Tras publicar la entrada anterior y dos entradas atrás sobre CRISPR, y en el camino de entender la dimensión de las posibilidades de esta herramienta, he encontrado una interesante iniciativa, que entre otras cosas tiene un repositorio de plásmidos: Addgene
We distribute 81,207 plasmids on behalf of 4,062 labs from around the world. We also produce 446 ready-to-use viral vectors from our plasmid collection. Find what you need for your next experiment
He bajado su eBook Addgene's eBook: CRISPR 101 en el que se habla de numerosas herramientas de edición génica que están siendo, no sé si descubiertas ó inventadas, para muy diversos usos:
Cpf1 family members contain a RuvC-like endonuclease domain, but they lack Cas9’s second HNH endonuclease domain. Cpf1 cleaves DNA in a staggered pattern and requires only one RNA rather than the two (tracrRNA and crRNA) needed by Cas9 for cleavage.
En la línea de disminuir los off-target están la eSpCas9 y SpCas9-HF1.
Buscando mejorar la tabla de la entrada anterior sobre los CT con CRISPR en Clinicaltrials.gov he encontrado el artículo From fiction to science: clinical potentials and regulatory considerations of gene editing El artículo de Schacker y Seimetz tiene una tabla con 31 CT de edición génica referenciados en clinicaltrial.gov a julio de 2019. Son CT en los que se usa ZF, TALEN y CRISPR. Están 18 que coinciden con los publicados en la entrada anterior de este blog - no están los de diagnóstico y de ciencia básica - más otros con ZF y TALEN. Me ha parecido genial. Copio la tabla 2 del artículo.
NCT (status)
|
Country/region
|
Sponsor
|
Disease
|
Target/modification
|
Nuclease
|
Delivery
| |
|---|---|---|---|---|---|---|---|
Ex vivo
|
NCT00842634 (completed)
|
US
|
Sangamo Therapeutics
|
HIV
|
CCR5 modified CD4+ T cells
|
ZFN
|
Adenoviral vector
|
NCT01044654 (completed)
|
US
|
Sangamo Therapeutics
|
HIV
|
CCR5 modified CD4+ T cells
|
ZFN
|
Adenoviral vector
| |
NCT01252641 (completed)
|
US
|
Sangamo Therapeutics
|
HIV
|
CCR5 modified CD4+ T cells
|
ZFN
|
Adenoviral vector
| |
NCT02388594 (completed)
|
US
|
University of Pennsylvania
|
HIV
|
CCR5 modified CD34+ T cells
|
ZFN
|
mRNA electroporation
| |
NCT02500849 (active, not recruiting)
|
US
|
City of Hope Medical Center
|
HIV
|
CCR5 modified CD34+ HSPCs
|
ZFN
|
mRNA electroporation
| |
NCT03617198 (not yet recruiting)
|
US
|
University of Pennsylvania
|
HIV
|
CCR5 modified, C34-CXCR4, CD4 CAR T cells
|
ZFN
|
Not specified
| |
NCT03666871 (not yet recruiting)
|
Not specified
|
Case Western Reserve University
|
HIV
|
CCR5 modified CD4+ T cells
|
ZFN
|
Not specified
| |
NCT03190278 (recruiting)
|
US
|
Cellectis S.A.
|
Acute myeloid leukemia
|
Allogeneic CAR T cells targeting CD123, TCR disruption
|
TALEN
|
Not specified
| |
NCT03164135 (recruiting)
|
China
|
Affiliated Hospital to Academy of Military Medical Sciences (China)
|
HIV-1
|
CCR5 modified CD34+ HSPCs (from donor)
|
CRISPR/Cas
|
Not specified
| |
NCT03655678 (recruiting)
|
Canada, Europe
|
Vertex Pharmaceuticals Incorporated
|
Beta Thalassemia
|
Autologous CD34+ HSPCs modified at the enhancer of the BCL11A gene
|
CRISPR/Cas9
|
Ribonucleoprotein electroporation
| |
NCT03728322 (not yet recruiting)
|
Not specified
|
Allife Medical Science and Technology Co., Ltd
|
Beta thalassemia
|
HBB gene correction in patient specific iHSCs
|
CRISPR/Cas9
|
Not specified
| |
NCT03745287 (recruiting)
|
US, Europe
|
Vertex Pharmaceuticals Incorporated
|
Sickle cell disease
|
Autologous CD34+ HSPCs modified at the enhancer of the BCL11A gene
