Small molecule inhibitors that block accumulation of ALS-associated RNA-binding proteins (RBPs) such as TDP-43 from accumulating in stress granules in the brain of ALS/FTD patients may be clinically beneficial in treating these and other incurable neuropathological conditions \cite{Fang2019}. For example, in a diverse screen of small molecule libraries molecules to search for those that could prevent persistent stress granule formation in proliferating cells (HEK293xT, NPCs and in human iPSC-derived motor neurons), Fang et al identified a novel class of small molecules which possess a planar aromatic moiety which modulated the size and number of stress granules. The authors used the PubChem database, from the National Center for Biotechnology Information, to annotate targets for these and other lead small molecules, and found, for example, that the molecules with planar structures were often DNA intercalating molecules ( mitoxantrone, quinacrine, doxorubicin and daunorubicin). Of great importance is that some of the small molecules identified inhibited TDP-43 aggregates in the cytoplasm of ALS derived iPSC motor neurons.
A very interesting high throughput drug discovery screen of 3,850 small molecules tested for efficacy in ALS model organisms having mutant versions of the TDP-43 gene, the transgenic TDP-43 mutant
C.
elegans (
TARDBPA315T)
and zebrafish (
TARDBPG348C) which displayed neuromuscular junction deficits, the amelioration of which was employed as a read-out of drug activity
\cite{Patten_2017}. In ALS muscle fatigue, weakness and neuromuscular conduction clinical deficits are prevalent
\cite{Mulder_1959}\cite{Killian_1994}. Pimozide was identified as the lead small molecule with ability to rescue the motor deficits observed in the ALS model organisms, including synaptic transmission and the correction of the paralysis phenotype and neurodegeneration observed in the TDP-43 mutant
C.
elegans and the aberrant swimming and motor neuron disease phenotypes that characterized the mutant TDP-43 zebrafish
\cite{Patten_2017} . Interestingly, Pimozide is a neuroleptic drug used in the treatment of patients with Tourette syndrome to suppress the occurrence of motor and vocal tics via a mechanism that antagonized dopamine D2 signaling as well as blocking Ca
2+ channel activity
\cite{Patten_2017} . Presently, there is a double blind, phase II clinical trial (clinicaltrials.gov number
NCT03272503 ) underway to test the effects of pimozide in 100 ALS patients randomized to receive 2mg/day (4 mg/day at study initiation) pimozide or placebo for 22 weeks. The primary endpoint will be the ALSFRS-R, while secondary endpoints will be Change in Slow Vital Capacity , Decremental responses on repetitive nerve stimulation, changes in motor power, quality of life, frequency of cramps and adverse events. Reports are not posted at this time, but are anticipated at the end of 2020 when the study is completed.