In vivo genome editing improves motor function and extends survival in a mouse model of ALS
Open accessAbstract
Amyotrophic lateral sclerosis (ALS) is a fatal and incurable neurodegenerative disease characterized by the progressive loss of motor neurons in the spinal cord and brain. In particular, autosomal dominant mutations in the superoxide dismutase 1 (SOD1) gene are responsible for ~20% of all familial ALS cases. The clustered regularly interspaced short palindromic repeats (CRISPR)-CRISPR-associated (Cas9) genome editing system holds the potential to treat autosomal dominant disorders by facilitating the introduction of frameshift-induced mutations that can disable mutant gene function. We demonstrate that CRISPR-Cas9 can be harnessed to disrupt mutant SOD1 expression in the G93A-SOD1 mouse model of ALS following in vivo delivery using an adeno-associated virus vector. Genome editing reduced mutant SOD1 protein by >2.5-fold in the lumbar and thoracic spinal cord, resulting in improved motor function and reduced muscle atrophy. Crucially, ALS mice treated by CRISPR-mediated genome editing had ~50% more motor neurons at end stage and displayed a ~37% delay in disease onset and a ~25% increase in survival compared to control animals. Thus, this study illustrates the potential for CRISPR-Cas9 to treat SOD1-linked forms of ALS and other central nervous system disorders caused by autosomal dominant mutations.
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CRISPR/Cas9 system holds tremendous promise for gene therapy and can correct causal mutations in the original genome and rescue disease phenotypes of monogenic disorders permanently.
“Furthermore, CRISPR/Cas9 system holds tremendous promise for gene therapy [46–51]. It can correct causal mutations in the original genome and rescue the disease phenotypes of monogenic disorders permanently, which currently represents the most translatable field in CRISPR/Cas9-mediated disease therapy.”
From Non-viral delivery systems for CRISPR/Cas9-based genome editing: challenges and opportunities (2018) · cites this paper as [50]
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“In addition, a phase 1 clinical trial based on AAV9-mediated delivery of the survival ofmotor neuron1 (SMN1) gene for spinalmuscular atrophy (63, 64) in infants is under way, underscoring the therapeutic potential of this serotype.”
BackgroundStroes, E. S., Nierman, M. C., Meulenberg, J. J., Franssen, R., Twisk, J., Henny, C. P., Maas, M. M., Zwinderman, A. H., Ross, C., Aronica, E., et al. (2008) · Arteriosclerosis, Thrombosis, and Vascular Biology · doi:10.1161/atvbaha.108.175620 · Cited by 209 · see citing works
Foust, K. D., Salazar, D. L., Likhite, S. B., Ferraiuolo, L., Ditsworth, D., Ilieva, H. S., Meyer, K., Schmelzer, L., Braun, L., Cleveland, D. W., et al. (2013) · Molecular Therapy · doi:10.1038/mt.2013.211 · Cited by 205 · see citing works
The use of transgenic mouse models of amyotrophic lateral sclerosis in preclinical drug studies
Gurney, M. E. (1997) · Journal of the Neurological Sciences · doi:10.1016/s0022-510x(97)00247-5 · Cited by 189 · cited 1× · see citing works
“Thismouse carries ~25 tandem repeat copies of the hSOD1 transgene, and previous reports have indicated that a reduction in hSOD1 copy number can have a profound effect on the ALS phenotype (68).”
BackgroundOligodendrocytes contribute to motor neuron death in ALS via SOD1-dependent mechanism
Ferraiuolo, L., Meyer, K., Sherwood, T. W., Vick, J. S., Likhite, S. B., Frakes, A., Miranda, C. J., Braun, L., Heath, P. R., Pineda, R., et al. (2016) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1607496113 · Cited by 189 · cited 1× · see citing works
“Optimization of AAV-mediated gene delivery and/ or SaCas9 expression in astrocytes (35, 40), microglia (34, 46, 48), and oligodendrocyte precursors (49, 50) may further enhance efficacy.”
BackgroundRobust ZFN-mediated genome editing in adult hemophilic mice
Anguela, X. M., Sharma, R., Doyon, Y., Miller, J. C., Li, H., Haurigot, V., Rohde, M., Wong, S., Davidson, R. J., Zhou, S., et al. (2013) · Blood · doi:10.1182/blood-2013-04-497354 · Cited by 178 · see citing works
Carpentier, A. C., Frisch, F., Labbé, S. M., Gagnon, R., de Wal, J., Greentree, S., Petry, H., Twisk, J., Brisson, D., & Gaudet, D. (2012) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2011-3002 · Cited by 165 · see citing works
Quantifying on- and off-target genome editing
Hendel, A., Fine, E. J., Bao, G., & Porteus, M. H. (2015) · Trends in biotechnology · doi:10.1016/j.tibtech.2014.12.001 · Cited by 152 · cited 1× · see citing works
“Given that the OT activity of a nuclease is proportional to its concentration and the amount of time it is exposed to the cell (74), future work elucidating the kinetics of Cas9 expression in vivo could shed light on its function and inform methods for improving its specificity.”
MethodSong, S., Miranda, C. J., Braun, L., Meyer, K., Frakes, A. E., Ferraiuolo, L., Likhite, S. B., Bevan, A. K., Foust, K. D., McConnell, M. J., et al. (2016) · Nature Medicine · doi:10.1038/nm.4052 · Cited by 146 · see citing works
Thomsen, G. M., Gowing, G., Latter, J., Chen, M., Vit, J., Staggenborg, K., Avalos, P., Alkaslasi, M. R., Ferraiuolo, L., Likhite, S. B., et al. (2014) · Journal of Neuroscience · doi:10.1523/jneurosci.2037-14.2014 · Cited by 137 · see citing works
Chadderton, N., Millington‐Ward, S., Palfi, A., O’Reilly, M., Tuohy, G., Humphries, M. M., Li, T., Humphries, P., Kenna, P. F., & Farrar, G. J. (2009) · Molecular Therapy · doi:10.1038/mt.2008.301 · Cited by 123 · cited 1× · see citing works
“If needed, an allele-specific CRISPR system configured to target disease-causing SOD1 mutations (including A4V, G37R, H46R, G85R, and G93A) or a gene knockoutand-replace therapy (70) could be used to overcome the toxicity arising from a lack of allele specificity.”
