Experimental ALS Therapy Uses Antibodies to Target TDP-43 protein

A new study details the work of a research team from the Université Laval in Québec City, Canada, on a new therapeutic approach for amyotrophic lateral sclerosis (ALS).

ALS is a rare neurological condition that mainly involves the nerve cells, or neurons, responsible for controlling voluntary muscle movement. Cases of ALS progress rapidly and as motor neurons degenerate and die, they stop sending messages to muscles, which then gradually weaken and atrophy. Early symptoms include muscle twitching and weakness in the arms, hands, legs, and swallowing muscles, and later progress into difficulties moving, swallowing, and speaking.

Patients with ALS typically die of respiratory failure within 3 to 5 years of onset, though about 10% of ALS patients go on to live for 10 or more years. There are 2 new cases of ALS each year per 100,000 people, and worldwide, ALS affects white males ages 60 years and older more than any other group.

There is currently no cure for ALS or any treatment that halts or reverse the progression of the disease, though research continues into potential new therapies, such as trazodone. In the recent study published in The Journal of Clinical Investigation investigators detail research on an antibody they developed to target the TDP-43 protein—which the team had previously found is overexpressed in the spinal cords of people with ALS—in the brains of mice with ALS. The development of TDP-43 aggregates in nerve cells leads to an exaggerated inflammatory response that increases neurons’ vulnerability.

The investigators produced the TDP-43-targeting antibodies by inserting genetic material encoding the antibody into viruses, and for 2 months gave them to mice that had developed TDP-43 aggregates. The mice receiving the antibodies showed significant improvements in their cognitive and motor performance.

In an interview with Rare Disease Report®, principal investigator Jean-Pierre Julien, PhD, described the team’s findings. “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.”

The investigative team is currently working on a way to create the antibodies that doesn’t use viruses. “The alternative to viral-mediated transfer of small single chain antibody is to use full length antibodies against TDP-43,” explained Julien. “We have preliminary data, unpublished yet, suggesting that antibodies can penetrate motor neurons when injected chronically intrathecally in mice. Work is in progress in my lab to test this approach in a mouse model of ALS. Intrathecal administration of antibodies with a mini-pump would be a suitable approach for ALS patients.”

If full length antibodies injected intrathecally succeeds in mitigating TDP-43 pathology, said Julien, the next step will be to humanize the antibody and to test it in model systems. “If all does well, it will take about 3 years before initial testing in human ALS patients.”

The study, “Viral-mediated delivery of antibody targeting TAR DNA—binding protein 43 mitigates associated neuropathology,” was published in The Journal of Clinical Investigation.