The Scientific and Therapeutic Rationale for Off-Label Treatments in Amyotrophic Lateral Sclerosis

Overview

Journal Ann Neurol

Specialty Neurology

Date 2024 Nov 6

PMID 39503319

Authors

Richard Bedlack

Xiaoyan Li

Baggio Angelo Evangelista

Maria E Panzetta

Justin Kwan

Lauren M Gittings

Rita Sattler

Affiliations

Soon will be listed here.

Abstract

There are no dramatically effective pharmacological treatments for most patients with amyotrophic lateral sclerosis, a complex disease with multiple underlying mechanisms, such as neuroinflammation, oxidative stress, mitochondrial dysfunction, microbiome alteration, and antiretroviral activity. We sifted through 15 years of reviews by a group called ALSUntangled to identify 8 alternative and off-label treatments that target ≥1 of these mechanisms, and have ≥1 human trial suggesting meaningful benefits. Given the overlapping pathological mechanisms of the highlighted products, we suggest that combinations of these treatments targeting diverse mechanisms might be worthwhile for future amyotrophic lateral sclerosis therapy development. ANN NEUROL 2024.

References

Prather I, Brown D, North P, Wilson J . Clenbuterol: a substitute for anabolic steroids?. Med Sci Sports Exerc. 1995; 27(8):1118-21. View

Ferri A, Cozzolino M, Crosio C, Nencini M, Casciati A, Gralla E . Familial ALS-superoxide dismutases associate with mitochondria and shift their redox potentials. Proc Natl Acad Sci U S A. 2006; 103(37):13860-5. PMC: 1557633. DOI: 10.1073/pnas.0605814103. View

Walters G, Usachev Y . Mitochondrial calcium cycling in neuronal function and neurodegeneration. Front Cell Dev Biol. 2023; 11:1094356. PMC: 9902777. DOI: 10.3389/fcell.2023.1094356. View

Stoica R, De Vos K, Paillusson S, Mueller S, Sancho R, Lau K . ER-mitochondria associations are regulated by the VAPB-PTPIP51 interaction and are disrupted by ALS/FTD-associated TDP-43. Nat Commun. 2014; 5:3996. PMC: 4046113. DOI: 10.1038/ncomms4996. View

Rowland L . HIV-related neuromuscular diseases: nemaline myopathy, amyotrophic lateral sclerosis and bibrachial amyotrophic diplegia. Acta Myol. 2011; 30(1):29-31. PMC: 3185829. View

Hemendinger R, Armstrong 3rd E, Brooks B . Methyl Vitamin B12 but not methylfolate rescues a motor neuron-like cell line from homocysteine-mediated cell death. Toxicol Appl Pharmacol. 2011; 251(3):217-25. DOI: 10.1016/j.taap.2011.01.003. View

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; 9:68. PMC: 5360725. DOI: 10.3389/fnagi.2017.00068. View

Gold J, Rowe D, Kiernan M, Vucic S, Mathers S, van Eijk R . Safety and tolerability of Triumeq in amyotrophic lateral sclerosis: the Lighthouse trial. Amyotroph Lateral Scler Frontotemporal Degener. 2019; 20(7-8):595-604. DOI: 10.1080/21678421.2019.1632899. View

Tzeplaeff L, Jurs A, Wohnrade C, Demleitner A . Unraveling the Heterogeneity of ALS-A Call to Redefine Patient Stratification for Better Outcomes in Clinical Trials. Cells. 2024; 13(5. PMC: 10930688. DOI: 10.3390/cells13050452. View

10.

Li W, Lee M, Henderson L, Tyagi R, Bachani M, Steiner J . Human endogenous retrovirus-K contributes to motor neuron disease. Sci Transl Med. 2015; 7(307):307ra153. PMC: 6344353. DOI: 10.1126/scitranslmed.aac8201. View

11.

Casanova A, Wevers A, Navarro-Ledesma S, Pruimboom L . Mitochondria: It is all about energy. Front Physiol. 2023; 14:1114231. PMC: 10167337. DOI: 10.3389/fphys.2023.1114231. View

12.

Corcia P, Tauber C, Vercoullie J, Arlicot N, Prunier C, Praline J . Molecular imaging of microglial activation in amyotrophic lateral sclerosis. PLoS One. 2013; 7(12):e52941. PMC: 3534121. DOI: 10.1371/journal.pone.0052941. View

13.

Imahashi M, Ode H, Kobayashi A, Nemoto M, Matsuda M, Hashiba C . Impact of long-term antiretroviral therapy on gut and oral microbiotas in HIV-1-infected patients. Sci Rep. 2021; 11(1):960. PMC: 7806981. DOI: 10.1038/s41598-020-80247-8. View

14.

Vande Velde C, McDonald K, Boukhedimi Y, McAlonis-Downes M, Lobsiger C, Bel Hadj S . Misfolded SOD1 associated with motor neuron mitochondria alters mitochondrial shape and distribution prior to clinical onset. PLoS One. 2011; 6(7):e22031. PMC: 3136936. DOI: 10.1371/journal.pone.0022031. View

15.

Li Y, King O, Shorter J, Gitler A . Stress granules as crucibles of ALS pathogenesis. J Cell Biol. 2013; 201(3):361-72. PMC: 3639398. DOI: 10.1083/jcb.201302044. View

16.

Cova E, Bongioanni P, Cereda C, Metelli M, Salvaneschi L, Bernuzzi S . Time course of oxidant markers and antioxidant defenses in subgroups of amyotrophic lateral sclerosis patients. Neurochem Int. 2010; 56(5):687-93. DOI: 10.1016/j.neuint.2010.02.004. View

17.

Viola M, Frazier M, White L, Brody J, Spiegelman S . RNA-instructed DNA polymerase activity in a cytoplasmic particulate fraction in brains from Guamanian patients. J Exp Med. 1975; 142(2):483-94. PMC: 2189894. DOI: 10.1084/jem.142.2.483. View

18.

Cox P, Davis D, Mash D, Metcalf J, Banack S . Dietary exposure to an environmental toxin triggers neurofibrillary tangles and amyloid deposits in the brain. Proc Biol Sci. 2016; 283(1823). PMC: 4795023. DOI: 10.1098/rspb.2015.2397. View

19.

Nalbandian A, Llewellyn K, Badadani M, Yin H, Nguyen C, Katheria V . A progressive translational mouse model of human valosin-containing protein disease: the VCP(R155H/+) mouse. Muscle Nerve. 2012; 47(2):260-70. PMC: 3556223. DOI: 10.1002/mus.23522. View

20.

Piccoli T, Castro F, La Bella V, Meraviglia S, Di Simone M, Salemi G . Role of the immune system in amyotrophic lateral sclerosis. Analysis of the natural killer cells and other circulating lymphocytes in a cohort of ALS patients. BMC Neurol. 2023; 23(1):222. PMC: 10251617. DOI: 10.1186/s12883-023-03255-x. View