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    2020-01-17

    A vueltas con los Ensayos Clínicos de edición génica en Clinicaltrial.gov






    Dando vueltas a los datos  de los ensayos clínicos de edición génica obtenidos de la página web de clínicaltrials.gov tras conocer del trabajo de Schacker entiendo que son las siguientes variables las que definen las diversas soluciones que se vienen ensayando:




    Con relación a la enfermedad a tratar, son 21 diferentes las listadas por Sacher, que se han agrupado en 6 grupos para facilitar su tabulación, y que son los siguientes:

    Cáncer hemático: 




    Cáncer no hemático: 




    Hemáticas:




    HIV




    Lisosomas:




    Visión: Leber congenital amaurosis 10



    Hemos cruzado las variables que nos parecen más significativas y presentamos las tablas que hemos obtenido.




























































































































































































































































































    CT´s por 
    Enfermedad  (Grupo), Target y Modificación

    Allogeneic CAR T cells       Autologous CAR T cells Autologous CD34+ HSPCs CD4 CAR T cells CD4+ T cells CTL cells Patient specific iHSCs T cells sin modificación (in vivo) Total 
    Cáncer hemático 3 1 4
    CD123 1 1
    CD19 and CD20/22  1 1
    CD19; TCR and B2-M  1 1
    CD7 1 1
    Cáncer no hemático 3 1 5 3 12
    E7/E6,E7 3 3
    NY-ESO-1;  TCR and PD-1 1 1
    PD-1 2 1 5 8
    Hemáticas 2 1 1 4
    BCL11A 2 2
    gene of  Albumin 1 1
    HBB 1 1
    HIV 2 1 5 8
    CCR5 2 1 5 8
    Lisosomas 2 2
    gene of  Albumin 2 2
    Visión 1 1
    CEP290 1 1
    Total general 3 4 4 1 5 1 1 5 7 31











































































































































    CT por nucleasa, Target y exvivo/invivo
    Ex vivo In vivo Total
    CRISPR/Cas9 16 1 17
    BCL11A 2 2
    CCR5 1 1
    CD19 and CD20/22  1 1
    CD7 1 1
    CEP290 1 1
    HBB 1 1
    PD-1 8 8
    NY-ESO-1; 
    TCR and PD-1
    1 1
    CD19; TCR and B2-M  1 1
    TALEN 1 1 2
    CD123 1 1
    E7/E6,E7 1 1
    TALEN  CRISPR/Cas9 1 1
    E7/E6,E7 1 1
    ZFN 7 4 11
    CCR5 7 7
    gene of 
    Albumin
    3 3
    E7/E6,E7 1 1
    Total 24 7 31















































































































































































    CT´s por Enf (Grupo), Nucleasa y Delivery

    CRISPR/Cas9 TALEN TALEN  CRISPR/Cas9 ZFN Total 
    Cáncer hemático 3 1 4
    Not specified 3 1 4
    Cáncer no hemático 9 1 1 1 12
    mRNA electroporation 1 1
    Not specified 8 1 9
    Plasmid in gel 1 1 2
    Hemáticas 3 1 4
    AAV 1 1
    Not specified 1 1
    Ribonucleoprotein
    electroporation
    2 2
    HIV 1 7 8
    Adenoviral vector 3 3
    mRNA electroporation 2 2
    Not specified 1 2 3
    Lisosomas 2 2
    AAV 2 2
    Visión 1 1
    AAV 1 1
    Total general 17 2 1 11 31

























































































































































































































    DT¨s por Enfermedad (G), Nucleasa y Delivery
    AAV Adenoviral vector mRNA electroporation Not specified Plasmid in gel Ribonucleoprotein electroporation Total general
    Cáncer hemático 4 4
    CRISPR/Cas9 3 3
    TALEN 1 1
    Cáncer no hemático 1 9 2 12
    CRISPR/Cas9 1 8 9
    TALEN 1 1
    TALEN 
    CRISPR/Cas9
    1 1
    ZFN 1 1
    Hemáticas 1 1 2 4
    CRISPR/Cas9 1 2 3
    ZFN 1 1
    HIV 3 2 3 8
    CRISPR/Cas9 1 1
    ZFN 3 2 2 7
    Lisosomas 2 2
    ZFN 2 2
    Visión 1 1
    CRISPR/Cas9 1 1
    Total general 4 3 3 17 2 2 31

    2020-01-17 16:08 | 0 Comentarios


    2020-01-09

    Sangamo Therapeutics versus CRISPR Therapeutics

    Tirando del hilo de las tablas de CT´s  de edición génica he llegado a un interesante artículo de Cory Renauer: Better Buy: CRISPR Therapeutics vs. Sangamo Therapeutics en el que se plantea qué es mejor, comprar acciones de una empresa o de la otra.

