ProMIS Neurosciences announced that it is moving toward selecting antibodies — from the many identified in earlier work — that specifically target the toxic proteins that accumulate in the brains of amyotrophic lateral sclerosis (ALS) and Alzheimer’s patients, and that may work as therapies.
Specifically for ALS, the identified antibodies target TDP43 — the TAR DNA binding protein — that is present in every cell and plays a key role in response to oxidative stress, a chemical reaction that damages cells.
TDP43 also participates in gene expression, the process by which a gene creates a working protein.
Misfolded TDP43 aggregates (or clumps of protein) are unusual in that they migrate from the nucleus to the cytoplasm of nerve cells, where their presence is thought to cause cell death. These toxic TDP43 forms can also propagate neurons, moving from nerve cell to nerve cell.
ProMIS detailed the process it is taking to possibly ALS — targeting the abnormal TDP43 protein — in a June 2017 release. Basically, researchers at ProMIS and University of British Columbia started by identifying the genetic sequence and shape of the TDP43 they would target.
Because TPD43 is necessary for the healthy functioning of cells, they are aiming for a therapy that specifically works against the misfolded protein (called a epitope target), without impacting cells with normal TDP43. (An epitope is the specific portion of a protein that an antibody will bind to, and remove.)
The first stage of work used the company’s discovery platform to select targets and “generate large numbers of candidate antibodies,” Neil Cashman, ProMIS’ chief scientific officer, said in a recent press release.
Now work is shifting to a second stage, where researchers plan to “validate selectivity, functional activity, and select the best leads,” Cashman added.
“We are very pleased with our progress so far in identifying epitopes displayed by the two additional toxic oligomers that are the root cause of these devastating diseases [ALS and Alzheimer’s] and are moving into the validation and selection phase with these targets,” he said.
Previous research has shown that TDP43 protein migration — or leakage — from the nucleus of cells, where it belongs, into the cytoplasm triggered a series of events that produced stress to the cell. Ultimately, it led to serious damage to key cellular components, including the cell’s powerhouse, the mitochondria, and eventually motor neuron cell death.
Studies have also reported that TDP-43 leakage and aggregation could be found in about 95% of all ALS cases.
The company expects to have selected those antibodies it will further develop as possible therapies in “the coming months,” according to the release.