secuencia de ADN para los cuales se han aislado
10 y secuenciado grupos de variantes de endonucleasas muy activas.
Tabla 4
- Posición
- Ubicación cromosómica Secuencia Identificador de secuencia
- Tipo silvestre
- N/D TTTCCACTTATTCAACCTTTTA SEQ ID NO: 5
- f 13/303
- Chr11: 5.214.235 -5.214.256 TGTGGCCCTATTCTTGTGTTCA SEQ ID NO: 6
- f 79/303
- Chr11: 5.214.169 -5.214.190 CATTGTCACTTTCTTCCCTACT SEQ ID NO: 7
- f 143/303
- Chr11: 5.214.105 -5.214.126 TAAAATACATTTCTTCACTAAG SEQ ID NO: 8
- f 124/303
- Chr11: 5.214.089-5.214.110 ACTAAGTGAGAATAATCTTTTA SEQ ID NO: 9
- f 200/303
- Chr11: 5.214.048 -5.214.069 GCCACCACCTTTCTTGAATTAT SEQ ID NO: 10
- f 211/303
- Chr11: 5.214.037 -5.214.058 TCTTGAATTATTCAATATCTTT SEQ ID NO: 11
- f 274/303
- Chr11: 5.213.974 -5.213.995 TTAAAGGTCATTCATGGCTCCT SEQ ID NO: 12
[0134] La Tabla 5 presenta una región de -100 pb a 210 pb aguas arriba de los genes de la globina, que es
15 idéntica tanto para los genes de la globina Aγ como para la Gγ y que contiene muchas de las mutaciones de HPFH no suprimidas. La edición de genes que resulta en estas mutaciones da lugar a la disminución de la represión, y por lo tanto a la activación, de un gen gamma y produce un aumento de HbF.
Tabla 5
- Secuencia
- Identificador de secuencia
- Tipo silvestre
- SEQ ID NO: 16
- G-gamma -202 C → G
- SEQ ID NO: 17
- G-gamma -175 T → C
- SEQ ID NO: 18
- G-gamma -114 C → T
-
imagen22 SEQ ID NO: 19
- A-gamma -196 C → T
-
imagen23 SEQ ID NO: 20
- A-gamma -175 T → C
-
imagen24 SEQ ID NO: 21
23
NLS y para producir un andamio TALEN que comienza en el resto 154 (con respecto al efector PthXo1 TAL de tipo silvestre) y termina 63 restos más allá de la secuencia final de la 'mitad de repetición TAL'.
[0139] Los efectores TAL se construyen utilizando los siguientes RVD para dirigir cada nucleótido específico:
5 A-NI, C-HD, G-NN y T-NG. Después de que la clonación del efector de TAL se repite en el vector de destino, se clona un enlazador de proteína individual ('Zn4'; VGGS) y las variantes de endonucleasa homing modificadas por ingeniería genética en lugar del dominio catalítico de la nucleasa FokI, entre los sitios de restricción Xba-I y Sal-I modificados por ingeniería genética.
10 [0140] Se trata de un "caso de prueba modelo" MegaTAL (una fusión de un efector TAL en el extremo Nterminal de una única cadena proteica, fusionada a través de un enlazador flexible a la endonucleasa homing Y2 I-Anil de tipo silvestre, que se ha descrito originalmente en Takeuchi et al., Nucl. Acids Res. 37 (3): 877-890 (2009).
Ejemplo 7
15 Sistema de endonucleasas basadas en Cas9 para interrumpir una región de silenciamiento de hemoglobina fetal (HbF) regulada con Bcl 11a
[0141] La reciente comprensión mecanicista del sistema de repetición palindrómica corta agrupadas
20 interespaciadas regularmente (CRISPR) que utilizan las bacterias para la inmunidad adaptativa ha llevado al desarrollo de una poderosa herramienta que permite la edición de genomas de células de mamíferos, que se pueden emplear en las composiciones y métodos para el tratamiento de hemoglobinopatías que se describen en la presente memoria:
(a) para alterar una región codificante de Bcl 11a; (b) para interrumpir un elemento o vía de regulación del ADN silenciador de HbF, tal como una región de silenciamiento de HbF regulada por Bcl 11a; (c) para mutar uno o más
25 promotores del gen de γ-globina para conseguir una mayor expresión de un gen de γ-globina; (d) para mutar uno o más promotores del gen de δ-globina para conseguir una mayor expresión de un gen de δ-globina; y/o (e) para corregir una o más mutaciones del gen de β-globina. El sistema CRISPR bacteriano se describe en Jinek et al., Science 337: 816-821 (2013); Cong et al., Science (3 de enero de 2013) (Epub antes de impresión); y Mali et al., Science (3 de enero de 2013) (Epub antes de impresión).
