The University of Laval in Quebec City Canada recently published preclinical work in the Journal of Clinical Investigation evidencing a research potential direction for Amyotrophic Lateral Sclerosis (ALS) treatment. A rare neurological condition, it impacts the nerve cells (neurons) responsible for controlling voluntary muscle movement. TrialSite News recently learned of this initiative via Einav Keet’s article in the Rare Disease Report. ®
What is Amyotrophic Lateral Sclerosis (ALS)?
A rare neurological condition, cases progress rapidly; motor neurons degenerate and die and stop sending messages to muscles. Consequently, they weaken, and atrophy sets in. Symptoms include muscle twitching and weakness in the arms, hands, legs and swallowing muscles. As the disease progresses, patients have difficulty swallowing and even speaking. Ultimately patients can die from respiratory failure within 3 to 5 years of onset. Approximately 10% of patients go on to live for 10 or more years. Presently no ALS cures exists—nor is there a treatment to slow its’ progression. Researchers are looking into potential treatments such as trazodone.
5,000 new patients diagnosed each year in the United States. The incidence is two per 100,000 people and it is estimated that there are 20,000 living with ALS at any given time.
What is TDP-43 Protein?
TAR DNA-binding protein 43 (TDP-43, transactive response DNA binding protein 43 kDa), is a protein that in humans is encoded by the TARDBP gene. TDP-43 was recently identified as the major pathological protein in sporadic ALS and in the most common pathological subtype of FTD, frontotemporal lobar degeneration with ubiquitinated inclusions (FLTD-U). In these conditions, abnormal C-terminal fragments of TDP-43 are ubiquitinated, hyperphosphorylated and accumulate as cellular inclusions in neurons and glia. Cells with inclusions show absence of the normal nuclear TDP-43 localization. Recently, missense mutations in the gene encoding TDP-43 have been identified in patients with sporadic and familial ALS.
University of Laval Research
Keet’s recent article noted researchers recently developed an antibody targeting the TDB-43 protein. This protein was found to be overexpressed in the spinal cords of people with ALS—in the brains of mice with ALS as well. As Rare Disease Report noted TDP-43 aggregates in nerve cells and contributes to exaggerated inflammatory responses thereby increasing neurons’ vulnerability. University of Laval investigators developed the TDP-43-targeting antibodies—they inserted genetic material encoding the antibody into the viruses. For two months thereafter, they gave them to mice that had developed TDP-43 aggregates. Notably, mice that received the antibodies exhibited promising improvements in both cognitive and motor performance. Rare Disease Report interviewed principal investigator Jean-Pierre Julie who noted “The mice were analyzed for pathological changes. The treatment ameliorated pathological defects including the preservation of neuromuscular junctions. So, in principle and providing that antibodies are present in the appropriate motor neurons, there should be amelioration of deficits,” said Julien. “However, we did not monitor respiratory function in the mice and phrenic motor neurons following the treatment in the mice.”