    Sangamo Tx es el mayor esponsor de CT´s de edición génica recogidos en la tabla de Schacker (n=8) y CRISPR Tx comparte con Vertex la esponsorización de otros dos CT´s. La primera empresa es una veterana con sus casi 35 años y la segunda es mucho más joven con 7 años de vida.

    En dos tablas, una referida a la empresa y otra a los productos, las comparo para ver qué compraríamos.

    Sangamo Therapeutics

    CRISPR Therapeutics

    Creación

    1995


    2013


    Valor en bolsa (6/1/2020). Ver abajo trayectoria bursátil

    $ 954 million


    $ 3566,65 million


    Popes

    Carpentier

    Oficinas centrales

    7000 Marina Blvd, Brisbane, CA 94005, EE. UU.

    Baarerstrasse 14 ZUG V8 CH-6300 Switzerland

    Alianzas

    Pfizer, Kite, Takeda, Sanofi

    Vertex


    Productos

    De los pipelines de sus respectivas páginas web y de informes para inversores, en el caso de Sangamo ,  he obtenido los datos de esta tabla.

    BLA (Biologics License Application de FDA)

    ninguno

    ninguno

    Fast Track´s de FDA

    4: SB-913 para MPS-2;

        SB-318 para MPS-1;

        SB-525 para Hemofilia A;

        SB-FIX para Hemofilia B




    1: CTX001 para anemia falciforme

    Pipeline preclínico

    PKU (ST-101) SANGAMO WHOLLY OWNED


    IBD SANGAMO WHOLLY OWNED


    MS SANGAMO WHOLLY OWNED


    Oncology (Kite-037) PARTNER: Kite


    Solid Organ Transplant (TX200) SANGAMO WHOLLY OWNED


    α-Synucleiin (ST-502) SANGAMO WHOLLY OWNED


    ALS/FTD PARTNER: Pfizer


    Huntington’s Disease PARTNER: Takeda


    Tauopathies (ST-501) SANGAMO WHOLLY OWNED

    Immuno-Oncology


    CTX120 (IND-enabling)


    CTX130  (IND-enabling) 


     Regenerative Medicine: Type I diabetes mellitus (Research)

    InVivo Approaches:


    Glycogen storage disease type Ia (GSD Ia) (Research)


    Duchenne muscular dystrophy (DMD) (Research)


    Myotonic dystrophy type 1 (DM1) (Research)


    Cystic fibrosis (CF) (Research)

    Nucleasas

    ZFN

    CRISPR Cas9

    Observaciones

    NCT04046224, CT  de producto contra enfermedad de Fabry, (ST-920) también está en fase clínica, luego serían 6 los en fase clínica. "Actual Study Start Date  : July 23, 2019"




    Trayectorias bursátiles






    Dice Renauer:  It's probably best to cheer for CRISPR from the sidelines, and put the better buy, Sangamo, in a diverse portfolio, CRISPR Therapeutics (NASDAQ: CRSP) y Vertex Pharmaceuticals Incorporated (NASDAQ: VRTX) publicaron la siguiente nota: 
     today announced positive, interim data from the first two patients with severe hemoglobinopathies treated with the investigational CRISPR/Cas9 gene-editing therapy CTX001 in ongoing Phase 1/2 clinical trials. One patient with transfusion-dependent beta thalassemia (TDT) received CTX001 in the first quarter of 2019 and data for this patient reflect nine months of safety and efficacy follow-up. One patient with severe sickle cell disease (SCD) received CTX001 in mid-2019 and data for this patient reflect four months of safety and efficacy follow-up. These studies are ongoing and patients will be followed for approximately two years following infusion. Several additional patients have been enrolled and have had drug product manufactured across the two studies. 
    Información, cuyo efecto en el valor de la acción, que nos parece ver reflejada en la gráfica que arriba se presenta.

    2020-01-09 19:06 | 0 Comentarios


    2019-12-29

    Avances en edición génica: Addgene y Biopharma Excellence

    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  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

    Sangamo (6), que es de US, aunque parezca de Japón, destaca en el número de CT´s


    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.


