CRISPR-Cas9 Gene Editing: A Promising Frontier in Revolutionizing Alzheimer’s Disease Management

Authors

  • Yuxin Jin

DOI:

https://doi.org/10.61173/mfdht347

Keywords:

Alzheimer’s disease, CRISPR-Cas9, dCas9, genome editing, gene therapy

Abstract

Alzheimer’s disease (AD) is a globally devastating neurodegenerative disorder with a significant burden on public health. Currently, the pathophysiology of AD remains uncertain. Meanwhile, conventional pharmacological treatments for AD accomplished with limited efficacy and undesirable side effects necessitate the exploration of novel therapeutic approaches. This paper highlights the potential of clustered regularly interspaced short palindromic repeats-associated proteins nine systems (CRISPR-Cas9) as a promising approach to cure AD by examining its applications in genome editing and mechanism of action on specific AD-related genes. In addition to targeted therapeutic options for either familial or sporadic AD, the review also emphasizes the importance of utilizing in vivo and in vitro AD experimental models to evaluate the efficacy and safety of CRISPR-Cas9 interventions. The significance of this research lies in its potential to revolutionize AD management and serve as a valuable reference for future studies. However, unresolved issues, such as the complexity of on-target effects and the need for improved delivery efficiency, underscore areas for future ongoing investigation and development in the field of AD therapeutics.

References

[1] Gustavsson, A., Norton, N., Fast, T., et al. Global estimates on the number of persons across the Alzheimer‘s disease continuum. Alzheimer‘s & Dementia, 2023, 19(2), 658-670.

[2] Roda, A. R., Serra-Mir, G., Montoliu-Gaya, L., Tiessler, L., & Villegas, S. Amyloid-beta peptide and tau protein crosstalk in Alzheimer’s disease. Neural regeneration research, 2022, 17(8), 1666.

[3] Pardridge, W. M. Treatment of Alzheimer’s disease and blood–brain barrier drug delivery. Pharmaceuticals, 2020, 13(11), 394.

[4] Pandey, G., & Ramakrishnan, V. Invasive and non-invasive therapies for Alzheimer’s disease and other amyloidosis. Biophysical Reviews, 2020, 12, 1175-1186.

[5] Bhardwaj, S., Kesari, K. K., Rachamalla, M., et al. CRISPR/ Cas9 gene editing: New hope for Alzheimer‘s disease therapeutics. Journal of Advanced Research, 2022, 40, 207-221.

[6] Makarova, K. S., Wolf, Y. I., Iranzo, J., Shmakov, S. A., Alkhnbashi, O. S., Brouns, S. J., ... & Koonin, E. V. Evolutionary classification of CRISPR–Cas systems: a burst of class 2 and derived variants. Nature Reviews Microbiology, 2020, 18(2), 67- 83.

[7] Mir, A., Edraki, A., Lee, J., & Sontheimer, E. J. Type II-C CRISPR-Cas9 biology, mechanism, and application. ACS chemical biology, 2018, 13(2), 357-365.

[8] Kazi, T. A., & Biswas, S. R. CRISPR/dCas system as the modulator of gene expression. Progress in Molecular Biology and Translational Science, 2021, 178, 99-122.

[9] Sims, R., Hill, M., & Williams, J. The multiplex model of the genetics of Alzheimer’s disease. Nature Neuroscience, 2020, 23(3), 311-322.

[10] György, B., Lööv, C., Zaborowski, M. P., Takeda, S., et al. CRISPR/Cas9 mediated disruption of the Swedish APP allele as a therapeutic approach for early-onset Alzheimer’s disease. Molecular Therapy-Nucleic Acids, 2018, 11, 429-440.

[11] Ortiz-Virumbrales, M., Moreno, C. L., Kruglikov, I., et al. CRISPR/Cas9-Correctable mutation-related molecular and physiological phenotypes in iPSC-derived Alzheimer’s PSEN2 Dean&Francis N141I neurons. Acta Neuropathologica Communications, 2017, 5, 1-20.

[12] Park, H., Oh, J., Shim, G., et al. In vivo, neuronal gene editing via CRISPR–Cas9 amphiphilic nanocomplexes alleviates deficits in mouse models of Alzheimer‘s disease. Nature Neuroscience, 2019, 22(4), 524-528.

[13] Park, H., Hwang, Y., & Kim, J. Transcriptional activation with Cas9 activator nanocomplexes rescues Alzheimer‘s disease pathology. Biomaterials, 2021, 279, 121229.

[14] Raikwar, S. P., Thangavel, R., Dubova, I., et al. Targeted gene editing of glia maturation factor in microglia: a novel Alzheimer’s disease therapeutic target. Molecular neurobiology, 2019, 56, 378-393.

[15] Wang, C., Najm, R., Xu, Q., et al. Gain of toxic apolipoprotein E4 effects in human iPSC-derived neurons is ameliorated by a small-molecule structure corrector. Nature Medicine, 2018, 24(5), 647-657.

[16] Sun, J., Carlson-Stevermer, J., Das, U., et al. CRISPR/Cas9 editing of APP C-terminus attenuates β-cleavage and promotes α-cleavage. Nature Communications, 2019, 10(1), 53.

[17] Tai, L. M., Weng, J. M., LaDu, M. J., & Brady, S. T. (2021). Relevance of transgenic mouse models for Alzheimer‘s disease. Progress in molecular biology and translational science, 2021, 177, 1-48.

[18] Serneels, L., T’Syen, D., Perez-Benito, L., et al. Modeling the β-secretase cleavage site and humanizing amyloid-beta precursor protein in rat and mouse to study Alzheimer’s disease. Molecular Neurodegeneration, 2020, 15(1), 1-11.

[19] Nagata, K., Takahashi, M., Matsuba, Y., et al. Generation of App knock-in mice reveals deletion mutations protective against Alzheimer’s disease-like pathology. Nature Communications, 2018, 9(1), 1800.

[20] Saito, T., Mihira, N., Matsuba, Y., et al. Humanization of the entire murine Mapt gene provides a murine model of pathological human tau propagation. Journal of Biological Chemistry, 2019, 294(34), 12754-12765.

[21] Takalo, M., Wittrahm, R., Wefers, B., et al. The Alzheimer’s disease-associated protective Plcγ2-P522R variant promotes immune functions. Molecular Neurodegeneration, 2020, 15(1), 1-14.

[22] Knupp, A., Mishra, S., Martinez, R., et al.. Depletion of the AD risk gene SORL1 selectively impairs neuronal endosomal traffic independent of amyloidogenic APP processing. Cell Reports, 2020, 31(9).

[23] Naeem, M., Majeed, S., Hoque, M. Z., & Ahmad, I. Latest developed strategies to minimize the off-target effects in CRISPR-Cas-mediated genome editing. Cells, 2020, 9(7), 1608.

[24] Haeussler, M., Schönig, K., Eckert, H., et al. Evaluation of off-target and on-target scoring algorithms and integration into the guide RNA selection tool CRISPOR. Genome biology, 2016, 17, 1-12.

Downloads

Published

2024-06-06