Antibody Decreases TDP-43 Protein Accumulation Easing ALS Symptoms, Mouse Study Suggests

A potential therapy for amyotrophic lateral sclerosis (ALS) consisting of an antibody that reduces the abnormal accumulation of the TDP-43 protein improved cognitive and motor performance in mice, a study shows.

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

ALS is a neurodegenerative disease that causes the death of motor neurons — which are responsible for muscle activity — leading to progressive loss of movement and muscle degeneration.

Many ALS patients have excessive amounts of the transitive response DNA/RNA-binding protein 43 kDa (TDP-43), which stabilizes the RNA in the nerve cells. In ALS, the surplus of TDP-43 accumulates in the cells causing excessive inflammation and making the neurons more vulnerable.

The researchers developed an antibody that specifically binds to a part of the TDP-43 protein called the RRM1 domain, marking it for degradation. They inserted the DNA sequence with the instruction to produce the antibody into a virus that was injected into mice producing excessive TDP-43 and showing symptoms similar to those of ALS.

“We subsequently observed a reduction in the number of aggregates of this protein,” Jean-Pierre Julien, PhD, principal investigator and professor at the Université Laval’ Faculty of Medicine in Quebec, said in a press release. “We also found a decrease in the immune response (inflammation) and a significant improvement in the mice’s cognitive and motor performance.”

The authors also reported that the mice showed no adverse response to the antibody.

These preliminary results pave the way for the development of immunotherapies — therapies based on the natural immune mechanisms that specifically target molecules causing disease — that provide new methods of treating ALS and other conditions involving TDP-43 accumulation such as some forms of frontotemporal dementia.

Therapies based on antibodies have become popular because they are easily applied to different tissues and usually are well-tolerated.

“We are now trying to develop an approach that would not require the use of viruses,” Julien said. “Preliminary results suggest that injecting TDP-43 antibodies directly into the cerebrospinal fluid (a liquid found in the brain a spinal cord) could effectively reduce protein aggregates in nerve cells.”