    Nuclease

    Total 

    0

    1

    2

    3

    CRISPR

    17

    4

    13

    TALEN

    2

    2

    TALEN  CRISPR/Cas9

    1

    1

    ZFN

    11

    1

    2

    5

    3

    Total

    31

    1

    2

    9

    19


    Por el método de transfección no han podido encontrarlo en 17 de los CT

    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




    2019-12-29 17:51 | 0 Comentarios


    2019-12-23

    Ensayos clínicos en Clinicaltrials.gov con uso de CRISPR

    Decía en la ultima entrada de los 31 ensayos clínicos de clinicaltrials.gov  con la palabra CRISPR. Uno se retiró y de los 30 restantes he tenido referencia de resultados de los de CTX001 de anemia falciforme NCT03745287 y de betatalasemia NCT03655678 en Highly Efficient Therapeutic Gene Editing of Human Hematopoietic Stem Cells



    NCT Number

    Title

    Conditions

    Interventions

    Sponsor/Collaborators

    Phases

    Funded Bys

    URL

    NCT03057912

    A Safety and Efficacy Study of TALEN and CRISPR/Cas9 in the Treatment of HPV-related Cervical Intraepithelial Neoplasiaâ… 

    Human Papillomavirus-Related Malignant Neoplasm

    Biological: TALEN , Biological: CRISPR/Cas9

    First Affiliated Hospital, Sun Yat-Sen University , Jingchu University of Technology

    Phase 1

    Other

    https://ClinicalTrials.gov/show/NCT03057912

    NCT04074369

    Evaluation of CRISPR-based Test for the Rapid Identification of TB in Pulmonary Tuberculosis Suspects

    Tuberculosis, Pulmonary

    Diagnostic Test: CRISPR-based Test

    Huashan Hospital , Wenzhou Central Hospital , Hangzhou Red Cross Hospital

    Other

    https://ClinicalTrials.gov/show/NCT04074369

    NCT04178382

    Effect of PCR-CRISPR/Cas12a on the Early Anti-infective Schemes in Patients With Open Air Pneumonia

    Severe Sepsis

    Diagnostic Test: PCR-CRISPR/Cas12a detection

    Chinese Medical Association

    Not Applicable

    Other

    https://ClinicalTrials.gov/show/NCT04178382

    NCT03164135

    Safety of Transplantation of CRISPR CCR5 Modified CD34+ Cells in HIV-infected Subjects With Hematological Malignances

    HIV-1-infection

    Genetic: CCR5 gene modification

    Affiliated Hospital to Academy of Military Medical Sciences , Peking University , Capital Medical University

    Not Applicable

    Other

    https://ClinicalTrials.gov/show/NCT03164135

    NCT03545815

    Study of CRISPR-Cas9 Mediated PD-1 and TCR Gene-knocked Out Mesothelin-directed CAR-T Cells in Patients With Mesothelin Positive Multiple Solid Tumors.

    Solid Tumor, Adult

    Biological: anti-mesothelin CAR-T cells

    Chinese PLA General Hospital

    Phase 1

    Other

    https://ClinicalTrials.gov/show/NCT03545815

    NCT03655678

    A Safety and Efficacy Study Evaluating CTX001 in Subjects With Transfusion-Dependent β-Thalassemia

    Beta-Thalassemia , Thalassemia , Genetic Diseases, Inborn , Hematologic Diseases , Hemoglobinopathies

    Biological: CTX001

    Vertex Pharmaceuticals Incorporated , CRISPR Therapeutics

    Phase 1 , Phase 2

    Industry

    https://ClinicalTrials.gov/show/NCT03655678

    NCT03399448

    NY-ESO-1-redirected CRISPR (TCRendo and PD1) Edited T Cells (NYCE T Cells)

    Multiple Myeloma , Melanoma , Synovial Sarcoma , Myxoid/Round Cell Liposarcoma

    Biological: NY-ESO-1 redirected autologous T cells with CRISPR edited endogenous TCR and PD-1 , Drug: Cyclophosphamide , Drug: Fludarabine , Device: NY-ESO-1 expression testing

    University of Pennsylvania , Parker Institute for Cancer Immunotherapy , Tmunity Therapeutics

    Phase 1

    Other , Industry

    NCT04037566

    CRISPR (HPK1) Edited CD19-specific CAR-T Cells (XYF19 CAR-T Cells) for CD19+ Leukemia or Lymphoma.