BackgroundVirus‐delivered small RNA silencing sustains strength in amyotrophic lateral sclerosis
Miller, T. M., Kaspar, B. K., Kops, G. J. P. L., Yamanaka, K., Christian, L. J., Gage, F. H., & Cleveland, D. W. (2005) · Annals of Neurology · doi:10.1002/ana.20453 · Cited by 120 · see citing works
Therapeutic rAAVrh10 Mediated SOD1 Silencing in Adult SOD1 G93A Mice and Nonhuman Primates
Borel, F., Gernoux, G., Cardozo, B. H., Metterville, J., Cabrera, G. T., Song, L., Su, Q., Gao, G. P., ElMallah, M. K., Brown, R. H., et al. (2015) · Human Gene Therapy · doi:10.1089/hum.2015.122 · Cited by 111 · see citing works
Gingras, M., Gagnon, V., Minotti, S., Durham, H. D., & Berthod, F. (2007) · Journal of Neuroscience Methods · doi:10.1016/j.jneumeth.2007.02.024 · Cited by 109 · cited 1× · see citing works
“Second, because of the difficulty in isolating spinal cord motor neurons from juvenile and adult mice (77), we could not measure the frequency of hSOD1 gene modification in transduced cells.”
BackgroundStoica, L., Todeasa, S. H., Cabrera, G. T., Salameh, J. S., ElMallah, M. K., Mueller, C., Brown, R. H., & Sena‐Esteves, M. (2016) · Annals of Neurology · doi:10.1002/ana.24618 · Cited by 104 · cited 1× · see citing works
“Because neonatal delivery has proven effective for evaluating RNAi-based gene therapies in G93A-SOD1 mice (10, 12, 14), we reasoned that this strategy would enable us to assess the impact of genome editing on disease onset and progression.”
BackgroundDalkara, D., Byrne, L. C., Lee, T., Hoffmann, N., Schaffer, D. V., & Flannery, J. G. (2011) · Gene Therapy · doi:10.1038/gt.2011.163 · Cited by 82 · cited 2× · see citing works
“At 24 hours after seeding or once cells were 90% confluent, the cells were transfectedwith 15 mg of pAAV-CMV-SaCas9-U6-sgRNA or pAAV-CMV-EGFP, 15 mg of pAAV9-2YF (41) [encoding the double tyrosine–to–phenylalanine mutant of the AAV9 capsid (42)], and 15 mg of pHelper using 145 ml of polyethylamine (1mg/ml).”
MethodStevens, J. C., Chia, R., Hendriks, W. T. J., Bros‐Facer, V., van Minnen, J., Martin, J. E., Jackson, G. S., Greensmith, L., Schiavo, G., & Fisher, E. (2010) · PLoS ONE · doi:10.1371/journal.pone.0009541 · Cited by 76 · see citing works
SOD1 silencing in motoneurons or glia rescues neuromuscular function in ALS mice
Dirren, E., Aebischer, J., Rochat, C., Towne, C. L., Schneider, B. L., & Aebischer, P. (2015) · Annals of Clinical and Translational Neurology · doi:10.1002/acn3.162 · Cited by 65 · see citing works
Morpholino-mediated SOD1 reduction ameliorates an amyotrophic lateral sclerosis disease phenotype
Nizzardo, M., Simoné, C., Rizzo, F., Ulzi, G., Ramirez, A., Rizzuti, M., Bordoni, A., Bucchia, M., Gatti, S., Bresolin, N., et al. (2016) · Scientific Reports · doi:10.1038/srep21301 · Cited by 33 · cited 1× · see citing works
“Reducing mutant SOD1expression in the spinal cord using antisense oligonucleotides (ASOs) (7, 8) or RNA interference (RNAi) (9–15) can slow disease onset and improve survival in these animal models.”
BackgroundGaj, T., & Schaffer, D. V. (2016) · Cold Spring Harbor Protocols · doi:10.1101/pdb.prot086868 · Cited by 18 · cited 1× · see citing works
“AAV vector production AAV vector was produced, as previously described (83).”
Method
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CRISPR-Cas guides the future of genetic engineering
Knott, G. J., & Doudna, J. A. (2018) · Science · doi:10.1126/science.aat5011 · Cited by 1,410 · see citing works
Therapeutic in vivo delivery of gene editing agents
Raguram, A., Banskota, S., & Liu, D. R. (2022) · Cell · doi:10.1016/j.cell.2022.03.045 · Cited by 532 · see citing works
Non-viral delivery systems for CRISPR/Cas9-based genome editing: challenges and opportunities
Li, L., Hu, S., & Chen, X. (2018) · Biomaterials · doi:10.1016/j.biomaterials.2018.04.031 · Cited by 415 · see citing works
Emerging insights into the complex genetics and pathophysiology of amyotrophic lateral sclerosis
Goutman, S. A., Hardiman, O. M., Al‐Chalabi, A., Chiò, A., Savelieff, M. G., Kiernan, M. C., & Feldman, E. L. (2022) · The Lancet Neurology · doi:10.1016/s1474-4422(21)00414-2 · Cited by 413 · see citing works
CRISPR Ethics: Moral Considerations for Applications of a Powerful Tool
Brokowski, C., & Adli, M. (2018) · Journal of Molecular Biology · doi:10.1016/j.jmb.2018.05.044 · Cited by 320 · see citing works
“The system offers nearly boundless potential to promote progress in combating HIV [93], hemophilia [94], cancer [95], Duchenne muscular dystrophy [96], amyotrophic lateral sclerosis [97], sickle-cell anemia [98], cystic fibrosis [99], infertility [100], and any number of novel diseases.”
