We appreciate the discussion of hopes and difficulties with gene therapy for Amyotrophic lateral sclerosis (ALS) in the excellent review by Scarrott et al. Citation[1]. The authors point out the molecular and economic problems resulting from a wide variety of genes and mutations in ALS, which necessitate multiple allele-specific constructs. Although non-allele-specific ablation of the endogenous superoxide dismutase-1 (SOD-1) by anti-sense oligonucleotide delivered into the cerebrospinal fluid has a current potential in SOD-1 related disease, gene therapy for the majority of patients with sporadic disease appears to be a hope for the future.
However, sporadic ALS is accompanied by strong inflammation in the affected spinal cord resulting from misfolded proteins, such as fibrillar SOD-1. This inflammation is mediated by macrophages and T and possibly B cells that damage motor neurons by cytokines and phagocytize damaged apoptotic and non-apoptotic neurons Citation[2]. Sporadic patients are heterogeneous, as there are subgroups with different type of inflammation, including Th1, Th17 and B cell type (Fiala and Pellegrini, submitted for publication 2015). Two patients with strong evidence of Th1 inflammatory activation were treated using the antibody to IL-6 receptor α called tocilizumab (Actemra) with strong biochemical and immune effects and apparent slowing of the disease progression Citation[3]. The pre-clinical studies of tocilizumab will culminate in a clinical trial of Actemra that is scheduled to start this year in four centers in USA. Thus, anti-inflammatory therapy as well as gene therapy could together be components of a more effective approach to ALS.
Declaration of interest
The authors state no conflict of interest and have received no payment in preparation of this manuscript.
Bibliography
- Scarrott JM, Herranz-Martin S, Alrafiah AR, et al. Current developments in gene therapy for amyotrophic lateral sclerosis. Expert Opin Biol Ther 2015;1-13
- Fiala M, Chattopadhay M, La Cava A, et al. IL-17A is increased in the serum and in spinal cord CD8 and mast cells of ALS patients. J Neuroinflammation 2010;7:76-90
- Fiala M, Mizwicki MT, Weitzman R, et al. Tocilizumab infusion therapy normalizes inflammation in sporadic ALS patients. Am J Neurodegener Dis 2013;2:129-39