CRISPR/Cas9-mediated genome editing has demonstrated significant promise for genetic correction in autologous hematopoietic stem/progenitor cells (HSPCs) and induced pluripotent stem cells (iPSCs)

2021 ◽  
Author(s):  
Moataz Dowaidar
Keyword(s):  
Stem Cells ◽  
Gene Therapy ◽  
Induced Pluripotent Stem Cells ◽  
Progenitor Cells ◽  
Genome Editing ◽  
Pluripotent Stem Cells ◽  
Genetic Disorders ◽  
Hematopoietic Stem ◽  
Hematological Disorders ◽  
Induced Pluripotent

According to current research, CRISPR/Cas9-mediated genome editing has shown enormous potential in the correction of genetic defects in autologous hematopoietic stem/progenitor cells (HSPCs) and induced pluripotent stem cells (iPSCs). Furthermore, the advancement of iPSC reprogramming technology as well as the CRISPR/Cas9 system has opened the door to new possibilities in the field of gene and cell therapy combinations. Despite the fact that there are a number of technological obstacles to overcome, CRISPR/Cas9 remains a promising therapeutic method with a great deal of potential for future gene therapy applications. Early success in treating hereditary hematological disorders opens the door to new options for treating other genetic disorders and constitutes a significant step forward in the development of gene therapy.

scholarly journals Generation and Genetic Correction of USH2A c.2299delG Mutation in Patient-Derived Induced Pluripotent Stem Cells

Genes ◽  
2021 ◽  
Vol 12 (6) ◽  
pp. 805
Author(s):  
Xuezhong Liu ◽  
Justin Lillywhite ◽  
Wenliang Zhu ◽  
Zaohua Huang ◽  
Anna M. Clark ◽  
...  
Keyword(s):  
Stem Cells ◽  
Gene Therapy ◽  
Induced Pluripotent Stem Cells ◽  
Genome Editing ◽  
Pluripotent Stem Cells ◽  
Usher Syndrome ◽  
The United States ◽  
Specific Marker ◽  
Recessive Trait ◽  
Induced Pluripotent

Usher syndrome (USH) is the leading cause of inherited combined hearing and vision loss. As an autosomal recessive trait, it affects 15,000 people in the United States alone and is responsible for ~21% of inherited blindness and 3 to 6% of early childhood deafness. Approximately 2/3 of the patients with Usher syndrome suffer from USH2, of whom 85% have mutations in the USH2A gene. Patients affected by USH2 suffer from congenital bilateral progressive sensorineural hearing loss and retinitis pigmentosa which leads to progressive loss of vision. To study the molecular mechanisms of this disease and develop a gene therapy strategy, we generated human induced pluripotent stem cells (iPSCs) from peripheral blood mononuclear cells (PBMCs) obtained from a patient carrying compound heterozygous variants of USH2A c.2299delG and c.1256G>T and the patient’s healthy sibling. The pluripotency and stability were confirmed by pluripotency cell specific marker expression and molecular karyotyping. Subsequent CRISPR/Cas9 genome editing using a homology repair template was used to successfully correct the USH2A c.2299delG mutation back to normal c.2299G in the generated patient iPSCs to create an isogenic pair of lines. Importantly, this manuscript describes the first use of the recombinant Cas9 and synthetic gRNA ribonucleoprotein complex approach to correct the USH2A c.2299delG without additional genetic effects in patient-derived iPSCs, an approach that is amenable for therapeutic genome editing. This work lays a solid foundation for future ex vivo and in vivo gene therapy investigations and these patient’s iPSCs also provide an unlimited resource for disease modeling and mechanistic studies.

scholarly journals Induced Pluripotent Stem Cells to Model Juvenile Myelomonocytic Leukemia: New Perspectives for Preclinical Research

Cells ◽  
2021 ◽  
Vol 10 (9) ◽  
pp. 2335
Author(s):  
Zeinab Wehbe ◽  
Foued Ghanjati ◽  
Christian Flotho
Keyword(s):  
Stem Cells ◽  
Induced Pluripotent Stem Cells ◽  
Progenitor Cells ◽  
Pluripotent Stem Cells ◽  
Treatment Modalities ◽  
Juvenile Myelomonocytic Leukemia ◽  
Ras Signaling ◽  
Hematopoietic Stem ◽  
Induced Pluripotent ◽  
Myelomonocytic Leukemia

Juvenile myelomonocytic leukemia (JMML) is a malignant myeloproliferative disorder arising in infants and young children. The origin of this neoplasm is attributed to an early deregulation of the Ras signaling pathway in multipotent hematopoietic stem/progenitor cells. Since JMML is notoriously refractory to conventional cytostatic therapy, allogeneic hematopoietic stem cell transplantation remains the mainstay of curative therapy for most cases. However, alternative therapeutic approaches with small epigenetic molecules have recently entered the stage and show surprising efficacy at least in specific subsets of patients. Hence, the establishment of preclinical models to test novel agents is a priority. Induced pluripotent stem cells (IPSCs) offer an opportunity to imitate JMML ex vivo, after attempts to generate immortalized cell lines from primary JMML material have largely failed in the past. Several research groups have previously generated patient-derived JMML IPSCs and successfully differentiated these into myeloid cells with extensive phenotypic similarities to primary JMML cells. With infinite self-renewal and the capability to differentiate into multiple cell types, JMML IPSCs are a promising resource to advance the development of treatment modalities targeting specific vulnerabilities. This review discusses current reprogramming techniques for JMML stem/progenitor cells, related clinical applications, and the challenges involved.

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