BackgroundThe delivery challenge: fulfilling the promise of therapeutic genome editing
van Haasteren, J., Li, J., Scheideler, O. J., Murthy, N., & Schaffer, D. V. (2020) · Nature Biotechnology · doi:10.1038/s41587-020-0565-5 · Cited by 285 · see citing works
Treatment of a Mouse Model of ALS by In Vivo Base Editing
Lim, C. K. W., Gapinske, M., Brooks, A. K., Woods, W. S., Powell, J. E., C., M. A. Z., Winter, J., Pérez‐Piñera, P., & Gaj, T. (2020) · Molecular Therapy · doi:10.1016/j.ymthe.2020.01.005 · Cited by 225 · see citing works
Gene therapy for ALS: A review
Amado, D. A., & Davidson, B. L. (2021) · Molecular Therapy · doi:10.1016/j.ymthe.2021.04.008 · Cited by 192 · see citing works
Gene-based therapies for neurodegenerative diseases
Sun, J., & Roy, S. (2021) · Nature Neuroscience · doi:10.1038/s41593-020-00778-1 · Cited by 189 · see citing works
Ekman, F. K., Ojala, D. S., Adil, M. M., Zapana, P. A. L., Schaffer, D. V., & Gaj, T. (2019) · Molecular Therapy — Nucleic Acids · doi:10.1016/j.omtn.2019.07.009 · Cited by 163 · see citing works
Balderston, S., Taulbee, J. J., Celaya, E., Fung, K., Jiao, A., Smith, K., Hajian, R., Gasiūnas, G., Kutanovas, S., Kim, D., et al. (2021) · Nature Biomedical Engineering · doi:10.1038/s41551-021-00706-z · Cited by 162 · see citing works
Wei, T., Cheng, Q., Farbiak, L., Anderson, D. G., Langer, R., & Siegwart, D. J. (2020) · ACS Nano · doi:10.1021/acsnano.0c04707 · Cited by 137 · see citing works
Khoshandam, M., Soltaninejad, H., Mousazadeh, M., Hamidieh, A. A., & Hosseinkhani, S. (2023) · Genes & Diseases · doi:10.1016/j.gendis.2023.02.027 · Cited by 130 · see citing works
“Recently, intravenous infusion of AAV encoding SaCas9 and SOD1-targeting sgRNA appeared to delay disease appearance and enhance the applicability in ALS mouse models.(66) Glycogen capacity illness Ia (GSD1A, OMIM #232200), too known as von Gierke illness, is caused by pathogenic mutations within the glucose-6-phosphat…”
BackgroundCRISPR/Cas9 for Cancer Therapy: Hopes and Challenges
Martínez-Lage, M., Puig-Serra, P., Menéndez, P. R., Torres-Ruiz, R., & Rodríguez, S. (2018) · Biomedicines · doi:10.3390/biomedicines6040105 · Cited by 126 · see citing works
“Moreover, AAVs have been successfully used in mouse models [86,87], and their efficacy and safety have been tested in clinical trials with recent approval [88].”
MethodApplications of CRISPR-Cas Enzymes in Cancer Therapeutics and Detection
Huang, C., Lee, K.-C., & Doudna, J. A. (2018) · Trends in cancer · doi:10.1016/j.trecan.2018.05.006 · Cited by 118 · see citing works
“Among these, AAVs are currently the most advanced methodology for in vivo gene delivery (Figure 2B) [71, 73] with successful examples of treating mouse models of neurodegenerative diseases [74, 75], and the efficacy and safety of which have been tested in clinical trials and has been approved recently [76].”
BackgroundAdeno-Associated Viral Vectors in Neuroscience Research
Haggerty, D. L., Grecco, G. G., Reeves, K. C., & Atwood, B. K. (2019) · Molecular Therapy — Methods & Clinical Development · doi:10.1016/j.omtm.2019.11.012 · Cited by 123 · see citing works
Abati, E., Bresolin, N., Comi, G. P., & Corti, S. P. (2020) · Expert Opinion on Therapeutic Targets · doi:10.1080/14728222.2020.1738390 · Cited by 104 · see citing works
Advancements and Obstacles of CRISPR-Cas9 Technology in Translational Research
You, L., Tong, R., Li, M., Liu, Y., Xue, J., & Lü, Y. (2019) · Molecular Therapy — Methods & Clinical Development · doi:10.1016/j.omtm.2019.02.008 · Cited by 107 · see citing works
“13 June 2 dominant hearing loss.(52,53) These advancements provide promising insights into the eventual translation of CRISPR gene editing into the clinical setting.”
BackgroundCas9-edited immune checkpoint blockade PD-1 DNA polyaptamer hydrogel for cancer immunotherapy
Lee, J., Le, Q., Yang, G., & Oh, Y. (2019) · Biomaterials · doi:10.1016/j.biomaterials.2019.119359 · Cited by 99 · see citing works
Gene Therapy for ALS—A Perspective
Cappella, M., Ciotti, C., Cohen-Tannoudji, M., & Biferi, M. G. (2019) · International Journal of Molecular Sciences · doi:10.3390/ijms20184388 · Cited by 96 · see citing works
SOD1 in ALS: Taking Stock in Pathogenic Mechanisms and the Role of Glial and Muscle Cells
Peggion, C., Scalcon, V., Massimino, M. L., Nies, K., Lopreiato, R., Rigobello, M. P., & Bertoli, A. (2022) · Antioxidants · doi:10.3390/antiox11040614 · Cited by 101 · see citing works
“antisense oligonucleotides [97,98], and CRISPR/Cas9 system targeting the mutant SOD1 gene [99], to other strategies such as those involving, for example, small molecules, peptides, and monoclonal antibodies [100].”
BackgroundTargeted gene silencing in the nervous system with CRISPR-Cas13
Powell, J. E., Lim, C. K. W., Krishnan, R. S. G., McCallister, T. X., Saporito-Magriñá, C., C., M. A. Z., McPheron, G. D., & Gaj, T. (2022) · Science Advances · doi:10.1126/sciadv.abk2485 · Cited by 94 · see citing works
“…cord astrocytes ( 26 – 28 ) and the fact that disease onset in SOD1-ALS mice is modulated by the expression of mutant SOD1 in motor neurons ( 21 , 31 ), we observed no delay in the onset of the disease (measured as peak weight) in mice treated by RfxCas13d versus the controls ( P > 0.05; Fig.”
BackgroundInfluentialGenome editing methods in animal models
Lee, H., Yoon, D. E., & Kim, K. (2020) · Animal Cells and Systems · doi:10.1080/19768354.2020.1726462 · Cited by 81 · see citing works
“The Schaffer group demonstrated that disruption of mutant SOD1 expression in the G93A-SOD1 mouse model of ALS via in vivo CRISPR/Cas9 genome editing using an AAV vector resulted in delayed disease onset, improved motor function, and reduced muscle atrophy (Gaj et al. 2017).”
