**7. Future directions**

as well as a more efficient and specific design of therapies by specifically taking into account

Among the drugs mentioned that have been evaluated in pre-clinical models, celecoxib and pioglitazone were both assessed in a randomized, double-blind, placebo-controlled trial, but gave disappointing results as there were no effects on motor function and survival rate [240, 241]. When minocycline was tested in a randomized placebo-controlled phase III trial, it not only did not show any benefits, it in fact displayed serious harmful effect in patients [242]. Thalidomide, an analogue of lenalidomide, which showed therapeutic potential in SOD1 mutant mice, was used in a single arm, open label phase II study. Unfortunately, similar to minocycline, thalidomide led to undesirable side effects, without any positive effects [243]. A pilot trial (double-blind, placebo-controlled, randomized) where G-CSF was administered to ALS patients for over 25 days does however show encouraging results on the prevention of degeneration of several white matter tracts [244]. This study supports a larger scale trial in

The translational therapy of neuroinflammatory and immunomodulatory effectors has thus shown both exciting and disappointing outcomes. There are many factors that could help explain the discrepancy between pre-clinical and clinical evaluations of potential therapies. Firstly, most drugs are typically assessed in the mutant SOD1 animal models. This poses an important caveat, as not only there exists an obvious difference between humans and animals, but SOD1 models also represent hereditary ALS, which account for only 4% of ALS cases. Thus, a drug may show a positive influence on an inherited disease model without having any effect on sporadic cases. There is therefore the risk of wrongly eliminating or pushing forward an ALS treatment due to the lack of diverse familial and sporadic pre-clinical models. Secondly, the exact timing of a specific treatment could also impact its efficiency. Indeed, as described in the present chapters, neuroinflammation consists of dynamic mechanisms, combining over time and space, different cell types with opposing neuroprotective and neurotoxic functions. Thus, depending on the desired target, the therapeutic window of various drugs may differ one from another. Thirdly, while establishing a dosage regimen (concentration of drug and treatment length) is amenable in pre-clinical models, determining the exact dose and duration of a therapy in human patients is somewhat more complex. Further, it remains unclear if the treatment of ALS patients should take place daily for several months or periodically in pulses. It thus becomes imperative to develop new analytical methods to adequately extract from preclinical studies the equivalent doses for humans as well as the optimal treatment protocol. Finally, in light of the high heterogeneity of ALS forms, it is possible that not all patients will respond equally to a particular therapy. Therefore, all of these parameters, including addi‐ tional ones not mentioned herein, have to be thoroughly considered and analyzed to ensure

When dealing with neuroinflammation in ALS, the therapeutic intervention is of a different kind than the previous major clinical trials. It is not compulsorily a matter of influencing the disease process, that is the motoneuron death itself, but a matter of stopping a potential amplification and/or diffusion phenomenon. In animal models, this strategy has given

which the immunomodulatory aspect of G-CSF should be further explored.

that we do not wrongly disregard or promote a drug.

the clinical heterogeneity of the disease.

118 Current Advances in Amyotrophic Lateral Sclerosis

In the present chapter, we have described the cellular and molecular events characterizing the neuroinflammation in ALS. We have also highlighted the beneficial potential of various therapeutic approaches specifically targeting these neuroinflammatory effectors. While the reports discussed herein support a role for astrocytes, microglia and immune cells in ALS, it remains unclear how they influence disease onset, progression or both. Hence, a thorough investigation of the neuroinflammatory pathways that impact neurodegeneration will ultimately enhance our understanding of how and when to therapeutically modulate this pathological process. Further, it is important to remember that the astrocytosis and microglio‐ sis that typify ALS stem from the chronicity of this neurodegenerative disorder and thus, there is an active communication with the neurotoxic environment that is composed of neurons, glial cells and immune cells. Therefore, it is with caution that we should proceed with defining a causal or consequential role for neuroinflammation in ALS, but instead, our focus should be on identifying its exact pathological contribution.
