Nearly all ALS cases are characterized by the formation of toxic aggregates (clumps) containing the TDP-43 protein. These clumps appear to affect the normal function of mitochondria (cells’ “powerhouses”) and to be associated with nerve cell death in several neurodegenerative diseases, including ALS, frontotemporal dementia and Alzheimer’s disease.
TDP-43 clumps are considered to be involved in a common mechanism of neurodegeneration and may hold potential as biomarkers of these diseases, as well as responses to treatment.
However, TDP-43 detection is “currently limited to post-mortem tissues and therefore cannot be accurately measured or monitored in living subjects, limiting the ability to use it as a biomarker for ALS and other neurodegenerative diseases,” Kuldip Dave, PhD, the ALS Association’s vice president of research, said in a press release.
“As TDP-43 [clumps] is a hallmark in most cases of ALS, developing reliable assays [tests] to measure TDP-43 or [disease-associated] species of TDP-43 in biofluids is a priority and will be of great value to the ALS community and other scientific investigators,” said Robert Bowser, MD, lead investigator of both projects and director of the ALS Research Center at the Barrow Neurological Institute, in Arizona.
This precompetitive initiative between academic researchers, industry partners, and nonprofit foundations is an extension of the Target ALS Innovation Ecosystem, which so far has promoted more than 150 research collaborations, leading to four new therapies currently in clinical trials.
The first project will focus on the development of reliable immunoassay-based tests within the Meso Scale Discovery (MSD) platform to detect different forms of TDP-43 in the blood and cerebrospinal fluid (CSF, the fluid inside the spine) of ALS patients.
These tests involve two types of specific proteins called antibodies: those that bind to the target protein (capture antibody) and those that bind to the first antibody and can be used to measure the levels of the target protein (detection antibody).
In the first part of the project, purified TDP-43 protein will be collected from human cells grown in the lab and from brain tissue samples from patients with or without known TDP-43-associated disease.
Then, distinct combinations of capture and detection antibodies — provided by commercial, academic, and industry partners — will be tested to identify the optimal pair of antibodies that recognize different forms of TDP-43 in ALS patients, when compared to healthy people, and ultimately to appropriate disease controls.
The second project, conducted by Caprion Biosciences, in Montreal, Canada, will use a different technique — called mass spectrometry — to identify, measure, and determine the chemical properties of different TDP-43 forms present in ALS patients with TDP-43 clumps.
The patients’ blood, CSF, and brain and spinal cord tissues will be analyzed to determine what forms of TDP-43 are present in their biofluids (blood and CSF).
The project is expected to shed light on the different disease-associated forms of TDP-43 present in the biofluids of ALS patients. This information will be used not only in the first project to help develop new tests for relevant forms of the protein, but also to help create new TDP-43-based animal models and new ways to detect these forms in images of the brain.
The results and tests generated from both projects will be made available to the research community to support the development of TDP-43-based biomarkers for ALS and other neurodegenerative diseases.
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