BackgroundDuan, W., Guo, M., Yi, L., Liu, Y., Li, Z., Ma, Y., Zhang, G., Liu, Y., Bu, H., Song, X., et al. (2019) · Gene Therapy · doi:10.1038/s41434-019-0116-1 · Cited by 79 · see citing works
“strated that the delivery of AAV9-SaCas9-hSOD1 to SOD1G93A mice via facial vein injection results in an ~37% delay in disease onset and an ~25% increase in survival [12].”
BackgroundGene Therapy in Amyotrophic Lateral Sclerosis
Fang, T., Je, G., Pacut, P., Keyhanian, K., Gao, J., & Ghasemi, M. (2022) · Cells · doi:10.3390/cells11132066 · Cited by 82 · see citing works
“(2017), AAV9 vectors containing CRISPR/Cas9 were administered into the facial veins of one-day-old transgenic G93A-SOD1 ALS mice to disrupt mutant SOD1 expression [49].”
BackgroundInfluentialSafe and effective superoxide dismutase 1 silencing using artificial microRNA in macaques
Borel, F., Gernoux, G., Sun, H., Stock, R. E., Blackwood, M., Brown, R. H., & Mueller, C. (2018) · Science Translational Medicine · doi:10.1126/scitranslmed.aau6414 · Cited by 77 · see citing works
Advances in CRISPR-Cas technology and its applications: revolutionising precision medicine
Azeez, S. S., Hamad, R. S., Hamad, B., Shekha, M. S., & Bergsten, P. (2024) · Frontiers in Genome Editing · doi:10.3389/fgeed.2024.1509924 · Cited by 84 · see citing works
In Vivo Genome Editing as a Therapeutic Approach
Ho, B. X., Loh, S. J. H., Chan, W., & Soh, B.-S. (2018) · International Journal of Molecular Sciences · doi:10.3390/ijms19092721 · Cited by 76 · see citing works
“, G93A-SOD1 treated mice displayed delayed disease onset, prolonged survival, improved rotarod performance, and maintained or gained weight [52].”
BackgroundInfluentialA perspective on therapies for amyotrophic lateral sclerosis: can disease progression be curbed?
Xu, X., Shen, D., Gao, Y., Zhou, Q., Ni, Y., Meng, H., Shi, H., Le, W., Chen, S., & Chen, S. (2021) · Translational Neurodegeneration · doi:10.1186/s40035-021-00250-5 · Cited by 77 · see citing works
“Moreover, when delivered by the AAV vector in SOD1 mice, CRISPR/Cas9 could disrupt expression of mutant SOD1 and reduce the protein level of mutant SOD1 in the spinal cord, accompanied by prolonged survival and improved motor function [126, 143].”
BackgroundLipid Nanoparticles Deliver mRNA to the Brain after an Intracerebral Injection
Tuma, J., Chen, Y.-J., Collins, M. G., Paul, A., Li, J., Han, H., Sharma, R., Murthy, N., & Lee, H. Y. (2023) · Biochemistry · doi:10.1021/acs.biochem.3c00371 · Cited by 65 · see citing works
Current Status and Challenges Associated with CNS-Targeted Gene Delivery across the BBB
Kimura, S., & Harashima, H. (2020) · Pharmaceutics · doi:10.3390/pharmaceutics12121216 · Cited by 64 · see citing works
CRISPR/Cas9-Mediated Gene Correction to Understand ALS
Yun, Y., & Ha, Y. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21113801 · Cited by 64 · see citing works
“, 2017 [78] SOD1 G93A hSOD1 G93A transgenic N/R”
BackgroundCRISPR/Cas9 directed to the Ube3a antisense transcript improves Angelman syndrome phenotype in mice
Schmid, R. S., Deng, X., Panikker, P., Msackyi, M., Breton, C. A., & Wilson, J. M. (2021) · Journal of Clinical Investigation · doi:10.1172/jci142574 · Cited by 68 · see citing works
“, into the striatum of a Huntington’s disease mouse model (21), into the spinal cord of an ALS mouse model (22), or into the hippocampus of a mouse model of familial Alzheimer’s disease (23).”
BackgroundEfficacy and long-term safety of CRISPR/Cas9 genome editing in the SOD1-linked mouse models of ALS
Deng, H., Zhai, H., Shi, Y., Liu, G., Lowry, J., Liu, B., Ryan, É. B., Yan, J., Yang, Y., Zhang, N., et al. (2021) · Communications Biology · doi:10.1038/s42003-021-01942-4 · Cited by 62 · see citing works
An Update on the Application of CRISPR Technology in Clinical Practice
Morshedzadeh, F., Ghanei, M., Lotfi, M., Ghasemi, M., Ahmadi, M., Najari-Hanjani, P., Sharif, S., Mozaffari‐Jovin, S., Peymani, M., & Abbaszadegan, M. R. (2023) · Molecular Biotechnology · doi:10.1007/s12033-023-00724-z · Cited by 60 · see citing works
Non-Viral Vector-Mediated Gene Therapy for ALS: Challenges and Future Perspectives
Ediriweera, G. R., Chen, L., Yerbury, J. J., Thurecht, K. J., & Vine, K. L. (2021) · Molecular Pharmaceutics · doi:10.1021/acs.molpharmaceut.1c00297 · Cited by 56 · see citing works
Genetic therapeutic advancements for Dravet Syndrome
Chilcott, E. M., Diaz, J. F. A., Bertram, C., Berti, M., & Karda, R. (2022) · Epilepsy & Behavior · doi:10.1016/j.yebeh.2022.108741 · Cited by 60 · see citing works
“Programs in various stages of preclinical and clinical development for other neurological disorders include Batten’s disease caused by mutations in MFSD8 [110], Huntington’s disease (NCT02519036: [111]), ALS (NCT01041222: [112–114]) and more.”
