Tinjauan Literatur Sistematis; Pemanfaatan Teknologi CRISPR-CAS9 Untuk Pengobatan Penyakit Huntington’s

Meliana Sari; Ahsanal Kasasiah

doi:10.32382/mf.v20i2.704

Penulis

Meliana Sari Universitas Singaperbangsa Karawang, Karawang, Indonesia
Ahsanal Kasasiah Universitas Singaperbangsa Karawang, Karawang, Indonesia

DOI:

https://doi.org/10.32382/mf.v20i2.704

Kata Kunci:

CRISPR-Cas9, Huntington's Disease, neurodegeneratif, pengeditan gen, terapi genetik

Abstrak

A Systematic Literature Review: Utilization of CRISPR-CAS9 Technology for Treating Huntington's Disease

Huntington's Disease (HD) is a neurodegenerative disorder caused by a CAG triple expansion (>36) in the first exon of the HTT gene encoding the huntingtin protein. Advances in gene editing technologies, such as CRISPR-Cas9, provide new hope for correcting the genetic mutations underlying HD. This review article aims to review the potential and effectiveness of CRISPR-Cas9 technology as a therapeutic tool for HD. The writing method used was Systematic Literature Review, with literature searches conducted using three databases: PubMed, ScienceDirect, and SpringerLink. This study reviewed several studies that used in vivo and in vitro models to evaluate the impact of HTT gene editing on mutant huntingtin protein expression and HD symptoms. Results showed that CRISPR-Cas9 can effectively reduce mutant huntingtin protein expression, reduce neuronal toxicity, and improve motor symptoms in mouse models of HD. Although these results are promising, further studies are needed to optimize the safety and effectiveness of using CRISPR-Cas9 in genetic therapy for HD.

Huntington’s Disease (HD) adalah kelainan neurodegeneratif yang disebabkan oleh ekspansi tripel CAG (>36) pada ekson pertama gen HTT yang mengkode protein huntingtin. Kemajuan teknologi pengeditan gen, seperti CRISPR-Cas9, memberikan harapan baru untuk mengoreksi mutasi genetik yang mendasari HD. Review artikel ini bertujuan untuk meninjau potensi dan efektivitas teknologi CRISPR-Cas9 sebagai alat terapi untuk HD. Metode penulisan yang digunakan adalah Systematic Literature Review, dengan pencarian studi literatur dilakukan menggunakan tiga basis data: PubMed, ScienceDirect, dan SpringerLink. Penelitian ini mengkaji beberapa studi yang menggunakan model in vivo dan in vitro untuk mengevaluasi dampak pengeditan gen HTT terhadap ekspresi protein huntingtin mutan dan gejala HD. Hasil menunjukkan bahwa CRISPR-Cas9 dapat secara efektif mengurangi ekspresi protein huntingtin mutan, mengurangi toksisitas neuronal, dan memperbaiki gejala motorik pada model tikus HD. Meskipun hasil ini menjanjikan, penelitian lebih lanjut diperlukan untuk mengoptimalkan keamanan dan efektivitas penggunaan CRISPR-Cas9 dalam terapi genetik untuk HD.

Referensi

Barrangou, R. and Doudna, J.A. 2016. Applications of CRISPR technologies in research and beyond, Nature Biotechnology, 34(9), pp. 933–941. Available at: https://doi.org/10.1038/nbt.3659.

Cong, L. et al. 2013. Multiplex genome engineering using CRISPR/Cas systems, Science, 339(6121), pp. 819–823. Available at: https://doi.org/10.1126/science.1231143.

Doudna, J.A. and Charpentier, E. 2014. The new frontier of genome engineering with CRISPR-Cas9, Science, 346. Available at: http://science.sciencemag.org/.

Ekman, F.K. et al. 2019. CRISPR-Cas9-Mediated Genome Editing Increases Lifespan and Improves Motor Deficits in a Huntingtons Disease Mouse Model, Molecular Therapy Nucleic Acids, 17, pp. 829–839. Available at: https://doi.org/10.1016/j.omtn.2019.07.009.

Food and Drug Administration (FDA). 2018. What is Gene Therapy? Available at: www.fda.gov (Accessed: June 2024)

Ginn, S.L. et al. 2018. Gene therapy clinical trials worldwide to 2017: An update, The journal of gene medicine, 20(5), e3015. Blackwell Publishing Inc. Available at: https://doi.org/10.1002/jgm.3015.

Guo, C. et al. 2023. Off-target effects in CRISPR/Cas9 gene editing, Frontiers in bioengineering and biotechnology, 11. Available at: https://doi.org/10.3389/fbioe.2023.1143157.

Hryhorowicz, M. et al. 2016. CRISPR/Cas9 Immune System as a Tool for Genome Engineering, Archivum Immunologiae et Therapiae Experimentalis, 65(3), pp. 233–240. Available at: https://doi.org/10.1007/s00005-016-0427-5.

Hsu, P.D., Lander, E.S. and Zhang, F. 2014. Development and applications of CRISPR-Cas9 for genome engineering, Cell, 157(6), pp. 1262–1278. Available at: https://doi.org/10.1016/j.cell.2014.05.010.

Jimenez-Sanchez, M. et al. 2017. Huntington’s Disease: Mechanisms of Pathogenesis and Therapeutic Strategies, Cold Spring Harbor Perspectives Medicine, 7(7). Available at: https://doi.org/10.1101/cshperspect.a024240.