30 [0142] La proteína Cas9 genera una rotura de doble cadena en un sitio específico cuya localización está determinada por una secuencia de guía de ARN. Todos los ARN guía contienen la misma secuencia de andamio que se une a Cas9, así como una secuencia de direccionamiento variable que tiene la estructura G-N20-GG, que proporciona la especificidad de escisión del complejo Cas9-ARN. La co-expresión de la proteína Cas9 y un ARN guía
35 da como resultado la escisión eficiente y la disrupción en una localización específica de la secuencia dentro del genoma humano, cuya división específica de la secuencia se define por la secuencia de ARN guía. La co-expresión de Cas9 y ARN guía que son específicos de múltiples dianas da lugar a la supresión eficiente de la región intermedia entre los sitios diana.
40 [0143] Por lo tanto, dentro de ciertos aspectos de la presente descripción se emplea la edición de genoma mediada por Cas9: (1) para interrumpir el sitio de unión de Bcl 11a dentro de la región de silenciamiento de HbF, (2) para interrumpir la función del gen Bcl 11a, y (3) para suprimir la región de silenciamiento de HbF. Las regiones diana se identifican y los ARN guía se diseñan y se generan basándose en la consideración de las secuencias diana de ARN guía óptimas. En la presente invención se ejemplifican los ARN guía que se dirigen a la región de unión a Bcl 11a
45 dentro de la región de silenciamiento de HbF, así como el motivo de unión a GATA-1 único. Estos ARN guía se usan individualmente o en combinación para conseguir la disrupción dirigida de la región de silenciamiento de HbF. También se usan individualmente y en combinación Cas9 con ARN guía a regiones adicionales dentro de las regiones de silenciamiento de HbF que corresponden a picos de ocupación Bcl 11a. También se pueden coexpresar varios pares de ARN guía que flanquean el sitio de unión de Bcl 11a y el motivo GATA-1, así como la huella completa, con Cas9
50 con el fin de generar supresiones dentro de la región de silenciamiento de HbF.
[0144] La secuencia de una Cas9 optimizada con codones humanos de Mali et al., Science (3 de enero de 2013) se presenta en la Figura 26, SEC ID NO: 37. Se presenta la secuencia genérica de un ARN guía (Mali et al.) en la Figura 27, SEQ ID NO: 38, cuyos elementos de secuencia clave se presentan en la Tabla 7. Ejemplos de secuencias
55 de ARN guía de Cas9 de unión específica a diana y escisión de la región de silenciamiento de la hemoglobina fetal humana (HbF) (Fig. 6, SEQ ID NO: 1 y Fig. 7, SEQ ID NO: 2) se presentan en la Tabla 8.