BackgroundCRISPR-Cas9-Mediated Gene Therapy in Neurological Disorders
Guan, L., Han, Y., Yang, C., Lu, S., Du, J., Li, H., & Lin, J. (2021) · Molecular Neurobiology · doi:10.1007/s12035-021-02638-w · Cited by 58 · see citing works
In vivo delivery of CRISPR-Cas9 genome editing components for therapeutic applications
Huang, K. L., Zapata, D. A., Tang, Y., Teng, Y., & Li, Y. (2022) · Biomaterials · doi:10.1016/j.biomaterials.2022.121876 · Cited by 55 · see citing works
Applications of CRISPR-Cas9 in Alzheimer’s Disease and Related Disorders
Plano, L. M. D., Calabrese, G., Sabrina Conoci, A., Guglielmino, S. P. P., Oddo, S., & Caccamo, A. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms23158714 · Cited by 54 · see citing works
“In complementary experiments, and similarly to what has been performed in other neurodegenerative diseases, CRISPR-Cas9 has been used to revert mutations causing diseases in animal models [87,88].”
ResultGao, L., Wang, J., & Bi, Y. (2025) · International Journal of Nanomedicine · doi:10.2147/ijn.s549893 · Cited by 52 · see citing works
CRISPR–Cas9 in genome editing: Its function and medical applications
Khadempar, S., Familghadakchi, S., Motlagh, R. A., Farahani, N., Dashtiahangar, M., Rezaei, H., & Hayat, S. M. G. (2018) · Journal of Cellular Physiology · doi:10.1002/jcp.27476 · Cited by 51 · see citing works
“It cannot yet be said that the disease is treated, but the system is necessary to be optimized to target a greater percentage of cells (Gaj et al., 2017).”
BackgroundClinical applications of CRISPR‐based genome editing and diagnostics
Foss, D. V., Hochstrasser, M. L., & Wilson, R. C. (2019) · Transfusion · doi:10.1111/trf.15126 · Cited by 50 · see citing works
The Biogenesis of miRNAs and Their Role in the Development of Amyotrophic Lateral Sclerosis
Liu, J., Zhou, F., Guan, Y., Meng, F., Zhao, Z., Su, Q., Bao, W., Wang, X., Zhao, J., Huo, Z., et al. (2022) · Cells · doi:10.3390/cells11030572 · Cited by 49 · see citing works
Recent Therapeutic Gene Editing Applications to Genetic Disorders
Deneault, É. (2024) · Current Issues in Molecular Biology · doi:10.3390/cimb46050255 · Cited by 49 · see citing works
“A few years ago, a proof-of-concept study examined the SOD1 G93A mouse model of ALS, carrying about 25 tandem repeat copies of the human transgene hSOD1 G93A [79].”
BackgroundGene Therapy in ALS and SMA: Advances, Challenges and Perspectives
Lejman, J., Panuciak, K., Nowicka, E., Mastalerczyk, A., Wojciechowska, K., & Lejman, M. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms24021130 · Cited by 47 · see citing works
Raikwar, S. P., Kikkeri, N. S., Sakuru, R. C., Saeed, D., Zahoor, H., Premkumar, K., Mentor, S., Thangavel, R., Dubova, I., Ahmed, M. E., et al. (2019) · Journal of Neuroimmune Pharmacology · doi:10.1007/s11481-019-09849-y · Cited by 47 · see citing works
Uses for humanised mouse models in precision medicine for neurodegenerative disease
Nair, R., Corrochano, S., Gasco, S., Tibbit, C., Thompson, D., Maduro, C., Ali, Z., Fratta, P., Acevedo‐Arozena, A., Cunningham, T. J., et al. (2019) · Mammalian Genome · doi:10.1007/s00335-019-09807-2 · Cited by 41 · see citing works
Nishiguchi, K. M., Fujita, K., Miya, F., Katayama, S., & Nakazawa, T. (2020) · Nature Communications · doi:10.1038/s41467-019-14181-3 · Cited by 43 · see citing works
Translating CRISPR-Cas Therapeutics: Approaches and Challenges
Tay, L. S., Palmer, N. D., Panwala, R., Chew, W. L., & Mali, P. (2020) · The CRISPR Journal · doi:10.1089/crispr.2020.0025 · Cited by 43 · see citing works
“SaCas9 improved locomotor functions and survival when administered intravenously or via intracerebroventricular injection.(193,194) A CSF-administered cytidine base editor was able to disrupt mutant Sod1 in adult ALS transgenic mice and improve survival.”
Hana, S., Peterson, M. A., McLaughlin, H., Marshall, E., Fabian, A. J., McKissick, O. P., Koszka, K., Marsh, G., Craft, M., Xu, S., et al. (2021) · Gene Therapy · doi:10.1038/s41434-021-00224-2 · Cited by 43 · see citing works
Rare Variant Burden Analysis within Enhancers Identifies CAV1 as an ALS Risk Gene
Cooper‐Knock, J., Zhang, S., Kenna, K. P., Moll, T., Franklin, J., Allen, S., Nezhad, H. G., Iacoangeli, A., Yacovzada, N., Eitan, C., et al. (2020) · Cell Reports · doi:10.1016/j.celrep.2020.108456 · Cited by 39 · see citing works
“Extreme reductions in CAV1/CAV2 expression are notable; however, phenotypic change in excess of editing efficiency is well described and may be a consequence of CRISPR interference (Gaj et al., 2017).”
BackgroundApproaches to gene modulation therapy for ALS
Meijboom, K. E., & Brown, R. H. (2022) · Neurotherapeutics · doi:10.1007/s13311-022-01285-w · Cited by 38 · see citing works
“Intravenous injections of AAV9 expressing Staphylococcus aureus (Sa) Cas9 and a gRNA targeting SOD1 in neonatal SOD1G93A mice extended survival by 30 days and significantly improved motor function [132].”
BackgroundCRISPR/Cas-Dependent and Nuclease-Free In Vivo Therapeutic Gene Editing
Dasgupta, I., Flotte, T. R., & Keeler, A. M. (2021) · Human Gene Therapy · doi:10.1089/hum.2021.013 · Cited by 37 · see citing works
Al-Khayri, J. M., Ravindran, M., Banadka, A., Devaiah, V. C., Priya, K., Nagella, P., & Kukkemane, K. (2024) · Pharmaceuticals · doi:10.3390/ph17101391 · Cited by 35 · see citing works
CRISPR/Cas9: Nature's gift to prokaryotes and an auspicious tool in genome editing
Manzoor, K. N., & Khan, A. A. (2019) · Journal of Basic Microbiology · doi:10.1002/jobm.201900420 · Cited by 35 · see citing works
“Results showed approximately 50% retention of motor neurons, approximately 37% showed a delayed onset of disease, and approximately 25% showed more chances of survival in treated rats [87].”
