Amyotrophic Lateral Sclerosis (ALS) is one of the most common motor neurodegenerative diseases. Approximately 9 per 100,000 people in the US suffer from it, most of whom are between 55 and 75 years old (CDC, 2018). ALS affects the nerve cells of the spinal cord and brain, resulting in the loss of control of voluntary muscle movements. This loss of control significantly impacts the patient's life, as ALS is a progressive disease without a definite cure. The main symptoms are found in changes to the patient's walking, drinking, and breathing, which ultimately leads to death (NINDS).
The current treatment for ALS aims to alleviate symptoms and increase the patient's quality of life. For ALS, the most common medication is Riluzole, an oral medication that reduces neuronal damage by decreasing the level of glutamate transmitted between motor neurons and neurotransmitters (Lazarevic et al., 2018). In addition, Edaravone, which is an antioxidant given either orally or intravenously, has been shown to slow functional decline in some patients (NINDS). However, about 10% of all ALS cases are hereditary. There are several genes that can cause familial ALS, which account for between 25% and 40% of all familial cases, and a small group of sporadic cases that are caused by a defect in the C9orf72 gene, which produces a protein found in motor neurons and neurons of the brain. For C9orf72, the disease-causing mutation is a hexanucleotide repeat expansion of GGGGCC (G4C2) in the first intron of the C9orf72 gene (Lejman et al.,2023). For another group, approximately 12% to 20% of familial cases are due to mutations in the superoxide dismutase 1 (SOD1) gene. SOD1 is involved in the production of the enzyme copper-zinc superoxide dismutase 1, an antioxidant enzyme that protects the cell from the toxicity of reactive oxygen species (Bunton-Stasyshyn et al., 2014).
Given these factors, a possible cure for ALS is gene therapy.
Using gene therapy can lead to more sustainable cures, as over traditional treatment does not necessarily provide a better quality of life or an increase in life expectancy. Currently, adeno-associated viruses (AAV) have been widely used for different neurodegenerative diseases. A recent study (Chen et al., 2022) shows that a CRISPR system with delivery of SOD1 single-guide RNAs (sgRNAs) by AAV-PHP.B and AAV-PHP.eB in mice with ALS significantly reduces the mutant SOD1 protein. These results extended neuronal cell survival compared to previous studies that employed other CRISPR strategies. It is also suggested that the constitutive expression of Cas9 and the use of more efficient AAV variants contribute to these results. Additionally, other research shows that CRISPR-Cas9 could be used with induced Pluripotent Stem Cells (iPSC), which facilitates immunocompatibility and aids in fully understanding the pathophysiology of ALS (Yun et al., 2020).
In conclusion, direct clinical translation is still hampered by challenges such as the need to package complete CRISPR systems and consider immune responses between different ALS cases to devise effective therapeutic approaches. These efforts underscore the therapeutic potential of CRISPR-based gene editing in preclinical models for ALS, aiming to reduce mutant proteins and improve neuronal cell survival. Furthermore, they emphasize the critical importance of improving gene expression and transport systems to enhance therapeutic efficacy and specificity. Further exploration and research into CRISPR will not only help understand the various cases of ALS but also have the potential to significantly impact patients' lives beyond progressive symptom reduction.
About the Author
Violeta Vilcapoma-Torres is a sophomore at Universidad Peruana Cayetano Heredia in Lima, Peru, studying Biomedical Engineering.
References:
The current treatment for ALS aims to alleviate symptoms and increase the patient's quality of life. For ALS, the most common medication is Riluzole, an oral medication that reduces neuronal damage by decreasing the level of glutamate transmitted between motor neurons and neurotransmitters (Lazarevic et al., 2018). In addition, Edaravone, which is an antioxidant given either orally or intravenously, has been shown to slow functional decline in some patients (NINDS). However, about 10% of all ALS cases are hereditary. There are several genes that can cause familial ALS, which account for between 25% and 40% of all familial cases, and a small group of sporadic cases that are caused by a defect in the C9orf72 gene, which produces a protein found in motor neurons and neurons of the brain. For C9orf72, the disease-causing mutation is a hexanucleotide repeat expansion of GGGGCC (G4C2) in the first intron of the C9orf72 gene (Lejman et al.,2023). For another group, approximately 12% to 20% of familial cases are due to mutations in the superoxide dismutase 1 (SOD1) gene. SOD1 is involved in the production of the enzyme copper-zinc superoxide dismutase 1, an antioxidant enzyme that protects the cell from the toxicity of reactive oxygen species (Bunton-Stasyshyn et al., 2014).