Karimian, A. et al. 2019. CRISPR/Cas9 technology as a potent molecular tool for gene therapy, Journal of Cellular Physiology, 234(8), pp. 12267–12277. Available at: https://doi.org/10.1002/jcp.27972.

Kolli, N. et al. 2017. CRISPR-Cas9 mediated gene-silencing of the mutant huntingtin gene in an in vitro model of huntington’s disease, International Journal of Molecular Sciences, 18(4). Available at: https://doi.org/10.3390/ijms18040754.

Koonin, E. V. and Makarova, K.S. 2019. Origins and evolution of CRISPR-Cas systems, Philosophical Transactions of the Royal Society B: Biological Sciences, 374. Available at: https://doi.org/10.1098/rstb.2018.0087.

Kumar, A., Singh, A. and Ekavali 2015. A review on Alzheimer’s disease pathophysiology and its management: An update, Pharmacological Reports, 67(2), pp. 195–203. Available at: https://doi.org/10.1016/j.pharep.2014.09.004.

Lanphier, E. et al. 2015. Don’t edit the human germ line, Nature, 519, pp. 410–411. Available at: https://doi.org/10.1038/519410a.

Malankhanova, T. et al. 2020. A human induced pluripotent stem cell-derived isogenic model of Huntington’s disease based on neuronal cells has several relevant phenotypic abnormalities, Journal of Personalized Medicine, 10(4), pp. 1–26. Available at: https://doi.org/10.3390/jpm10040215.

Mengstie, M.A. et al. 2024. Recent Advancements in Reducing the Off-Target Effect of CRISPR-Cas9 Genome Editing, Biologics: Targets and Therapy, 18, pp. 21–28. Available at: https://doi.org/10.2147/BTT.S429411.

Monteys, A.M. et al. 2017. CRISPR/Cas9 Editing of the Mutant Huntingtin Allele In Vitro and In Vivo, Molecular Therapy, 25(1), pp. 12–23. Available at: https://doi.org/10.1016/j.ymthe.2016.11.010.

Naldini, L. 2015. Gene therapy returns to centre stage, Nature, 526, pp. 351–360. Available at: https://doi.org/10.1038/nature15818.

Nopoulus, P.C. 2016. Huntington disease a single-gene degenerative disorder of the striatum, Dialogues in clinical neuroscience, 18(1), pp. 91–98.

Oura, S. et al. 2021 Precise CAG repeat contraction in a Huntington’s Disease mouse model is enabled by gene editing with SpCas9-NG, Communications Biology, 4(1). Available at: https://doi.org/10.1038/s42003-021-02304-w.

Papanna, B., Lazzari, C. and Rabottini, M. 2024 Huntington’s disease prevalence in Asia: a systematic review and meta-analysis. Rivista di psichiatria, 59(1), pp. 4–12. Available at: https://doi.org/10.1708/4205.41943.

Park, H.J. et al. 2022. SUPT4H1-edited stem cell therapy rescues neuronal dysfunction in a mouse model for Huntington’s disease, NPJ Regenerative Medicine, 7(1). Available at: https://doi.org/10.1038/s41536-021-00198-0.

Rawlins, M.D. et al. 2016. The prevalence of huntington’s disease, Neuroepidemiology, 46(2), pp. 144–153. Available at: https://doi.org/10.1159/000443738.

Rees, H.A. and Liu, D.R. 2018. Base editing: precision chemistry on the genome and transcriptome of living cells, Nature Reviews Genetics, 19(12), pp. 770–788. Available at: https://doi.org/10.1038/s41576-018-0059-1.

Shin, J.W. et al. 2016. Permanent inactivation of Huntington’s disease mutation by personalized allele-specific CRISPR/Cas9, Human Molecular Genetics, 25(20), pp. 4566–4576. Available at: https://doi.org/10.1093/hmg/ddw286.

Tsai, S.Q. and Joung, J.K. 2016. Defining and improving the genome-wide specificities of CRISPR-Cas9 nucleases, Nature Reviews Genetics, 17(5), pp. 300–312. Available at: https://doi.org/10.1038/nrg.2016.28.

Wang, H., La Russa, M. and Qi, L.S. 2016. CRISPR/Cas9 in Genome Editing and beyond, Annual Review of Biochemistry, 85, pp. 227–264. Available at: https://doi.org/10.1146/annurev-biochem-060815-014607.

Xu, X. et al. 2017. Reversal of Phenotypic Abnormalities by CRISPR/Cas9-Mediated Gene Correction in Huntington Disease Patient-Derived Induced Pluripotent Stem Cells, Stem Cell Reports, 8(3), pp. 619–633. Available at: https://doi.org/10.1016/j.stemcr.2017.01.022.

Yang, S. et al. 2017. CRISPR/Cas9-mediated gene editing ameliorates neurotoxicity in mouse model of Huntington’s disease, Journal of Clinical Investigation, 127(7), pp. 2719–2724. Available at: https://doi.org/10.1172/JCI92087.

Yin, H. et al. 2016. Therapeutic genome editing by combined viral and non-viral delivery of CRISPR system components in vivo, Nature Biotechnology, 34(3), pp. 328–333. Available at: https://doi.org/10.1038/nbt.3471.