BackgroundChung, S. H., Mollhoff, I. N., Nguyen, U. T. T., Nguyen, A. B., Stucka, N., Tieu, E., Manna, S. K., Meleppat, R. K., Zhang, P., Nguyen, E. L., et al. (2020) · Molecular Therapy — Methods & Clinical Development · doi:10.1016/j.omtm.2020.01.006 · Cited by 35 · see citing works
CRISPR/Cas9 system and its applications in nervous system diseases
Jiang, H., Tang, M.-Y., Xu, Z., Wang, Y., Li, M., Zheng, S., Zhu, J., Lin, Z., & Zhang, M. (2023) · Genes & Diseases · doi:10.1016/j.gendis.2023.03.017 · Cited by 37 · see citing works
“The results revealed that mutant SOD1 significantly reduced, the number of motor neurons increased significantly, and the motor function was effectively protected.(147) Based on this study, Duan et al injected a high dose (3.”
BackgroundIntrathecal delivery of AAV-NDNF ameliorates disease progression of ALS mice
Cheng, W., Huang, J., Fu, X.-Q., Tian, W.-Y., Zeng, P.-M., Li, Y., & Luo, Z. (2023) · Molecular Therapy · doi:10.1016/j.ymthe.2023.09.018 · Cited by 32 · see citing works
Battling Neurodegenerative Diseases with Adeno-Associated Virus-Based Approaches
Mijanović, O., Branković, A., Borovjagin, A. V., Butnaru, D. V., Bezrukov, E. A., Sukhanov, R. B., Shpichka, A. I., Timashev, P. S., & Ulasov, I. V. (2020) · Viruses · doi:10.3390/v12040460 · Cited by 32 · see citing works
“[132], who used the CRISPR-Cas9 gene targeting (Figure 1) approach to achieve a reduced expression of the glial maturation factor in glial cells that contributed to the formation of Alzheimer’s disease plaques and corrected an autosomal mutation in the SOD1 gene, responsible for ALS progression, respectively.”
MethodThe Off-Targets of Clustered Regularly Interspaced Short Palindromic Repeats Gene Editing
Vicente, M. M., Chaves‐Ferreira, M., Jorge, J. M. P., Proença, J. T., & Barreto, V. M. (2021) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2021.718466 · Cited by 31 · see citing works
“…and deep sequencing of amplicons from a modest number of potential off-targets, such as in a murine genetic model of amyotrophic lateral sclerosis (Gaj et al., 2017), and biased and unbiased methods (whole-exome and whole-genome sequencing), such as in a study of an Alzheimer’s disease model…”
BackgroundCharacterizing and controlling CRISPR repair outcomes in nondividing human cells
Ramadoss, G. N., Namaganda, S. J., Kumar, M. M., Hamilton, J. R., Sharma, R. K., Chow, K. G., Workley, L. A., Macklin, B. L., Sun, M., Ha, A. S., et al. (2025) · Nature Communications · doi:10.1038/s41467-025-66058-3 · Cited by 35 · see citing works
Chen, Y. A., Kankel, M. W., Hana, S., Lau, S. K., Zavodszky, M. I., McKissick, O. P., Mastrangelo, N., Dion, J., Wang, B., Ferretti, D., et al. (2022) · Gene Therapy · doi:10.1038/s41434-022-00375-w · Cited by 31 · see citing works
“We found a larger degree of suppression than two previously published studies employing AAV-mediated delivery of CRISPR to treat SOD1 mice [29, 30].”
BackgroundMethodResultInfluentialSuperior Fidelity and Distinct Editing Outcomes of SaCas9 Compared with SpCas9 in Genome Editing
Yang, Z.-X., Fu, Y.-W., Zhao, J.-J., Zhang, F., Li, S.-A., Zhao, M., Wen, W., Zhang, L., Cheng, T., Zhang, J., et al. (2022) · Genomics Proteomics & Bioinformatics · doi:10.1016/j.gpb.2022.12.003 · Cited by 32 · see citing works
“Using an optimized sgRNA scaffold and a novel Cas9 fusion protein improves genome editing efficiency Two early studies on the SaCas9-sgRNA editing system used a nuclear localization signal (NLS) from the NPM gene [18,19].”
BackgroundThe potential of gene editing for Huntington’s disease
Duan, W., Urani, E., & Mattson, M. P. (2023) · Trends in Neurosciences · doi:10.1016/j.tins.2023.02.005 · Cited by 30 · see citing works
Brain Delivery of Protein Therapeutics by Cell Matrix‐Inspired Biomimetic Nanocarrier
Huang, J., Fu, Y., Wang, A., Shi, K., Peng, Y., Yao, Y., Yu, R., Gao, J., Feng, J., Jiang, G., et al. (2024) · Advanced Materials · doi:10.1002/adma.202405323 · Cited by 29 · see citing works
González-Sánchez, M., Ramı́rez-Expósito, M. J., & Martı́nez-Martos, J. M. (2025) · Life · doi:10.3390/life15040647 · Cited by 30 · see citing works
“Both caregivers and patients benefit from detailed instructions on stretching techniques and dosage, as well as hand positioning [270].”
CRISPR/Cas9 Technology as an Emerging Tool for Targeting Amyotrophic Lateral Sclerosis (ALS)
Kruminis-Kaszkiel, E., Juranek, J. K., Maksymowicz, W., & Wojtkiewicz, J. (2018) · International Journal of Molecular Sciences · doi:10.3390/ijms19030906 · Cited by 29 · see citing works
“[64] demonstrated that the CRISPR/Cas9 can be applied to modify mutant expression in the G93A-SOD1 mouse model of ALS following in vivo delivery using an adeno-associated virus vector (AAV).”
