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CRISPR/Cas9 Mediated Therapeutic Approach in Huntington's Disease
Suleyman Serdar Alkanli1,2, Nevra Alkanli3, Arzu Ay4
1Department of Biophysics, Istanbul Faculty of Medicine, Istanbul University, Istanbul, Turkey. ss.alkanli@outlook.com.
Insights
CRISPR/Cas9 gene editing effectively corrects Huntington's disease (HD) cellular models. Induced pluripotent stem cells (iPSCs) from HD patients, when edited, restore normal gene expression and cellular function, offering therapeutic potential.
Area of Science:
- Neuroscience and Genetics
- Stem Cell Biology
- Gene Editing Technologies
Background:
- Huntington's disease (HD) is a dominant neurodegenerative disorder caused by CAG re-expansion in the Huntingtin gene.
- Understanding HD pathogenesis is crucial for developing effective treatments.
- Current genome editing tools include ZFNs, TALENs, and CRISPR/Cas9 systems.
Purpose of the Study:
- To provide an overview of Huntington's disease.
- To explain the role of CRISPR/Cas9 technology in conjunction with induced pluripotent stem cells (iPSCs) for HD treatment.
- To highlight the potential of gene editing for correcting HD-related genetic defects.
Main Methods:
- Utilizing CRISPR/Cas9 technology for gene editing in human-derived induced pluripotent stem cells (iPSCs).
- Employing a cut-and-paste mechanism with a piggyBac transposon-based selection system for gene correction.
- Generating isogenic control iPSC lines for comparison and validation.
- Differentiating HD-iPSCs into neural cells to assess therapeutic outcomes.
Main Results:
- CRISPR/Cas9 successfully corrected HD-iPSC lines in human and mouse models.
- Neural cells derived from corrected HD-iPSCs showed recovery from phenotypic abnormalities and normalized gene expression.
- The study demonstrated the feasibility of curing trinucleotide repeat disorders in HD models using sgRNA and exogenous DNA restoration.
Conclusions:
- CRISPR/Cas9 gene editing, combined with iPSCs, offers a promising therapeutic strategy for Huntington's disease.
- Isogenic control iPSC lines are valuable tools for validating gene editing efficacy in HD models.
- Restoration of normal gene function and cellular phenotypes in HD-iPSC-derived neural cells supports the potential of this approach for clinical translation.
Abstract:
The pathogenic mechanisms of these diseases must be well understood for the treatment of neurological disorders such as Huntington's disease. Huntington's Disease (HD), a dominant and neurodegenerative disease, is characterized by the CAG re-expansion that occurs in the gene encoding the polyglutamine-expanded mutant Huntingtin (mHTT) protein. Genome editing approaches include zinc-finger nucleases (ZFNs), transcription activator-like effector nucleases (TALENs) and Clustered Regularly Interspaced Short Palindromic Repeats/Caspase 9 (CRISPR/Cas9) systems. CRISPR/Cas9 technology allows effective gene editing in different cell types and organisms. Through these systems are created isogenic control of human origin induced pluripotent stem cells (iPSCs). In human and mouse models, HD-iPSC lines can be continuously corrected using these systems. HD-iPSCs can be corrected through the CRISPR/Cas9 system and the cut-and-paste mechanism using isogenic control iPSCs. This mechanism is a piggyBac transposon-based selection system that can effectively switch between vectors and chromosomes. In studies conducted, it has been determined that in neural cells derived from HD-iPSC, there are isogenic controls as corrected lines recovered from phenotypic abnormalities and gene expression changes. It has been determined that trinucleotide repeat disorders occurring in HD can be cured by single-guide RNA (sgRNA) and normal exogenous DNA restoration, known as the single guideline RNA specific to Cas9. The purpose of this review in addition to give general information about HD, a neurodegenerative disorder is to explained the role of CRISPR/Cas9 system with iPSCs in HD treatment.
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