Amyotrophic Lateral Sclerosis is a spectrum of diseases that needs a broad treatment approach
Main Article Content
Abstract
Amyotrophic lateral sclerosis consists of multiple diseases that lead to a common endpoint that initiates motor neuron loss. The difficulty in developing treatments is that both the presentation and the course of the disease differs for patients and there aren’t methods to stratify patients in clinical trials that are expected to benefit from a drug, thus most treatments that were positive in animal studies fail in Phase 2 human studies. It is possible harnessing innate immune responses involved with the cell danger responses may be a starting point to stack therapies in patients. A major step in regulating the cell danger response is creating a retro-inverso thymopentin that can increase innate immune targets to regulate T cell responses.
Recent work on thymopentin bring a major contribution to the ALS field and we present FC-12738 designed to regulate the cell danger response by natural innate immune pathways.
Keywords:
amyotrophic lateral sclerosis, thymopentin, thymopoietin, FC-12738, cell danger response
Article Details
How to Cite
ELLISON, Siobhan P.
Amyotrophic Lateral Sclerosis is a spectrum of diseases that needs a broad treatment approach.
Medical Research Archives, [S.l.], v. 12, n. 7, july 2024.
ISSN 2375-1924.
Available at: <https://esmed.org/MRA/mra/article/view/5448>. Date accessed: 05 aug. 2024.
doi: https://doi.org/10.18103/mra.v12i7.5448.
Section
Research Articles
The Medical Research Archives grants authors the right to publish and reproduce the unrevised contribution in whole or in part at any time and in any form for any scholarly non-commercial purpose with the condition that all publications of the contribution include a full citation to the journal as published by the Medical Research Archives.
References
1. Hoxhaj P, Hastings N, Kachhadia MP, Gupta R, Sindhu U, Durve SA, Azam A, Auz Vinueza MJ, Bhuvan, Win SH, Rathod DC, Afsar AP. “Exploring Advancements in the Treatment of Amyotrophic Lateral Sclerosis: A Comprehensive Review of Current Modalities and Future Prospects.” Cureus. 2023 Sep 18;15(9):e45489. Doi: 10.7759/cureus.45489. PMID: 37868386; PMCID: PMC10585945.
2. Henderson PA and McCombe RD. "The Role of Immune and Inflammatory Mechanisms in ALS." Curr Mol Med, 2011: 246-254.
3. Phan K, He Y, Bhatia S, Pickford R, McDonald G, Mazumder S, Timmins HC, Hodges JR, Piguet O, Dzamko N, Halliday GM, Kiernan MC, Kim WS. “Multiple pathways of lipid dysregulation in amyotrophic lateral sclerosis”. Brain Commun. 2022 Dec 26;5(1):fcac340.
Doi: 10.1093/braincomms/fcac340. PMID: 36632187; PMCID: PMC9825811.
4. Genin E, Abou-Ali M, Paquis-Flucklinger V. “Mitochondria, a key target in Amyotrophic Lateral Sclerosis Pathogenesis”. October 23, 2023. https://doi.org/10.3390/genes14111981.
5. Elhage R, Kelly M, Goudin N, Megret J, Legrand A, Nemazanyy I, Patitucci C, Quellec V, Wai T, Hamai A S, Ezine S. “Mitochondrial dynamics and metabolic regulation control T cell fate in the thymus.” Frontiers in Immunology. Jan 14, 2024. https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2023.1270268/full#B1.
6. Giovannelli I, Heath P, Shaw P, Kirby J. "The involvement of regulatory T cells in amyotrophic lateral sclerosis and their therapeutic potential." Amyotroph Lateral Scler Frontotemporal Degener., 2020: 435-444.
7. Thornhoff J, Berry J, Macklin E, Beers D, Mendoza P, Zhao W, Thome A, Triolo F, Moon J, Paganoni S, Cudkowicz M, Appel S. "Combined Regulatory T-Lymphocyte and IL-2 Treatment Is Safe, Tolerable, and Biologically Active for 1 Year in Persons With Amyotrophic Lateral Sclerosis." Neurol Neuroimmunol Neuroinflamm, 2022: 9(6):e200019.
Doi: 10.1212/NXI.0000000000200019. PMID: 36038262; PMCID: PMC9423710.
8. Povoleri G, Scotta C, Nova-Lamperti E, John S, Loombardi G, Afzali B. "Thymic versus induced regulatory T cells-who regulates the regulators?" Frontiers in Immunology, 2013: 1-22.