BackgroundLe, Q. A., Hirata, M., Nguyen, N. T., Takebayashi, K., Wittayarat, M., Sato, Y., Namula, Z., Nii, M., Tanihara, F., & Otoi, T. (2020) · Animal Science Journal · doi:10.1111/asj.13386 · Cited by 28 · see citing works
Recent advances in understanding amyotrophic lateral sclerosis and emerging therapies
Gittings, L. M., & Sattler, R. (2020) · Faculty Reviews · doi:10.12703/b/9-12 · Cited by 26 · see citing works
Mani, S., Jindal, D., & Singh, M. (2022) · Current Gene Therapy · doi:10.2174/1566523222666220328142427 · Cited by 30 · see citing works
Alemán-Villa, K. M., Armienta-Rojas, D. A., Camberos-Barraza, J., Rábago-Monzón, Á. R., Camacho-Zamora, A., Osuna‐Ramos, J. F., Magaña‐Gómez, J. A., Guadrón‐Llanos, A. M., Calderón-Zamora, L., Norzagaray-Valenzuela, C. D., et al. (2025) · NeuroImmunoModulation · doi:10.1159/000548021 · Cited by 30 · see citing works
Gene Therapy for Neurodegenerative Disease: Clinical Potential and Directions
Zhu, X., Zhang, Y., Yang, X., Hao, C., & Duan, H. (2021) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2021.618171 · Cited by 25 · see citing works
“With improvement of motor function, the average survival time of mice increased by 28–30 days (Gaj et al., 2017).”
BackgroundFeliciano, C. M., Wu, K. K.-Y., Watry, H. L., Marley, C. B. E., Ramadoss, G. N., Ghanim, H. Y., Liu, A. Z., Zholudeva, L. V., McDevitt, T. C., Saporta, M., et al. (2021) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2021.723023 · Cited by 25 · see citing works
“NHEJ is most useful for gene inactivation via frameshift-inducing indels, as in our approach, and is active even in post-mitotic neurons (Bétermier et al., 2014; Shalem et al., 2014; Gaj et al., 2017).”
MethodCRISPR/Cas therapeutic strategies for autosomal dominant disorders
Caruso, S. M., Quinn, P. M. J., da Costa, B. L., & Tsang, S. H. (2022) · Journal of Clinical Investigation · doi:10.1172/jci158287 · Cited by 26 · see citing works
Innovations in CRISPR technology
Brooks, A. K., & Gaj, T. (2018) · Current Opinion in Biotechnology · doi:10.1016/j.copbio.2018.03.007 · Cited by 25 · see citing works
Basic Principles and Clinical Applications of CRISPR-Based Genome Editing
Lim, J. M., & Kim, S. (2022) · Yonsei Medical Journal · doi:10.3349/ymj.2022.63.2.105 · Cited by 26 · see citing works
Fuentes, C., & Schaffer, D. V. (2018) · Current Opinion in Biomedical Engineering · doi:10.1016/j.cobme.2018.08.003 · Cited by 23 · see citing works
CRISPR/Cas9-mediated correction of mutated copper transporter ATP7B
Pöhler, M., Guttmann, S., Nadzemova, O., Lenders, M., Brand, E., Zibert, A., Schmidt, H., & Sandfort, V. (2020) · PLoS ONE · doi:10.1371/journal.pone.0239411 · Cited by 27 · see citing works
Paul, A., Collins, M. G., & Lee, H. Y. (2022) · Frontiers in Genome Editing · doi:10.3389/fgeed.2022.899209 · Cited by 23 · see citing works
Gene therapy breakthroughs in ALS: a beacon of hope for 20% of ALS patients
Xie, Q., Li, K., Chen, Y., Li, Y., Jiang, W., Cao, W., Yu, H., Fan, D., & Deng, B. (2025) · Translational Neurodegeneration · doi:10.1186/s40035-025-00477-6 · Cited by 22 · see citing works
“It can be used to correct mutations that cause ALS or to introduce new genetic material that can counteract the disease’s effects [20].”
Zhou, W., Yang, J., Zhang, Y., Hu, X., & Wang, W. (2022) · MedComm · doi:10.1002/mco2.155 · Cited by 22 · see citing works
Current potential therapeutics of amyotrophic lateral sclerosis
Lu, L., Deng, Y., & Xu, R. (2024) · Frontiers in Neurology · doi:10.3389/fneur.2024.1402962 · Cited by 22 · see citing works
Novel genome-editing-based approaches to treat motor neuron diseases: Promises and challenges
Miccio, A., Antoniou, P., Ciura, S., & Kabashi, E. (2021) · Molecular Therapy · doi:10.1016/j.ymthe.2021.04.003 · Cited by 21 · see citing works
Wang, S., Ichinomiya, T., Savchenko, P., Wang, D., Sawada, A., Li, X., Duong, T., Li, W., Bonds, J. A., Kim, E. J., et al. (2022) · Theranostics · doi:10.7150/thno.72614 · Cited by 20 · see citing works
“Typical age-of-onset is 58-63 years and 47-52 years for SALS and FALS, respectively, with both being phenotypically similar.”
BackgroundInfluentialGuan, T., Zhou, T., Zhang, X., Guo, Y., Yang, C., Lin, J. J., Zhang, J. V., Cheng, Y., Marzban, H., Wang, Y. T., et al. (2023) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-023-04956-9 · Cited by 20 · see citing works
Molecular mechanisms and therapeutic strategies for neuromuscular diseases
Zambon, A. A., Falzone, Y. M., Bolino, A., & Previtali, S. C. (2024) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-024-05229-9 · Cited by 20 · see citing works
“This intervention increased motor neurons, delayed disease onset, and extended survival in transgenic mice [47].”
BackgroundMòdol‐Caballero, G., García-Lareu, B., Herrando‐Grabulosa, M., Verdés, S., López‐Vales, R., Pagès, G., Chillón, M., Navarro, X., & Bosch, A. (2021) · Neurotherapeutics · doi:10.1007/s13311-021-01025-6 · Cited by 20 · see citing works
“And finally, viral vectors have been also used to deliver gene editing tools to the same mouse model with significant delay in the disease onset and survival [13, 14].”