    Leukemia Lymphocytic Acute (ALL) in Relapse , Leukemia Lymphocytic Acute (All) Refractory , Lymphoma, B-Cell , CD19 Positive

    Genetic: XYF19 CAR-T cell , Drug: Cyclophosphamide , Drug: Fludarabine

    Xijing Hospital , Xi'An Yufan Biotechnology Co.,Ltd

    Phase 1

    Other

    https://ClinicalTrials.gov/show/NCT04037566

    NCT03745287

    A Safety and Efficacy Study Evaluating CTX001 in Subjects With Severe Sickle Cell Disease

    Sickle Cell Disease , Hematological Diseases , Hemoglobinopathies

    Biological: CTX001

    Vertex Pharmaceuticals Incorporated , CRISPR Therapeutics

    Phase 1 , Phase 2

    Industry

    https://ClinicalTrials.gov/show/NCT03745287

    NCT04035434

    A Safety and Efficacy Study Evaluating CTX110 in Subjects With Relapsed or Refractory B-Cell Malignancies

    B-cell Malignancy , Non-Hodgkin Lymphoma , B-cell Lymphoma

    Biological: CTX110

    CRISPR Therapeutics AG , CRISPR Therapeutics

    Phase 1 , Phase 2

    Industry

    https://ClinicalTrials.gov/show/NCT04035434

    NCT03538613

    Study of People With Metastatic Gastrointestinal Epithelial Cancer Administering Tumor-Infiltrating Lymphocytes in Which the Gene Encoding CISH Was Inactivated Using the CRISPR/Cas9 System

    Gastrointestinal Epithelial Cancer , Gastrointestinal Neoplasm , Cancer of Gastrointestinal Tract , Cancer, Gastrointestinal

    Drug: Cyclophosphamide , Drug: Fludarabine , Drug: Aldesleukin , Biological: CISH inactivated TIL

    National Cancer Institute (NCI) , National Institutes of Health Clinical Center (CC)

    Phase 1 , Phase 2

    NIH

    https://ClinicalTrials.gov/show/NCT03538613

    NCT03728322

    iHSCs With the Gene Correction of HBB Intervent Subjests With β-thalassemia Mutations

    Thalassemia

    Biological: iHSCs treatment group

    Allife Medical Science and   Technology Co., Ltd.

    Early Phase 1

    Industry

    https://ClinicalTrials.gov/show/NCT03728322

    NCT03747965

    Study of PD-1 Gene-knocked Out Mesothelin-directed CAR-T Cells With the Conditioning of PC in Mesothelin Positive Multiple Solid Tumors

    Solid Tumor, Adult

    Biological: Mesothelin-directed CAR-T cells

    Chinese PLA General Hospital

    Phase 1

    Other

    https://ClinicalTrials.gov/show/NCT03747965

    NCT03855631

    Exploiting Epigenome Editing in Kabuki Syndrome: a New Route Towards Gene Therapy for Rare Genetic Disorders

    Kabuki Syndrome 1

    Genetic: Intervention on primary cultured cells

    University Hospital, Montpellier , Association Française contre les Myopathies Telethon

    Other

    https://ClinicalTrials.gov/show/NCT03855631

    NCT03342547

    Identification of Host Factors of Norovirus Infections in Mini-Gut Model

    Gastrointestinal Infection

    Procedure: Duodenal biopsy , Procedure: Saliva

    Chinese University of Hong Kong

    Not Applicable

    Other

    https://ClinicalTrials.gov/show/NCT03342547

    NCT03166878

    A Study Evaluating UCART019 in Patients With Relapsed or Refractory CD19+ Leukemia and Lymphoma

    B Cell Leukemia , B Cell Lymphoma

    Biological: UCART019

    Chinese PLA General Hospital

    Phase 1 , Phase 2

    Other

    https://ClinicalTrials.gov/show/NCT03166878

    NCT03606486

    Lavage of the Uterine Cavity for Diagnosis of Ovarian Cancer

    High Grade Ovarian Serous Adenocarcinoma , Stage III Ovarian Cancer AJCC v8 , Stage IIIA Ovarian Cancer AJCC v8 , Stage IIIA1 Ovarian Cancer AJCC v8 , Stage IIIA2 Ovarian Cancer AJCC v8 , Stage IIIB Ovarian Cancer AJCC v8 , Stage IIIC Ovarian Cancer AJCC v8 , Stage IV Ovarian Cancer AJCC v8 , Stage IVA Ovarian Cancer AJCC v8 , Stage IVB Ovarian Cancer AJCC v8

    Other: Biospecimen Collection , Other: Laboratory Biomarker Analysis , Other: Lavage , Other: Pap Smear