Tabla 7
Secuencia de elementos de un ARN guía de Cas9 genérica
25
- Descripción
- Identificador de secuencia Secuencia de nucleótidos
- Secuencia del promotor U6
- SEQ ID NO: 44 GGACGAAACACC
- Secuencia específica de la diana genérica
- SEQ ID NO: 45 GNNNNNNNNNNNNNNNNNN
- Secuencia del andamio ARN guía
-
SEQ ID NO: 46
imagen26
- Cola de poli T
- SEQ ID NO: 47 NNNNTTTTTT
Tabla 8
- Secuencias específicas de diana de un ARN guía de Cas9 ejemplar
- Designación
- Descripción Uso Identificador de secuencia Secuencia de nucleótidos
- GGN20GG-B
-
Se dirige al motivo de reconocimiento GATA-1
Se utiliza de forma individual, con #C para eliminar los motivos putativos Bcllla y GATA-1 conjuntamente, o con #E, #F o #G para eliminar todo el pico de Bcllla ChIP y las secuencias circundantes
SEQ ID NO: 48
imagen27
- GGN20GG-C
-
Se dirige al motivo de reconocimiento putativo Bcllla
Utilizado individualmente, con #B para eliminar los motivos putativos Bcllla y GATA-1 conjuntamente
SEQ ID NO: 49
imagen28
- GGN20GG-D
-
Se dirige al motivo de reconocimiento putativo Bcllla inmediatamente adyacente
Utilizado individualmente, con #B para eliminar los motivos putativos Bcllla y GATA-1 conjuntamente
SEQ ID NO: 50
imagen29
- GGN20GG-E
-
Se dirige aguas abajo dl pico de unión Bcllla
Utilizado con #B y/o #H para borrar todo el pico de Bcllla ChIP y las secuencias circundantes
SEQ ID NO: 51
imagen30
- GGN20GG-F
-
Se dirige aguas abajo del pico de unión Bcllla
Utilizado con #B y/o #H para borrar todo el pico de Bcllla ChIP y las secuencias circundantes
SEQ ID NO: 52
imagen31
- GGN20GG-G
-
Se dirige aguas abajo del pico de unión Bcllla
Utilizado con #B y/o #H para borrar todo el pico de Bcllla ChIP y las secuencias circundantes
SEQ ID NO: 53
imagen32
- GGN20GG-H
-
Se dirige aguas arriba del pico de unión Bcl11a
Utilizado con #E, #F o #G para borrar todo el pico de Bcllla ChIP y las secuencias circundantes
SEQ ID NO: 54
imagen33
Ejemplo 8
Sistemas vectoriales para expresar endonucleasas
[0145] Para los modelos de ratón NSG, de células falciformes y de talasemia, se transducen células CD34
26
Claims (1)
-
imagen1 imagen2
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US201261603231P | 2012-02-24 | 2012-02-24 | |
| US201261603231P | 2012-02-24 | ||
| PCT/US2013/027459 WO2013126794A1 (en) | 2012-02-24 | 2013-02-22 | Compositions and methods for the treatment of hemoglobinopathies |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| ES2641840T3 true ES2641840T3 (es) | 2017-11-14 |
Family
ID=49006265
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| ES13751886.6T Active ES2641840T3 (es) | 2012-02-24 | 2013-02-22 | Composiciones y métodos para el tratamiento de hemoglobinopatías |
Country Status (18)
| Country | Link |
|---|---|
| US (2) | US20150166969A1 (es) |
| EP (2) | EP3272356A1 (es) |
| JP (2) | JP6170080B2 (es) |
| KR (2) | KR20180009383A (es) |
| CN (1) | CN104284669A (es) |
| AU (2) | AU2013222170B2 (es) |
| BR (1) | BR112014020625A2 (es) |
| CA (1) | CA2865129A1 (es) |
| DK (1) | DK2836226T3 (es) |
| ES (1) | ES2641840T3 (es) |
| HK (1) | HK1249861A1 (es) |
| IL (2) | IL234225B (es) |
| IN (1) | IN2014DN07853A (es) |
| NZ (1) | NZ630900A (es) |
| RU (2) | RU2018109507A (es) |
| SG (2) | SG10201606959PA (es) |
| WO (1) | WO2013126794A1 (es) |
| ZA (1) | ZA201406187B (es) |
Families Citing this family (165)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2013066438A2 (en) | 2011-07-22 | 2013-05-10 | President And Fellows Of Harvard College | Evaluation and improvement of nuclease cleavage specificity |
