Immunosuppressants in the treatment of ALS though modulation of TDP-43
Rapamycin: Rapamycin inhibitor of the Mechanistic Target of Rapamycin (mTOR) is a clinically approved drug prescribed in cancer therapeutics \cite{Apontes2011}, and for the prevention of organ rejection via its immunosuppressant functions ref. Autophagy an important cell process for protein turnover and degradation of aberrant proteins is upregulated by rapamycin (Ref) . Rapamycin also downregulates protein synthesis, inhibits inflammatory responses, and has demonstrated efficacy in animal models of neurodegenerative disorders. Rapamycin was shown in vitro in N2A and SH-SY5Y cells to induce autophagy, decrease TDP-43 aggregates, and correct the mislocalization of TDP-43 from the cytoplamic aggregation to restore it to the nucleus \cite{Caccamo_2009}. The clearance of TDP-43 by autophagy has been demonstrated in murine and in human stem cell-derived neurons and astrocytes with mutant TDP43 \cite{Barmada_2014}.  In addition, it has been reported that rapamycin increases T lymphocytes  and that these increases in these cells is associated with slower disease progression in ALS \cite{Mandrioli2018}
In eight ALS treatment centers in Italy, the rapamycin for ALS trial (RAP-ALS) is being conducted. It is a phase II randomized, double-blind, placebo-controlled, and multicenter trial with patients randomized to one of three groups of (n=21 per group): 1 mg/m2/d rapamycin + riluzole, 2 mg/m2/d rapamycin + riluzole or placebo + riluzole, in addition to mainstay supportive care in accordance with established ALS guidelines (e.g. nutrition, respiratory, motor function, communication) \cite{Mandrioli_2018}. The treatment of ALS with  rapamycin, with the aim of modulation of TDP-43 clearance and correction of cytoplasmic mislocalization of TDP-43, will be an important novel therapeutic approach to follow in the years to come.  The change in baseline of   ALSFRS-R score,  T lymphocytes , 
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Therapeutics that target TDP-43 induced alterations in energy metabolism
Metformin
TDP-43 contributes to misregulation of energy metabolism \cite{Floare2020}.  Although pre-clinical trials in the SOD1(G93A) murine model of ALS initially suggest that metformin may not merit further study in human clinical trials for ALS as a result of the metformin-induced dose-dependent decrease in survival in this model \cite{Kaneb_2011},  in a subsequent study of C9orf72 ALS/FTD BAC mice, metformin was found to significantly improve phenotypes in these mice, such as  brake, brake/stance, and brake/stride, and increased center time by open field, along with decreased glial fibrillary acidic protein (GFAP), a marker of neuroinflammation, prevented motor neuron degeneration of the lumbar spinal cord,  reduction in the number of GA aggregates in the retrosplenial cortex and decrease in levels of soluble GP \cite{Zu_2020}.  
Currently, an open label interventional phase 2 trial of metformin in subjects with C9orf72 positive ALS,  A Single-Center, Open Label Study to Assess the Safety and Tolerability of Metformin in Subjects With C9orf72 Amyotrophic Lateral Sclerosis Over 24 Weeks of Treatment  ( NCT04220021) is underway. It will look at treatment-induced adverse events, change in RAN protein levels in cerebrospinal fluid (CSF)  and  ALSFRS-R score at a starting dose of 500 mg, increased incrementally by 500 mg every week to a maximal dosage of 2000mg in divided doses twice daily.    This study will be quite interesting to follow as the alterations in metabolism in neuropathology is an important feature that lends itself to treatment by the repurposing of diabetic medications for neurodegenerative diseases.