9. Wen Li H, Zhou C, Chen L, Zhang L, Chen Y, Zhang S, Pan X, Huang S, Shang W, Shen X, Liu X, Liu J, Chen D. "Thymopentin plays a key role in restoring the function of macrophages to alleviate the sepsis process." sciencedirect.com. December 4, 2023. https://www.sciencedirect.com/science/article/abs/pii/S1567576923016223.
10. Zou Q, Zhang L, Sun F. "The effect of thymopentin on immune function and inflammatory levels in end-stage renal diseases patients with maintneance hemodialysis." Am J Transl Res, 2022: 414-420.
11. Petrov D, Mansfield C, Moussy A, Hermine O. "ALS Clinical Trials Review: 20 years of failure. Are we any closer to registering a new treatment?" Front Aging Neurosci, 2017: 1-11.
12. Beers D, Zhao W, Wang J, Zhang X, Wen S, Neal D, Thonhoff J, Alsuliman A, Shpall E, Rezvani K and Appel S. "ALS patients' regulatory T lymphocytes are dysfunctiona, and correlate with disease progression rate and severity." J CI Insight, 2017.
13. Naviaux R K. "Mitochondrial and metabolic features of salugenesis and the healing cycle." Mitochondrion, 2023: 278-297.
14. Kokai L. Interview by NDR research group. Measuring Annexin V (apoptosis) and membrane permeability (necrosis) in real time with Promega following hourly extracellular ATP exposure Reddick: Neurodegenerative Disease Research Inc, (April 2023).
15. Olarte MR, Shafer SQ. "Levamisole is ineffective in the treatment of amyotrophic lateral sclerosis." Neurology, 1985: 1063-1066.
16. Borchelt D, Ellison S. "Assessment of levamisole HCl and thymosin alpha 1 in two mouse models of amyotrophic lateral sclerosis." Archives of clinical and Biomedical Research 7, 2023
17. Li J, Cheng LY, Zhang X. "The in vivo immunomodulatory and synergistic anti-tumor activity of thymosin alpha1-thymopentin fusion peptide and its binding to TLR2." Cancer Lett 337, 2013: 237-247.
18. Midthun KM, Nelson LS, Logan BK. “Levamisole- a Toxic Adulterant in Illicit Drug Preparations: a Review”. Ther Drug Monit. 2021 Apr 1;43(2):221-228. Doi: 10.1097/FTD.0000000000000851. PMID: 33298746.
19. Goldstein G, Audhya TK. "Thymopoietin to thymopentin: experimental studies." Surv Immunol, 1985: 1-10.
20. Goldstein G, Scheid MP, Boyse EA. "A synthetic pentapeptide with bilogical activity characteristic of the thymic hormone thymopoietin." Science, 1979: 1309-1310.
21. Singh VK, Biswas S. et al. “Thymopentin and splenopentin as immunomodulators.” Immunologic Research 1998: 17/3: 345-368.
22. Ellison, Siobhan. "Pharmacological Characterizaton of FC-12738: A Novel Retro-Inverso Pentapeptide for Treating Neuroinflammation." Archives of Clinical and Biomedical Research, 2023: 596-607.
23. McCluskey G, Donaghy C, Morrison K, McConville J, Duddy W, Duguez, S. "The Role of Sphingomyelin and Ceramide in Motor Neuron Diseases." J Personalized Medicine, 2022.
2. Henderson PA and McCombe RD. "The Role of Immune and Inflammatory Mechanisms in ALS." Curr Mol Med, 2011: 246-254.
3. Phan K, He Y, Bhatia S, Pickford R, McDonald G, Mazumder S, Timmins HC, Hodges JR, Piguet O, Dzamko N, Halliday GM, Kiernan MC, Kim WS. “Multiple pathways of lipid dysregulation in amyotrophic lateral sclerosis”. Brain Commun. 2022 Dec 26;5(1):fcac340.
Doi: 10.1093/braincomms/fcac340. PMID: 36632187; PMCID: PMC9825811.
4. Genin E, Abou-Ali M, Paquis-Flucklinger V. “Mitochondria, a key target in Amyotrophic Lateral Sclerosis Pathogenesis”. October 23, 2023. https://doi.org/10.3390/genes14111981.
5. Elhage R, Kelly M, Goudin N, Megret J, Legrand A, Nemazanyy I, Patitucci C, Quellec V, Wai T, Hamai A S, Ezine S. “Mitochondrial dynamics and metabolic regulation control T cell fate in the thymus.” Frontiers in Immunology. Jan 14, 2024. https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2023.1270268/full#B1.