Given these factors, a possible cure for ALS is gene therapy.
Using gene therapy can lead to more sustainable cures, as over traditional treatment does not necessarily provide a better quality of life or an increase in life expectancy. Currently, adeno-associated viruses (AAV) have been widely used for different neurodegenerative diseases. A recent study (Chen et al., 2022) shows that a CRISPR system with delivery of SOD1 single-guide RNAs (sgRNAs) by AAV-PHP.B and AAV-PHP.eB in mice with ALS significantly reduces the mutant SOD1 protein. These results extended neuronal cell survival compared to previous studies that employed other CRISPR strategies. It is also suggested that the constitutive expression of Cas9 and the use of more efficient AAV variants contribute to these results. Additionally, other research shows that CRISPR-Cas9 could be used with induced Pluripotent Stem Cells (iPSC), which facilitates immunocompatibility and aids in fully understanding the pathophysiology of ALS (Yun et al., 2020).
In conclusion, direct clinical translation is still hampered by challenges such as the need to package complete CRISPR systems and consider immune responses between different ALS cases to devise effective therapeutic approaches. These efforts underscore the therapeutic potential of CRISPR-based gene editing in preclinical models for ALS, aiming to reduce mutant proteins and improve neuronal cell survival. Furthermore, they emphasize the critical importance of improving gene expression and transport systems to enhance therapeutic efficacy and specificity. Further exploration and research into CRISPR will not only help understand the various cases of ALS but also have the potential to significantly impact patients' lives beyond progressive symptom reduction.
About the Author
Violeta Vilcapoma-Torres is a sophomore at Universidad Peruana Cayetano Heredia in Lima, Peru, studying Biomedical Engineering.
References:
- National ALS Registry Dashboard | Amyotrophic Lateral Sclerosis (ALS) | CDC. (n.d.) https://www.cdc.gov/als/dashboard/index.html
- Amyotrophic lateral sclerosis (ALS). (n.d.). National Institute of Neurological Disorders and Stroke. https://www.ninds.nih.gov/health-information/disorders/amyotrophic-lateral-sclerosis-als
- Lejman, J., Panuciak, K., Nowicka, E., Mastalerczyk, A., Wojciechowska, K., & Lejman, M. (2023). Gene therapy in ALS and SMA: Advances, challenges and perspectives. International Journal of Molecular Sciences, 24(2), 1130. https://doi.org/10.3390/ijms24021130
- Bunton-Stasyshyn, R., Saccon, R. A., Fratta, P., & Fisher, E. (2014). SOD1 function and its implications for amyotrophic lateral sclerosis pathology. The Neuroscientist, 21(5), 519–529. https://doi.org/10.1177/1073858414561795
- Chen, Y. A., Kankel, M. W., Hana, S., Lau, S. K., Zavodszky, M. I., McKissick, O., Mastrangelo, N., Dion, J., Wang, B., Ferretti, D., Koske, D., Lehman, S., Koszka, K., McLaughlin, H., Liu, M., Marshall, E., Fabian, A. J., Cullen, P., Marsh, G., . . . Lo, S. (2022). In vivo genome editing using novel AAV-PHP variants rescues motor function deficits and extends survival in a SOD1-ALS mouse model. Gene Therapy, 30(5), 443–454. https://doi.org/10.1038/s41434-022-00375-w
- Lazarevic, V., Yang, Y., Ivanova, D., Fejtová, A., & Svenningsson, P. (2018). Riluzole attenuates the efficacy of glutamatergic transmission by interfering with the size of the readily releasable neurotransmitter pool. Neuropharmacology, 143, 38–48 https://doi.org/10.1016/j.neuropharm.2018.09.021
- Yun, Y., & Ha, Y. J. (2020). CRISPR/CAS9-Mediated Gene Correction to understand ALS. International Journal of Molecular Sciences (Online), 21(11), 3801. https://doi.org/10.3390/ijms21113801