|
CRISPR/Cas9
|
Ribonucleoprotein electroporation
| |
NCT03398967 (recruiting)
|
China
|
Chinese PLA General Hospital
|
B cell leukemia, B cell lymphoma
|
Allogeneic CD19 and CD20/22 CAR T cells
|
CRISPR/Cas9
|
Not specified
| |
NCT03166878 (recruiting)
|
China
|
Chinese PLA General Hospital
|
B cell leukemia, B cell lymphoma
|
Allogeneic CD19-directed CAR T cells; TCR and B2 M disruption
|
CRISPR/Cas9
|
Not specified
| |
NCT03399448 (recruiting)
|
US
|
University of Pennsylvania
|
Multiple Myeloma, Melanoma, Synovial Sarcoma, Myxoid/Round Cell Liposarcoma
|
Autologous anti-NY-ESO CAR T cells, disruption of TCR and PD-1
|
CRISPR/Cas
|
mRNA electroporation
| |
NCT03690011 (not yet recruiting)
|
US
|
Baylor College of Medicine
|
T cell Acute Lymphoblastic Leukemia, T cell Acute Lymphoblastic Lymphoma, T-non-Hodgkin Lymphoma
|
Anti-CD7 CAR T cells, CD7 KO
|
CRISPR/Cas9
|
Not specified
| |
NCT03545815 (recruiting)
|
China
|
Chinese PLA General Hospital
|
Solid tumor
|
PD-1 and TCR KO anti-mesothelin CAR T cells
|
CRISPR/Cas9
|
Not specified
| |
NCT03747965 (recruiting)
|
China
|
Chinese PLA General Hospital
|
Solid tumor
|
Mesothelin-directed CAR T cells; PD-1 KO
|
CRISPR
|
Not specified
| |
NCT03081715 (completed)
|
China
|
Hangzhou Cancer Hospital
|
Esophageal cancer
|
PD-1 KO T cells
|
CRISPR/Cas9
|
Not specified
| |
NCT02793856 (active, not recruiting)
|
China
|
Sichuan University
|
Metastatic non-small cell lung cancer
|
PD-1 KO T cells
|
CRISPR/Cas9
|
Not specified
| |
NCT03044743 (recruiting)
|
China
|
Yang Yang, Nanjing University Medical School
|
EBV positive advanced stage malignancies
|
PD-1 KO EBV-CTL cells
|
CRISPR/Cas9
|
Not specified
| |
NCT02863913 (withdrawn—no funding)
|
China
|
Peking University
|
Invasive Bladder Cancer Stage IV
|
PD-1 KO T cells
|
CRISPR/Cas9
|
Not specified
| |
NCT02867345 (withdrawn—no funding)
|
China
|
Peking University
|
Hormone Refractory Prostate Cancer
|
PD-1 KO T cells
|
CRISPR/Cas9
|
Not specified
| |
NCT02867332 (withdrawn—no funding)
|
China
|
Peking University
|
Metastatic renal cell carcinoma
|
PD-1 KO T cells
|
CRISPR/Cas9
|
Not specified
| |
In vivo
|
NCT03041324 (recruiting)
|
US
|
Sangamo Therapeutics
|
Mucopolysaccharidosis II
|
Insertion of corrected copy of Iduronate 2-Sulfatase gene into the Albumin locus
|
ZFN
|
AAV
|
NCT02702115 (recruiting)
|
US
|
Sangamo Therapeutics
|
Mucopolysaccharidosis I
|
Insertion of corrected copy of α-l-iduronidase gene into the Albumin locus
|
ZFN
|
AAV
| |
NCT02695160 (recruiting)
|
US, Europe
|
Sangamo Therapeutics
|
Hemophilia B
|
Insertion of a corrected copy of the factor 9 gene into the albumin locus
|
ZFN
|
AAV
| |
NCT02800369 (active, not recruiting)
|
China
|
Huazhong University of Science and Technology
|
Human papillomavirus-Related malignant neoplasm
|
E7
|
ZFN
|
Not specified
| |
NCT03226470 (not yet recruiting)
|
China
|
Huazhong University of Science and Technology
|
Human papillomavirus-related malignant neoplasm
|
E6, E7
|
TALEN
|
Plasmid in gel
| |
NCT03057912 (unknown)
|
China
|
First Affiliated Hospital, Sun Yat-Sen University
|
Human papillomavirus-Related malignant neoplasm
|
E6, E7
|
TALEN
CRISPR/Cas9
|
Plasmid in gel
| |
NCT03872479 (not yet recruiting)
|
US
|
Allergan
|
Leber congenital amaurosis 10
|
CEP290
|
CRISPR/Cas9
|
AAV
|
Agrupando los datos por países son: Canadá, Europa (1); China (14); not specified,(2); US (12) y US, Europe (2). China está dispuesta a ser una potencia también en edición génica.
