Therapeutic Strategies Under Development Targeting Inflammatory Mechanisms in Amyotrophic Lateral Sclerosis

Abstract

Amyotrophic lateral sclerosis (ALS) is a neurological disease characterized by the progressive loss of cortical, bulbar, and spinal motor neurons (MNs). The cardinal manifestation of ALS is a progressive paralysis which leads to death within a time span of 3 to 5 years after disease onset. Despite similar final output of neuronal death, the underlying pathogenic causes are various and no common cause of neuronal damage has been identified to date. Inflammation-mediated neuronal injury is increasingly recognized as a major factor that promotes disease progression and amplifies the MN death-inducing processes. The neuroimmune activation is not only a physiological reaction to cell-autonomous death but is an active component of nonautonomous cell death. Such injury-perpetuating phenomenon is now proved to be a common mechanism in many human disorders characterized by progressive neurodegeneration. Therefore, it represents an interesting therapeutic target. To date, no single cell population has been proved to play a major role. The existing evidence points to a complex cross talk between resident immune cells and nonresident cells, like monocytes and T lymphocytes, and to a dysregulation in cytokine profile and in phenotype commitment. After a summary of the most important mechanisms involved in the inflammatory reaction in ALS, this review will focus on novel therapeutic tools that rely on tackling inflammation to improve motor function and survival. Herein, completed, ongoing, or planned clinical trials, which aim to modify the rapidly fatal course of this disease, are discussed. Anti-inflammatory compounds that are currently undergoing preclinical study and novel suitable molecular targets are also mentioned.

Toward in vivo determination of peripheral nervous system immune activity in amyotrophic lateral sclerosis

“…Finally, a larger sample of human SOD1 mutation carriers could aid to prove our theory. With additional evidence, our simple procedure may help to identify patients with ALS with a constellation of peripheral nerve immunity, permitting them to be selectively enrolled into therapeutic trials targeting PNS inflammation …”

“…It could be of pivotal importance for the development of new therapies to selectively stratify patients in vivo who display certain pathobiologies—such as immune activation—that are, in turn, likely to respond to specific therapeutic agents . In fact, not all patients with ALS manifest a strong inflammatory component; underpowered trials with insufficient differentiation of that possibly rather small patient group may thus account for the modest effects of immune‐modulating drugs in ALS . To this end, simple measures that can specifically identify those patients with disease‐related suspected immune activation are desirable.…”

Ibudilast attenuates doxorubicin‐induced cytotoxicity by suppressing formation of TRPC3 channel and NADPH oxidase 2 protein complexes

“…Our findings also suggest that the pathology‐specific interaction between TRPC3 and Nox2 could be a general mechanism underlying wasting in a range of tissues. Indeed, ibudilast has pleiotropic effects on amyotrophic lateral sclerosis and multiple sclerosis (Crisafulli, Brajkovic, Cipolat Mis, Parente, & Corti, ; Fox et al, ). Further studies will elucidate the involvement of TRPC3‐Nox2 complexes in these intractable diseases and allow us to propose the inhibition of TRPC3‐Nox2 complex as an innovative therapeutic strategy for their prevention and treatment.…”

CNS inflammation and neurodegeneration

“…There is evidence for both central and peripheral immune system activation in ALS. In early disease, there is evidence of homeostatic microglia and Treg infiltration, while in later disease stages, M1 microglia and activated astrocytes predominate (157). Tregs themselves are defective in ALS (99,100).…”

“…It failed two earlier trials in people with all stages of ALS. Other immune-directed strategies currently under investigation include ibudilast, anti-IL-6 (tocilizumab), and IL-1 receptor antagonist (anakinra) therapies (157). We have found that both microglia and peripheral monocytes have an inflammatory phenotype in the SOD model and in ALS and that targeting miR-155 ameliorates disease in this model (91); targeting of miR-155 is now being evaluated in clinical trials.…”