How is Parkinson’s Disease Best Treated? A Comparative Analysis of CRISPR-Cas9 and iPSC-Based Gene Therapies
DOI:
https://doi.org/10.54097/pzepvv11Keywords:
Parkinson’s Disease, Gene Therapy, CRISPR-Cas9, Induced Pluripotent Stem Cells (iPSCs), Neurodegeneration, Cell Replacement Therapy.Abstract
Parkinson's disease (PD) is a devastating neurological condition with little long-term treatment options. Gene therapy has emerged as a potential way to address the underlying pathology of the disease entirely. This paper has examined two main gene therapy approaches: direct in vivo gene editing with Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)-Cas9, and cell replacement therapy with induced pluripotent stem cells (iPSCs). The paper considers the mechanisms of action, therapeutic potential, and overall challenges and barriers to implementation for each approach. The analysis found that both CRISPR-Cas9 and iPSCs have potential as gene therapeutic approaches or modalities, with distinctions. CRISPR-Cas9 have the opportunity to correct the genetic cause of familial PD. However, there were large unresolved challenges about delivery and off-target safety. iPSCs therapy replaces the lost dopaminergic neurons and is a more generic approach, with challenges related to manufacturing the cells and clinical delivery, but these appear more tractable challenges and with more advanced methods available now. Overall, iPSCs based cell replacement therapy is a more preferable and promising short-to-medium term treatment option for a wider population of PD patients.
Downloads
References
[1] Tolosa E., Garrido A., Scholz S. W., et al. 2021. Challenges in the diagnosis of parkinson’s disease. The Lancet Neurology, 20 (5): 385-397.
[2] World Health Organization. 2022. Parkinson disease. Available from: https://www.who.int/news-room/fact-sheets/detail/parkinson-disease.
[3] Tomlinson C. L., Stowe R., Patel S., et al. 2010. Systematic review of levodopa dose equivalency reporting in parkinson’s disease. Movement Disorders, 25 (15): 2649-2553.
[4] Wirth T., Parker N., Ylä-Herttuala S. 2013. History of gene therapy. Gene, 525 (2): 162-169.
[5] Lovell-Badge R. 2019. CRISPR babies: A view from the centre of the storm. Development, 146 (3): dev175778.
[6] Barrangou R. 2015. The roles of CRISPR–Cas Systems in adaptive immunity and beyond. Current Opinion in Immunology, 32: 36-41.
[7] Zhang F., Wen Y., Guo X. 2014. CRISPR/Cas9 for genome editing: Progress, implications and challenges. Human Molecular Genetics, 23 (R1): R40-R46.
[8] Yang D., Zhao D., Ali Shah S. Z., et al. 2019. The role of the gut microbiota in the pathogenesis of Parkinson's disease. Frontiers in Neurology, 10: 1155.
[9] Safari F., Hatam G., Behbahani A. B., et al. 2020. CRISPR system: A high-throughput toolbox for research and treatment of parkinson’s disease. Cellular and Molecular Neurobiology, 40 (4): 477-493.
[10] Siddiqui I. J., Pervaiz N., Abbasi A. A. 2016. The Parkinson Disease gene SNCA: Evolutionary and structural insights with pathological implication. Scientific Reports, 6 (1): 24475.
[11] Soldner F., Stelzer Y., Shivalila C. S., et al. 2016. Parkinson-associated risk variant in distal enhancer of α-synuclein modulates target gene expression. Nature, 533 (7601): 95-99.
[12] Ge P., Dawson V. L., Dawson T. M. 2020. PINK1 and Parkin mitochondrial quality control: A source of regional vulnerability in Parkinson’s disease. Molecular Neurodegeneration, 15 (1): 20.
[13] Chang K. H., Huang C. Y., Ou-Yang C. H., et al. 2021. In vitro genome editing rescues parkinsonism phenotypes in induced pluripotent stem cells-derived dopaminergic neurons carrying LRRK2 p. G2019S mutation. Stem Cell Research & Therapy, 12 (1): 508.
[14] Wang Z., Zhang Q., Xing H. L., et al. 2018. Potential high-frequency off-target mutagenesis induced by CRISPR/Cas9 in Arabidopsis and its prevention. Plant Molecular Biology, 96 (4-5): 445-456.
[15] Anzalone A. V., Randolph P. B., Davis J. R., et al. 2019. Search-and-replace genome editing without double-strand breaks or donor DNA. Nature, 576 (7785): 149-157.
[16] Abbott N. J., Patabendige A. A., Dolman D. E., et al. 2010. Structure and function of the blood–brain barrier. Neurobiology of Disease, 37 (1): 13-25.
[17] Kimura S., Harashima H. 2022. Non-invasive gene delivery across the blood-brain barrier: Present and future perspectives. Neural Regeneration Research, 17 (4): 785-787.
[18] Sudhakar V., Richardson R. M. 2018. Gene therapy for Neurodegenerative Diseases. Neurotherapeutics, 16 (1): 166-175.
[19] Omole A. E., Fakoya A. O. J. 2018. Ten years of progress and promise of induced pluripotent stem cells: Historical origins, characteristics, mechanisms, limitations, and potential applications. PeerJ, 6: e4370.
[20] Shi Y., Inoue H., Wu J. C., et al. 2016. Induced pluripotent stem cell technology: A Decade of Progress. Nature Reviews Drug Discovery, 16 (2): 115-130.
[21] Kriks S., Shim J. W., Piao J., et al. 2011. Dopamine neurons derived from human ES cells efficiently engraft in animal models of Parkinson’s disease. Nature, 480 (7378): 547-551.
[22] Sonntag K. C., Song B., Lee N., et al. 2018. Pluripotent stem cell-based therapy for parkinson’s disease: Current status and future prospects. Progress in Neurobiology, 168: 1-20.
[23] Mandai M., Watanabe A., Kurimoto Y., et al. 2017. Autologous induced stem-cell-derived retinal cells for macular degeneration. New England Journal of Medicine, 376 (11): 1038-1046.
[24] Yamanaka S. 2020. Pluripotent stem cell-based cell therapy—promise and challenges. Cell Stem Cell, 27 (4): 523-531.
[25] Zhao T., Zhang Z. N., Rong Z., et al. 2011. Immunogenicity of induced pluripotent stem cells. Nature, 474(7350): 212-215.
[26] Taylor C. J., Peacock S., Chaudhry A. N., et al. 2012. Generating an iPSC bank for HLA-matched tissue transplantation based on known donor and recipient genotype frequencies. Cell Stem Cell, 11 (2): 147-152.
Downloads
Published
Issue
Section
License
This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.
