Italian Scientist Using $20K Grant to Research TDP-43 Antibody Therapy

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by Yedida Y Bogachkov PhD |

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An Italian scientist was awarded $20,000 for research that may help pave the way for a TDP-43 antibody-based treatment for amyotrophic lateral sclerosis (ALS).

The annual Paulo Gontijo Award from the Brazilian Paulo Gontijo Institute was granted to Silvia Tozzi, PhD, for her research, titled “Monoclonal full-length antibody against TAR DNA binding protein 43 reduces related proteinopathy in neurons.” Tozzi, of the Cervo Brain Research Centre at Laval University, in Quebec, Canada, and her colleagues published earlier findings in the journal JCI Insights in 2020.

Tozzi’s research focuses on both ALS and frontotemporal dementia or FTD — a rare disorder that results from damage to neurons in the frontal and temporal lobes of the brain — due to their shared TDP-43-related disease mechanisms. In about 97% of all ALS patients and half of those with FTD, the TDP-43 protein acquires an abnormal shape and disrupts normal cellular function.

Antibody-based approaches have been emerging as effective and feasible interventions for various neurodegenerative diseases, including ALS. In this study, Tozzi and her colleagues focused on developing an antibody against the protein TDP-43.

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TDP-43 is usually located in the nucleus, where it helps regulate messenger RNA (mRNA), the intermediate molecule generated from DNA that serves as a template for protein production.

However, as a result of certain genetic mutations in ALS and FTD, TDP-43 acquires an abnormal shape that makes it more prone to accumulate outside the nucleus and form toxic clumps that are damaging to cells. These clumps are able to spread from one nerve cell to another, causing progressive loss of nerve cell function.

“For this reason, we produced and tested the target specificity, in vivo [in the body] distribution, and therapeutic efficacy of a monoclonal full-length antibody generated against the protein TDP-43,” Tozzi said in a press release.

Tozzi’s antibody was designed to target the abnormal TDP-43 protein located in the cytoplasm, while leaving the normal functioning TDP-43 proteins in the nucleus unharmed. Her team demonstrated that this antibody was not only specific to the cytoplasmic protein, it also activated a number of degradation mechanisms that reduced TDP-43 toxic clumps.

Importantly, the team investigated multiple ways for potentially giving patients this antibody therapy in the future. These included intranasal (via the nose) administration, into-the-vein (intravenous) infusion, into-the-spinal-canal (intrathecal) injection, and an injection directly into a brain structure called the ventricle. The last two routes were determined to be the best ways to  deliver the antibody to motor neuron cells — the cells that are damaged in ALS.

“We demonstrated the ability of the antibody to specifically target the pathological protein in the cytoplasm of the cells,” Tozzi said. “We injected the antibody in TDP-43 mutant mice and showed that it was able to reduce the levels of this protein by activating degradative pathways inside the cell.”

The award was presented at the Annual International Symposium on ALS and Motor Neuron Diseases (MND), which ran online late last year.

The Paulo Gontijo Award has been granted since 2007 to young researchers whose work focuses on identifying the cause and possible cures for ALS. The theses nominated for the award are rigorously judged by a panel composed of internationally recognized researchers in the scientific and medical community, according to the Brazilian Institute.

Mamede de Carvalho, MD, PhD, chairman of the judging panel for the award, noted that Tozzi’s study may open doors to research into alternative treatments and therapies for ALS patients.