6. Giovannelli I, Heath P, Shaw P, Kirby J. "The involvement of regulatory T cells in amyotrophic lateral sclerosis and their therapeutic potential." Amyotroph Lateral Scler Frontotemporal Degener., 2020: 435-444.
7. Thornhoff J, Berry J, Macklin E, Beers D, Mendoza P, Zhao W, Thome A, Triolo F, Moon J, Paganoni S, Cudkowicz M, Appel S. "Combined Regulatory T-Lymphocyte and IL-2 Treatment Is Safe, Tolerable, and Biologically Active for 1 Year in Persons With Amyotrophic Lateral Sclerosis." Neurol Neuroimmunol Neuroinflamm, 2022: 9(6):e200019.
Doi: 10.1212/NXI.0000000000200019. PMID: 36038262; PMCID: PMC9423710.
8. Povoleri G, Scotta C, Nova-Lamperti E, John S, Loombardi G, Afzali B. "Thymic versus induced regulatory T cells-who regulates the regulators?" Frontiers in Immunology, 2013: 1-22.
9. Wen Li H, Zhou C, Chen L, Zhang L, Chen Y, Zhang S, Pan X, Huang S, Shang W, Shen X, Liu X, Liu J, Chen D. "Thymopentin plays a key role in restoring the function of macrophages to alleviate the sepsis process." sciencedirect.com. December 4, 2023. https://www.sciencedirect.com/science/article/abs/pii/S1567576923016223.
10. Zou Q, Zhang L, Sun F. "The effect of thymopentin on immune function and inflammatory levels in end-stage renal diseases patients with maintneance hemodialysis." Am J Transl Res, 2022: 414-420.
11. Petrov D, Mansfield C, Moussy A, Hermine O. "ALS Clinical Trials Review: 20 years of failure. Are we any closer to registering a new treatment?" Front Aging Neurosci, 2017: 1-11.
12. Beers D, Zhao W, Wang J, Zhang X, Wen S, Neal D, Thonhoff J, Alsuliman A, Shpall E, Rezvani K and Appel S. "ALS patients' regulatory T lymphocytes are dysfunctiona, and correlate with disease progression rate and severity." J CI Insight, 2017.
13. Naviaux R K. "Mitochondrial and metabolic features of salugenesis and the healing cycle." Mitochondrion, 2023: 278-297.
14. Kokai L. Interview by NDR research group. Measuring Annexin V (apoptosis) and membrane permeability (necrosis) in real time with Promega following hourly extracellular ATP exposure Reddick: Neurodegenerative Disease Research Inc, (April 2023).
15. Olarte MR, Shafer SQ. "Levamisole is ineffective in the treatment of amyotrophic lateral sclerosis." Neurology, 1985: 1063-1066.
16. Borchelt D, Ellison S. "Assessment of levamisole HCl and thymosin alpha 1 in two mouse models of amyotrophic lateral sclerosis." Archives of clinical and Biomedical Research 7, 2023
17. Li J, Cheng LY, Zhang X. "The in vivo immunomodulatory and synergistic anti-tumor activity of thymosin alpha1-thymopentin fusion peptide and its binding to TLR2." Cancer Lett 337, 2013: 237-247.
18. Midthun KM, Nelson LS, Logan BK. “Levamisole- a Toxic Adulterant in Illicit Drug Preparations: a Review”. Ther Drug Monit. 2021 Apr 1;43(2):221-228. Doi: 10.1097/FTD.0000000000000851. PMID: 33298746.
19. Goldstein G, Audhya TK. "Thymopoietin to thymopentin: experimental studies." Surv Immunol, 1985: 1-10.
20. Goldstein G, Scheid MP, Boyse EA. "A synthetic pentapeptide with bilogical activity characteristic of the thymic hormone thymopoietin." Science, 1979: 1309-1310.
21. Singh VK, Biswas S. et al. “Thymopentin and splenopentin as immunomodulators.” Immunologic Research 1998: 17/3: 345-368.
22. Ellison, Siobhan. "Pharmacological Characterizaton of FC-12738: A Novel Retro-Inverso Pentapeptide for Treating Neuroinflammation." Archives of Clinical and Biomedical Research, 2023: 596-607.
23. McCluskey G, Donaghy C, Morrison K, McConville J, Duddy W, Duguez, S. "The Role of Sphingomyelin and Ceramide in Motor Neuron Diseases." J Personalized Medicine, 2022.