    University of Washington , National Cancer Institute (NCI) , Minnesota Ovarian Cancer Alliance

    Not Applicable

    Other , NIH

    https://ClinicalTrials.gov/show/NCT03606486

    NCT03398967

    A Feasibility and Safety Study of Universal Dual Specificity CD19 and CD20 or CD22 CAR-T Cell Immunotherapy for Relapsed or Refractory Leukemia and Lymphoma

    B Cell Leukemia , B Cell Lymphoma

    Biological: Universal Dual Specificity CD19 and CD20 or CD22 CAR-T Cells

    Chinese PLA General Hospital

    Phase 1 , Phase 2

    Other

    https://ClinicalTrials.gov/show/NCT03398967

    NCT03081715

    PD-1 Knockout Engineered T Cells for Advanced Esophageal Cancer

    Esophageal Cancer

    Other: PD-1 Knockout T Cells

    Hangzhou Cancer Hospital , Anhui Kedgene Biotechnology Co.,Ltd

    Not Applicable

    Other

    https://ClinicalTrials.gov/show/NCT03081715

    NCT03332030

    Stem Cells in NF1 Patients With Tumors of the Central Nervous System

    Neurofibromatosis Type 1 , Tumors of the Central Nervous System

    Diagnostic Test: Collection of Stem Cells

    Children's Research Institute

    Other

    https://ClinicalTrials.gov/show/NCT03332030

    NCT03690011

    Cell Therapy for High Risk T-Cell Malignancies Using CD7-Specific CAR Expressed On Autologous T Cells

    T-cell Acute Lymphoblastic Leukemia , T-cell Acute Lymphoblastic Lymphoma , T-non-Hodgkin Lymphoma

    Genetic: CD7.CAR/28zeta CAR T cells , Drug: Fludarabine , Drug: Cytoxan

    Baylor College of Medicine , The Methodist Hospital System , Texas Children's Hospital , Center for Cell and Gene Therapy, Baylor College of Medicine

    Phase 1

    Other

    https://ClinicalTrials.gov/show/NCT03690011

    NCT03681951

    First-time-in-human (FTIH) Study of GSK3145095 Alone and in Combination With Other Anticancer Agents in Adults With Advanced Solid Tumors

    Neoplasms, Pancreatic

    Drug: GSK3145095 , Drug: Pembrolizumab

    GlaxoSmithKline , Parexel

    Phase 2

    Industry

    https://ClinicalTrials.gov/show/NCT03681951

    NCT02863913

    PD-1 Knockout Engineered T Cells for Muscle-invasive Bladder Cancer

    Invasive Bladder Cancer Stage IV

    Biological: PD-1 Knockout T Cells , Drug: Cyclophosphamide , Drug: IL-2

    Peking University

    Phase 1

    Other

    https://ClinicalTrials.gov/show/NCT02863913

    NCT02867345

    PD-1 Knockout Engineered T Cells for Castration Resistant Prostate Cancer

    Hormone Refractory Prostate Cancer

    Biological: PD-1 Knockout T Cells , Drug: Cyclophosphamide , Drug: IL-2

    Peking University

    Other

    https://ClinicalTrials.gov/show/NCT02867345

    NCT02867332

    PD-1 Knockout Engineered T Cells for Metastatic Renal Cell Carcinoma.

    Metastatic Renal Cell Carcinoma

    Biological: PD-1 Knockout T Cells , Drug: Cyclophosphamide , Drug: IL-2

    Peking University

    Phase 1

    Other

    https://ClinicalTrials.gov/show/NCT02867332

    NCT02793856

    PD-1 Knockout Engineered T Cells for Metastatic Non-small Cell Lung Cancer

    Metastatic Non-small Cell Lung Cancer

    Drug: Cyclophosphamide , Other: PD-1 Knockout T Cells

    Sichuan University , Chengdu MedGenCell, Co., Ltd.

    Phase 1

    Other , Industry

    https://ClinicalTrials.gov/show/NCT02793856

    NCT03044743

    PD-1 Knockout EBV-CTLs for Advanced Stage Epstein-Barr Virus (EBV) Associated Malignancies

    Stage IV Gastric Carcinoma , Stage IV Nasopharyngeal Carcinoma , T-Cell Lymphoma Stage IV , Stage IV Adult Hodgkin Lymphoma , Stage IV Diffuse Large B-Cell Lymphoma

    Drug: Fludarabine , Drug: Cyclophosphamide , Drug: Interleukin-2

    Yang Yang , The Affiliated Nanjing Drum Tower Hospital of Nanjing University Medical School

    Phase 1 , Phase 2

    Other

    https://ClinicalTrials.gov/show/NCT03044743

    NCT03872479

    Single Ascending Dose Study in Participants With LCA10

    Blindness , Leber Congenital Amaurosis 10 , Vision Disorders , Eye Diseases , Eye Diseases, Hereditary , Eye Disorders Congenital , Retinal Disease , Retinal Degeneration

    Drug: AGN-151587

    Allergan , Editas Medicine, Inc.

