Review (6-8 sections clinical trials, what has been done, what drugs are available, types of diseases, therapeutic options) (fig 2)

Introduction to therapeutic modulators of TDP-43 

Therapeutic options remain very limited for the many neurodegenerative disease, especially the motor neuron disease amyotrophic lateral sclerosis (ALS), a fatal neurodegenerative disorder that occurs most often in late middle life. Classic ALS leads to progressive death of motor neurons in the cerebral motor cortex and spinal cord, and the gradual loss of respiratory ability, muscle paralysis and atrophy. Treatment consists of supportive care for respiratory difficulties, symptom relief and nutritional support. ALS often culminates in death within 2-5 years of clinical presentation, although there exist variants that have a slower progression and better prognosis. ⁠ There are currently only two FDA-approved medications for ALS, riluzole, an anti-glutamatergic compound and edaravone, an antioxidant, which only provide modest benefit in some patients \cite{Jaiswal_2018}.
New therapeutic options are therefore of very urgently needed for ALS spectrum of disorders as well as for the many other devastating neurological conditions, many of which exhibit TDP-43 pathology. 

Pre-clinical and clinical studies based on pharmacological modulation of TDP-43  

On June 20, 2020, we conducted a search on Clinical Trials.gov (https://clinicaltrials.gov) for clinical trials for patients with ALS based upon the modulation of TDP-43 ALS. We searched under the Other terms field for "TDP-43", which yielded 692 Studies. We then applied the following filters to limit studies to those that were further along in clinical development stages, to phase 2, 3, and 4 trials. Limiting studies to the terms TDP-43, Active, not recruiting, Completed, Unknown status Studies, Studies With Results and Phase 2, 3 or 4 yielded 39 studies. We will describe the results of those studies. In addition, a Pubmed Central Search  of TDP-43 with the filters Clinical Trial, Meta-Analysis and Randomized Controlled Trial yielded 19 results.

Tamoxifen Treatment in Patients With Motor Neuron Disease

Tamoxifen has been reported to decrease TDP-43 aggregates in animal models of ALS via tamoxifen-induced autophagy \cite{Wang_2013}. In a small clinical trial, eighteen ALS patients without mutations in superoxide dismutase-1 (SOD-1) or fused in sarcoma (FUS) gene,  were randomized to receive either 40 mg/day tamoxifen or placebo, with all participants receiving riluzole twice daily for a period of 1, 3 or 12 months \cite{Chen_2020}.  The primary end-points of time to death or need for mechanical ventilation, was not statistically different between the tamoxifen vs placebo group at any of the time points. However, at a 1, 3 and 6 month evaluation, one of the two secondary end points, ALSFRS-R score, but not forced vital capacity (FVC), decreased less in the tamoxifen group, while there were no statistically significant differences of any end point observed at 12 months. The authors conclude that larger studies would be required to confirm the modest, although transient, improvement in ALSFRS-R scores in the tamoxifen-treated group and to determine whether enhanced autophagy to decrease TDP-43 results in clinical improvement of ALS, particularly if administered at the earliest stages of the disease.

Perampanel (FYCOMPA), a selective non-competitive AMPA receptor antagonist

Downreguation of adenosine deaminase acting on RNA 2 (ADAR2) occurs in sporadic ALS (sALS) \cite{Kawahara_2004} . ADAR2 is an RNA adenosine-to-inosine  (A-to-I) mRNA editing enzyme. Modifying mRNA adenosine to inosine (translated into guanosine), results in new protein isoforms, and it is a dynamic process which diversifies the proteome \cite{Rosenthal2012}. The influx of Ca2+ through  α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptors  is regulated by ADAR2 A-to-I editing. However, in sALS, ADAR2 is deficient and the majority of patients with sALS have a GluA2 subunit of the glutamate AMPA receptor that is unedited \cite{Kawahara_2004}. The outcome of this loss of glutamate AMPA editing is that Ca2+ permeability is elevated, and this has been associated with TDP-43 pathology and glutamate-induced excitotoxicity in motor neurons. Perampanel is a non-competitive, selective antagonist of the AMPA receptor and is approved in the treatment of seizures. In mice in which the AMPA receptor is knocked out in motor neurons to model sALS, perampanel greatly attenuates neuopathology, decreased motor neuron death and prevented the TDP-43 mislocalization from the nucleus to the cytoplasm \cite{Akamatsu2016}. Currently, there is an ongoing phase 2 clinical trial of perampanel,   Perampanel for Sporadic Amyotrophic Lateral Sclerosis (ALS): A Multicenter, Randomized, Double-blind, Placebo-controlled, Parallel-group Phase 2 Trials,  (ClinicalTrials.gov Identifier NCT0301941) consisting of placebo, 4mg and 8mg per day for 48 weeks and the primary endpoint of change in ALS functional rating scale.   The results are currently unavailable \cite{Aizawa2019}