MethodYashooa, R. K., Nabi, A. Q., Smail, S. W., Azeez, S. S., Nooh, W. A., Mustafa, S. A., Al-Farha, A. A.-B., Capitanio, N., & Shekha, M. S. (2026) · Frontiers in Neurology · doi:10.3389/fneur.2025.1737468 · Cited by 20 · see citing works
CRISPR Systems Suitable for Single AAV Vector Delivery
Stevanovic, M., Piotter, E., McClements, M. E., & MacLaren, R. E. (2021) · Current Gene Therapy · doi:10.2174/1566523221666211006120355 · Cited by 19 · see citing works
A high-fidelity CRISPR-Cas13 system improves abnormalities associated with C9ORF72-linked ALS/FTD
McCallister, T. X., Lim, C. K. W., Singh, M., Zhang, S., Ahsan, N. S., Terpstra, W. M., Xiong, A. Y., C., M. A. Z., Powell, J. E., Drnevich, J. M., et al. (2025) · Nature Communications · doi:10.1038/s41467-024-55548-5 · Cited by 19 · see citing works
Clinical trials and promising preclinical applications of CRISPR/Cas gene editing
Çerçi, B., Uzay, İ. A., Kara, M. K., & Dinçer, P. (2022) · Life Sciences · doi:10.1016/j.lfs.2022.121204 · Cited by 18 · see citing works
Hereditary Ataxias: From Bench to Clinic, Where Do We Stand?
Pilotto, F., Bondio, A. D., & Puccio, H. M. (2024) · Cells · doi:10.3390/cells13040319 · Cited by 19 · see citing works
“Genome editing has been efficient in reducing the main disease phenotypes and rescuing the molecular defects in several animal models of neurodegenerative disorders (e.g., ALS, HD, AD, PD, and fragile-X syndrome) [227–231].”
BackgroundGene Therapy for Rare Neurological Disorders
Flotte, T. R., & Gessler, D. J. (2022) · Clinical Pharmacology & Therapeutics · doi:10.1002/cpt.2543 · Cited by 20 · see citing works
“saCas9 significantly decreased SOD1 expression in the mouse spinal cord, delayed disease onset, and extended overall survival when treated as neonates.(50) New technologies such as CRISPR also raise the question about their safety.”
BackgroundCRISPR/Cas9: implication for modeling and therapy of amyotrophic lateral sclerosis
Shi, Y., Zhao, Y., Lu, L., Gao, Q., Yu, D., & Sun, M. (2023) · Frontiers in Neuroscience · doi:10.3389/fnins.2023.1223777 · Cited by 17 · see citing works
Peplow, P., & Martinez, B. (2021) · Neural Regeneration Research · doi:10.4103/1673-5374.322431 · Cited by 16 · see citing works
“Both CRISPR nucleases (Gaj et al., 2017) and CRISPR base editors (Lim et al.”
BackgroundImaging Net Retrograde Axonal Transport In Vivo: A Physiological Biomarker
Lee, P., Kennedy, Z., Wang, Y., Lu, Y., Cefaliello, C., Uyan, Ö., Song, C., Godinho, B. M. D. C., Xu, Z., Rusckowski, M., et al. (2022) · Annals of Neurology · doi:10.1002/ana.26329 · Cited by 16 · see citing works
Sharma, R., Khan, Z., Mehan, S., Gupta, G. D., & Narula, A. S. (2024) · Mutation Research/Reviews in Mutation Research · doi:10.1016/j.mrrev.2024.108518 · Cited by 16 · see citing works
Finding a Treatment for ALS — Will Gene Editing Cut It?
Al‐Chalabi, A., & Brown, R. H. (2018) · New England Journal of Medicine · doi:10.1056/nejmcibr1716741 · Cited by 16 · see citing works
“There is evidence that the CRISPR-Cas9 approach is effective against structural changes to the genome, such as variations in the copy number of a gene; indeed, the mouse model in the Gaj et al. study harbors multiple copies of the transgene.”
BackgroundInfluentialBono, N., Fruzzetti, F., Farinazzo, G., Candiani, G., & Marcuzzo, S. (2025) · International Journal of Molecular Sciences · doi:10.3390/ijms26125671 · Cited by 15 · see citing works
“For instance, Gaj et al. [130] delivered CRISPR/Cas9 components via AAV9 vectors through the facial vein in SOD1-G93A mice, achieving approximately 30% reduction in mutant SOD1 protein in the spinal cord.”
- Authors
- Gaj, T., Ojala, D. S., Ekman, F. K., Byrne, L. C., Limsirichai, P., & Schaffer, D. V.
- Affiliations
- University of California, Berkeley (US)
- Corresponding author
- Schaffer, David V.
- Venue
- Science Advances
- Published
- 2017-12
- Volume
- 3
- Issue
- 12
- Pages
- eaar3952-eaar3952
- ISSN
- 2375-2548 (ISSN-L)
- PMC
- PMC5738228
- OpenAlex
- W2777540887
- Cited by
- 185
- References
- 88
- Citations by year
- 2026: 15 · 2025: 23 · 2024: 19 · 2023: 19 · 2022: 28 · 2021: 21 · 2020: 25 · 2019: 16 · 2018: 18 · 2017: 1
- FWCI
- 11.43
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- cc-by-nc
- Locations
- Science Advances (publishedVersion, cc-by-nc)
- Europe PMC (PubMed Central) (publishedVersion, cc-by-nc)
- PubMed Central (publishedVersion, cc-by-nc)
- PubMed (publishedVersion)
- eScholarship (California Digital Library) (submittedVersion, cc-by-nc)
- Funders
- National Institutes of Health (award359563, F32GM113446, award359564, F32EY023891, award359565, R01EY022975)
- NSF Graduate Research Fellowship (award362885)
- UC Berkeley Dissertation-Year Fellowship (award362886)
- Topics
- Health Sciences › Medicine › Neurology › Amyotrophic Lateral Sclerosis Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › CRISPR and Genetic Engineering
- Health Sciences › Medicine › Genetics › Neurogenetic and Muscular Disorders Research
- Keywords
- amyotrophic lateral sclerosis, SOD1 G93A mouse model, CRISPR/Cas9 genome editing, in vivo gene therapy, adeno-associated virus vectors, motor neuron survival, motor function, muscle atrophy, autosomal dominant mutations, superoxide dismutase 1, disease onset delay, survival extension
- MeSH terms
- Superoxide Dismutase-1, Gene Editing, CRISPR-Associated Protein 9, RNA, Guide, CRISPR-Cas Systems, Amyotrophic Lateral Sclerosis, Animals, Disease Models, Animal, Female, Genetic Vectors, Humans, Locomotion, Male, Mice, Transgenic, Mutation, Spinal Cord, Genetic Therapy, Genome, RNA, Guide, Kinetoplastida, CRISPR-Cas Systems
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