| US11021737B2 (en) | 2011-12-22 | 2021-06-01 | President And Fellows Of Harvard College | Compositions and methods for analyte detection |
| GB201122458D0 (en) | 2011-12-30 | 2012-02-08 | Univ Wageningen | Modified cascade ribonucleoproteins and uses thereof |
| IN2014DN07853A (es) | 2012-02-24 | 2015-04-24 | Hutchinson Fred Cancer Res | |
| DE202013012241U1 (de) | 2012-05-25 | 2016-01-18 | Emmanuelle Charpentier | Zusammensetzungen für die durch RNA gesteuerte Modifikation einer Ziel-DNA und für die durch RNA gesteuerte Modulation der Transkription |
| KR102474010B1 (ko) * | 2012-08-29 | 2022-12-02 | 상가모 테라퓨틱스, 인코포레이티드 | 유전적 병태를 치료하기 위한 방법 및 조성물 |
| SG10202110062SA (en) | 2012-11-27 | 2021-11-29 | Childrens Medical Center | Targeting Bcl11a Distal Regulatory Elements for Fetal Hemoglobin Reinduction |
| PL2928496T3 (pl) | 2012-12-06 | 2020-04-30 | Sigma-Aldrich Co. Llc | Modyfikacja i regulacja genomu w oparciu o CRISPR |
| BR112015013784A2 (pt) | 2012-12-12 | 2017-07-11 | Massachusetts Inst Technology | aplicação, manipulação e otimização de sistemas, métodos e composições para manipulação de sequência e aplicações terapêuticas |
| RU2699523C2 (ru) | 2012-12-17 | 2019-09-05 | Президент Энд Фэллоуз Оф Харвард Коллидж | Рнк-направляемая инженерия генома человека |
| EP2971184B1 (en) | 2013-03-12 | 2019-04-17 | President and Fellows of Harvard College | Method of generating a three-dimensional nucleic acid containing matrix |
| NZ712727A (en) | 2013-03-14 | 2017-05-26 | Caribou Biosciences Inc | Compositions and methods of nucleic acid-targeting nucleic acids |
| US10760064B2 (en) | 2013-03-15 | 2020-09-01 | The General Hospital Corporation | RNA-guided targeting of genetic and epigenomic regulatory proteins to specific genomic loci |
| KR102210322B1 (ko) | 2013-03-15 | 2021-02-01 | 더 제너럴 하스피탈 코포레이션 | Rna-안내 게놈 편집의 특이성을 증가시키기 위한 rna-안내 foki 뉴클레아제(rfn)의 용도 |
| CN105518146B (zh) | 2013-04-04 | 2022-07-15 | 哈佛学院校长同事会 | 利用CRISPR/Cas系统的基因组编辑的治疗性用途 |
| CN116083487A (zh) * | 2013-05-15 | 2023-05-09 | 桑格摩生物治疗股份有限公司 | 用于治疗遗传病状的方法和组合物 |
| US20140356956A1 (en) | 2013-06-04 | 2014-12-04 | President And Fellows Of Harvard College | RNA-Guided Transcriptional Regulation |
| EP3003392B1 (en) | 2013-06-04 | 2019-10-23 | President and Fellows of Harvard College | Rna-guideded transcriptional regulation |
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| EP4273242A1 (en) * | 2022-05-03 | 2023-11-08 | ETH Zurich | Crispr-based modification of human hbd gene |
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| CN101679959A (zh) | 2007-02-19 | 2010-03-24 | 赛莱克蒂斯公司 | 具有新的底物特异性的laglidadg归巢核酸内切酶变体及其用途 |
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| ES2738980T3 (es) * | 2008-09-15 | 2020-01-28 | Childrens Medical Ct Corp | Modulación de BCL11A para el tratamiento de hemoglobinopatías |
| WO2011156430A2 (en) * | 2010-06-07 | 2011-12-15 | Fred Hutchinson Cancer Research Center | Generation and expression of engineered i-onui endonuclease and its homologues and uses thereof |
| EP3603662B1 (en) * | 2011-02-28 | 2022-01-19 | Seattle Children's Research Institute | Coupling endonucleases with end-processing enzymes drive high efficiency gene disruption |
| IN2014DN07853A (es) | 2012-02-24 | 2015-04-24 | Hutchinson Fred Cancer Res | |
| KR102474010B1 (ko) * | 2012-08-29 | 2022-12-02 | 상가모 테라퓨틱스, 인코포레이티드 | 유전적 병태를 치료하기 위한 방법 및 조성물 |
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