Recombinant Intrabodies as Potential Therapeutics for Amyotrophic Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS) is a rapidly progressive motor neuron disease, invariably fatal and lacking effective treatments. Aggregates of hyper-phosphorylated TAR DNA-binding protein 43 (TDP-43) are present in the cytosol of affected motor neurons of almost all ALS patients and is considered as a hallmark of the disease. Several cellular and in vivo models of TDP-43 proteinopathy have shown a correlation between the presence of cytosolic TDP-43 aggregates and alterations in calcium homeostasis, bioenergetics, and neural transmission. The use of cellular models of TDP-43 proteinopathy allows searching for alterations in oxygen consumption, calcium signaling, and electrophysiological parameters. Besides, identifying compounds capable of rescuing cellular pathological markers of TDP-43 pathology will contribute for the development of novel drugs to treat ALS. In this sense, it is hypothesized that the removal of the cytoplasmic TDP-43 protein from motor neurons of ALS patients by anti-TDP-43 intrabodies could provide a revolutionary treatment for this untreatable fatal disease.