Agrupando los datos por patrocinador:
| Sponsor | n |
| Affiliated Hospital to Academy of Military Medical Sciences (China) | 1 |
| Allergan | 1 |
| Allife Medical Science and Technology Co., Ltd | 1 |
| Baylor College of Medicine | 1 |
| Case Western Reserve University | 1 |
| Cellectis S.A. | 1 |
| Chinese PLA General Hospital | 4 |
| City of Hope Medical Center | 1 |
| First Affiliated Hospital, Sun Yat-Sen University | 1 |
| Hangzhou Cancer Hospital | 1 |
| Huazhong University of Science and Technology | 2 |
| Peking University | 3 |
| Sangamo Therapeutics | 6 |
| Sichuan University | 1 |
| University of Pennsylvania | 3 |
| Vertex Pharmaceuticals Incorporated | 2 |
| Yang Yang, Nanjing University Medical School | 1 |
Por la enfermedad a resolver:
| Disease | n |
| Acute myeloid leukemia | 1 |
| B cell leukemia, B cell lymphoma | 2 |
| Beta thalassemia | 2 |
| EBV positive advanced stage malignancies | 1 |
| Esophageal cancer | 1 |
| Hemophilia B | 1 |
| HIV | 7 |
| HIV-1 | 1 |
| Hormone Refractory Prostate Cancer | 1 |
| Human papillomavirus-Related malignant neoplasm | 3 |
| Invasive Bladder Cancer Stage IV | 1 |
| Leber congenital amaurosis 10 | 1 |
| Metastatic non-small cell lung cancer | 1 |
| Metastatic renal cell carcinoma | 1 |
| Mucopolysaccharidosis I | 1 |
| Mucopolysaccharidosis II | 1 |
| Multiple Myeloma, Melanoma, Synovial Sarcoma, Myxoid/Round Cell Liposarcoma | 1 |
| Sickle cell disease | 1 |
| Solid tumor | 2 |
| T cell Acute Lymphoblastic Leukemia, T cell Acute Lymphoblastic Lymphoma, T-non-Hodgkin Lymphoma | 1 |
Por el Target son:
| Target/modification | n |
| Allogeneic CAR T cells targeting CD123, TCR disruption | 1 |
| Allogeneic CD19 and CD20/22 CAR T cells | 1 |
| Allogeneic CD19-directed CAR T cells; TCR and B2 M disruption | 1 |
| Anti-CD7 CAR T cells, CD7 KO | 1 |
| Autologous anti-NY-ESO CAR T cells, disruption of TCR and PD-1 | 1 |
| Autologous CD34+ HSPCs modified at the enhancer of the BCL11A gene | 2 |
| CCR5 modified CD34+ HSPCs | 1 |
| CCR5 modified CD34+ HSPCs (from donor) | 1 |
| CCR5 modified CD34+ T cells | 1 |
| CCR5 modified CD4+ T cells | 4 |
| CCR5 modified, C34-CXCR4, CD4 CAR T cells | 1 |
| CEP290 | 1 |
| E6, E7 | 2 |
| E7 | 1 |
| HBB gene correction in patient specific iHSCs | 1 |
| Insertion of a corrected copy of the factor 9 gene into the albumin locus | 1 |
| Insertion of corrected copy of Iduronate 2-Sulfatase gene into the Albumin locus | 1 |
| Insertion of corrected copy of α-L-iduronidase gene into the Albumin locus | 1 |
| Mesothelin-directed CAR T cells; PD-1 KO | 1 |
| PD-1 and TCR KO anti-mesothelin CAR T cells | 1 |
| PD-1 KO EBV-CTL cells | 1 |
| PD-1 KO T cells | 5 |
Por la nucleasa utilizada:
| Nuclease | n |
| CRISPR | 1 |
| CRISPR/Cas | 2 |
| CRISPR/Cas9 | 14 |
| TALEN | 2 |
| TALEN CRISPR/Cas9 | 1 |
| ZFN | 11 |
Viendo en el tiempo a partir del NCT qué nucleasa se usaba más al inicio de los CT de edición génica ó en la actualidad, es decir viendo el dígito séptimo (millones, M) vemos que los ZFN tienen cierta estabilidad en el tiempo (1,2,5,3) mientras que los con CRISPR (he sumado los 3 tipos de CRISPR descritos CRISPR, CRISPR Cas y CRISPR Cas9) son del periodo más reciente (0,0,4,13). También los de TALEN, aunque en menor número son del periodo más reciente.
|
| Delivery | n |
| AAV | 4 |
| Adenoviral vector | 3 |
| mRNA electroporation | 3 |
| Not specified | 17 |
| Plasmid in gel | 2 |
| Ribonucleoprotein electroporation | 2 |
Sus autoras son Maria Schacker y Diane Seimetz de Biopharma Excellence, una consultora para ayudar en las tramitaciones de los expedientes ante las agencias reguladoras.
De su brochure copiamos dos gráficas, una de tipos de productos
y otra de tipos de servicios
Le ruego evalúe la presente entrada asignando un valor de 1 a 5, de peor a mejor valorada, usando la opción de comentarios
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