**6. Future trends in modeling ALS and discovering new therapies**

The recent remarkable advancement in the cell biology field that adult fibroblasts can be re‐ programmed to virtually originate all cell types have created a unique opportunity to model neurological disorders *in vitro*. iPS technology has already been applied to several neurode‐ generative conditions, from Alzheimer's disease [93] to Down syndrome [94], as well schizo‐ phrenia [80], Rett syndrome [95] and ALS [14].

Although a large number of iPS cell lines from patients affected by various diseases have been made commercially available, it is still not clear how robustly these recapitulate the characteristics specific of each disease. Although the promises of iPS technology are to lead to high-throughput screenings to find new efficacious therapeutic targets, they are subject to some main limitations that have already been addressed in other sections of this book chap‐ ter. It is, therefore, of paramount importance that the properties of the differentiated cells are well characterized and it is verified that they are representative of the disease they are modeling.

However, some promising results have been obtained from a very recent study suggesting that iPS-derived motor neurons originated from patients carrying TDP-43 mutations display abnormalities typical of TDP-43 proteinopathy. These cells display elevated levels of soluble and detergent-resistant TDP-43 protein, decreased survival, and increased vulnerability to inhibition of phosphatidylinositol 3-kinase (PI3K) pathway [78] as well as shorter neurites and TDP-43 cytoplasmic aggregates [82]. These parameters can be used as readout for highthroughput drug screenings as well as short hairpin RNA (shRNA) library screenings. In‐ deed, Egawa and colleagues performed microarray analysis on iPS-derived motor neurons transduced with lentivirus expressing green fluorescent protein (GFP) under the control of the HB9 promoter. Based on the results obtained from gene expression analysis, the authors tested 4 drugs known to modulate transcription through histone modification and RNA splicing. Using the high content imaging analyzer InCell 6000, Egawa and colleagues found that anacardic acid had protective effects against arsenite-induced motor neuron death and was able to decrease TDP-43 cytoplasmic aggregates as well as increase neurite length [82].

A different approach was taken in 2011 by Haidet-Phillips and colleagues [15], producing cells from patients without the use of viral vectors or induction of major epigenetic modi‐ fications. In this study, astrocytes were derived from NPCs isolated from ALS patients and it was observed that, regardless of their familial or sporadic origin, these cells were toxic to wild type murine motor neurons expressing GFP under HB9 promoter [15]. The authors found that SOD1 knockout via shRNA could rescue motor neurons at different extents depending on whether these were co-cultured on astrocytes from familial or sporadic cases. This study overcomes some of the major issues related to iPS cells and sets the premises for drug and shRNA screening to target pathways and single genes in‐ volved in astrocyte toxicity.

Concluding, it is clear that in the past five years the ALS field has seen a major change of scenario, where more tools are available to study more forms of FALS as well as the striking majority of SALS. As the recent genetic discoveries have highlighted the importance of pre‐ viously unexplored pathways, i.e. RNA metabolism, also common targets linking sporadic and familial ALS have been identified, i.e. TDP-43 and SOD-1. Moreover, the advances in highthroughput screening technology with the advent of new gene profiling techniques, i.e. deep-sequencing, and high content imaging systems are bound to determine the beginning of a new era for ALS research.
