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CRISPR/Cas9 gene editing in hematology
fetal-to-adult hemoglobin switch and silencer of fetal hemoglobin. BCL11A disruption by CRISPR/Cas9 was shown to facilitate the achievement of threshold levels of functional fetal hemoglobin for treating β-hemoglo- binopathies.54 Likewise, sickle cell disease is caused by a major mutation in the HBB gene, resulting in abnormal hemoglobin and the production of malfunctioning ery- throcytes. CRISPR/Cas9-mediated gene editing has been employed to correct one HBB allele in iPSC generated from patients with sickle cell disease,55 and to create the hereditary persistence of a fetal hemoglobin genotype in HSPC, which is suggested as an approach for treating β- thalassemia and sickle cell disease.56,57 In the clinical set- ting, CTX001, a gene-edited autologous HSC therapy tar- geting the erythroid-specific enhancer of the BCL11A gene, is entering clinical trials for β-thalassemia (Europe) and sickle cell disease (USA) (Table 6). Specifically, ex vivo edited patients’ cells will be re-infused into patients to produce fetal hemoglobin-containing erythrocytes and overcome the hemoglobin deficiency. These approaches are remarkable because hemoglobinopathies represent a huge cost to healthcare systems as a consequence of fre- quent transfusions and hospital admissions. Accordingly, novel therapies for these diseases are in high demand.
CRISPR/Cas9 gene editing has recently been employed in Fanconi anemia, a rare genetic disease characterized by progressive bone marrow failure that results in decreased production of all blood cell types. In 80–90% of cases, Fanconi anemia is caused by mutations in FANCA,
Table 6. Current clinical trials in hematology using the CRISPR/Cas9 system.
FANCC or FANCG genes. CRISPR/Cas9-gene editing has successfully corrected a FANCC gene mutation in patient- derived fibroblasts using Cas9 nickase, obtaining a higher correction frequency than Cas9 nuclease.58 As the name might suggest, nickases introduce a single-strand break or “nick” rather than a DSB. Although clinical trials using other nucleases in Fanconi anemia are ongoing,59 to the best of our knowledge CRISPR/Cas9 gene editing to treat this disease has not been employed thus far.
Immunodeficiencies
Primary immunodeficiencies
Primary immunodeficiencies are a heterogeneous group of disorders characterized by variable susceptibility to infections due to hereditary defects in the immune sys- tem. One such immunodeficiency, X-linked chronic gran- ulomatous disease, is caused by mutations in the CYBB gene encoding gp91phox, a component of the NADPH oxidase in phagocytes which, when mutated, results in fatal infections. HDR-based therapeutic genome editing (zinc-finger nucleases and CRISPR/Cas9) has been employed to correct a CYBB mutation and restore the functional defect in human HSPC.29 Wiskott-Aldrich syn- drome (WAS) is a severe X-linked primary immunodefi- ciency caused by mutations in the WAS gene and charac- terized by thrombocytopenia, recurrent infections, tumor development, and autoimmune diseases. Recently, CRISPR/Cas9 gene editing of the WAS locus was reported in a leukemic cell line.60 These preclinical studies hold
Disease
β-thalassemia SCD
HIV-1 infection
B-cell leukemia B-cell lymphoma
CD19+ leukemia CD19+ lymphoma
Multiple myeloma
T-cell ALL
T-cell lymphoblastic lymphoma T-non-Hodgkin lymphoma
Product
CTX001
iHSC treatment group
CTX001
CCR5 gene modification
UCART019 CTX101
CTX110
NYCE T Cells CTX120
CD7.CAR/28zeta CAR-T cells
Aim/title
A safety and efficacy study evaluating CTX001 in subjects with transfusion-dependent β-thalassemia
iHSC with the gene correction of HBB intervent subjects with β-thalassemia mutations
A safety and efficacy study evaluating CTX001 in subjects
with severe sickle cell disease
Safety of transplantation of CRISPR CCR5 modified CD34+ HSPC in HIV-infected subjects with hematologic malignancies
A study evaluating UCART019 in patients with relapsed or refractory CD19+ leukemia and lymphoma
A feasibility and safety study of universal dual specificity CD19 and CD20 or CD22 CAR-T-cell immunotherapy
Anti-CD19 allogeneic CAR-T cells with TCR and B2M knocked-out
NY-ESO-1-redirected CRISPR (TCR endogenous and PD1) edited T cells
Anti-BCMA allogeneic CAR-T cells with TCR
and B2M knocked-out
Cell therapy for high risk T-cell malignancies using CD7-specific CAR expressed on autologous
T cells (CRIMSON)
Phase
Enrolling Not yet recruiting
IND & CTA approved
Enrolling
Phase I/II Phase I/II
Initiates in first-half of 2019
Preclinical Research
Phase I
CT identifier
NCT03655678 2017-003351-38
NCT03728322
NCT03745287
NCT03164135
NCT03166878 NCT03398967
NA
NCT03399448 NA
NCT03690011
Industry/Academy
CRISPR Therapeutics
Allife Medical Science and Technology
CRISPR Therapeutics
Beijing, China
Beijing, China Beijing, China
CRISPR Therapeutics
Pennsylvania, USA CRISPR Therapeutics
Houston, USA
SCD: sickle cell disease; HIV-1: human immunodeficiency virus type 1; ALL: acute lymphoblastic leukemia; iHSC: induced hematopoietic stem cells; CAR: chimeric antigen receptor; HBB: β hemo- globin; HSPC: hematopoietic stem and progenitor cells; UCART: universal CAR-T cells; TCR: T-cell receptor; B2M: β2-microglobulin; BCMA: B-cell maturation antigen; IND & CTA: investigational new drug and clinical trial authorization; CT: clinical trial; NA: not applicable.
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