    Phase 1 , Phase 2

    Industry

    https://ClinicalTrials.gov/show/NCT03872479

    NCT04122742

    Diagnosis of RSTS: Identification of the Acetylation Profiles as Epigenetic Markers for Assessing Causality of CREBBP Variants.

    Rubinstein-Taybi Syndrome

    Procedure: skin biopsy for the primary fibroblast culture and a 15 ml blood sample (3 unnamed samples of 5ml) in each of the 4 SRT patients included. , Other: Generation of Induced Pluripotent Stem Cells (iPSC) from fibroblasts obtained by skin biopsy , Other: Histone acetylation profiles of cells of SRT patients with CREBBP mutations , Other: Functional involvement of identified epigenetic alterations , Biological: Culture of lymphoblastoid line from blood sample

    University Hospital, Bordeaux

    Other

    https://ClinicalTrials.gov/show/NCT04122742

    NCT02964481

    Malignant Hyperthermia Registry and Genetic Testing

    Malignant Hyperthermia

    Children's Hospital Medical Center, Cincinnati

    Other

    https://ClinicalTrials.gov/show/NCT02964481


    2019-12-23 07:26 | 0 Comentarios


    2019-12-14

    ¿LVV o AAVV?: CRISPR Cas9

    Antes que nada diremos que el título de esta entrada plantea una dicotomía y solución que no siempre es cierta. Depende pues.


    En estos meses de sequía en la emisión de Autorizaciones de comercialización por parte de la EMA, ya que desde junio que se produjo la autorización de Zynteglo la única novedad ha sido la retirada por parte de Molmed de Zalmoxis,  he intentado mejorar mi conocimiento de los vectores virales.

    En el artículo de F Delgado, 2011, Características virológicas del VIH, veo de la estructura génica del virus VIH-1. a partir del cual se han obtenido los vectores lentivirales.





    Veo se la estructura del genoma del virus y lista de proteínas que a partir de él se generan




    En este artículo Gene Therapy of the β-Hemoglobinopathies by Lentiviral Transfer of the βA(T87Q)-Globin Gene en la gráfica 3, veo la estructura del vector viral HPV569 b-globin a partir de la que se ha obtenido el vector BB305  utilizado por bluebird bio en la elaboración de Zynteglo.












    En A Guide to Approaching Regulatory Considerations for Lentiviral-Mediated Gene Therapies  en la Figura 2 veo el esquema de elaboración del vector






    Y el esquema del vector para ser utilizado en la elaboración de diversas soluciones para modificación génica, similar al de dos gráficas más arriba.










    Me planteo ¿qué tecnología está siendo objeto de más investigación, el uso de LVV ó el de AAVV? Y le pregunto a Pubmed, restringido a humanos, ("lentiviral virus vector"  3911 resultados ; "adeno associated virus vector": 4336 resultados ). Obtengo los datos y elaboro la gráfica que viene a continuación que habla por sí sola: la investigación sobre AAVV  comenzó antes, el uso de LVV lo ha superado en interés y en los últimos años ambas técnicas están siendo objeto de menor interés.



    Teniendo claro que LVV y AAVV  son técnicas para hacer llegar el ADN  modificado al interior del núcleo celular y CRISPR Cas9 una herramienta de edición génica y por tanto dos herramientas distintas y complementarias.  ¿puede ser el interés por CRISPR  Cas9 la causa del menor interés en estas técnicas? Pregunto a Pubmed por CRISPR Cas9, en humanos, y genero esta nueva gráfica, que también habla por sí sola.






    Si buscamos ensayos clínicos en los dos principales registros (EUDRA: clinicaltrialsregister.eu  y clinicaltrials.gov) los resultados son:



    AAVV

    LVV

    CRISPR

    EUDRACT

    26

    49

    0

    CT.GOV

    46

    46

    31


    Le ruego evalúe la presente entrada asignando un valor de 1 a 5, de peor a mejor valorada, usando la opción de comentarios

    2019-12-14 07:43 | 0 Comentarios


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