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Amyotrophic Lateral Sclerosis "ALS" Diagnosis

Dr Emily Feneberg, University of Oxford; Prof. Martin Turner, University of Oxford; Prof. Kevin Talbot, University of Oxford; Dr Elizabeth Gray, University of Oxford; Prof. Olaf Ansorge, University of Oxford; Philip Charles, University of Oxford; Dr Roman Fischer, University of Oxford

Oxford University Innovation


Amyotrophic Lateral Sclerosis (ALS) is a fatal motor neuron disease with an incidence of 2 per 100,000 people annually. The pathogenesis of ALS involves nuclear clearance of TDP-43 in neurons and glia, with cytoplasmic inclusions of post-translationally modified and truncated C-terminal TDP-43 fragments. Attempts using commercially available TDP-43 antibodies to diagnose ALS has been unsuccessful due to their non-specificity against other proteins, the incapability to differentiate different truncated forms of TDP-43, and the low level of pathological TDP-43 isoforms in biofluids. Hence, a reliable measurement of disease-specific TDP-43 in biopsy samples and/or accessible biofluids is an unmet need for definitive diagnosis of ALS.


TDP-43 proteinopathy and ALS

TDP-43 proteinopathy is the neuropathological hallmark in 97% of ALS which is an untreatable neurodegenerative disease and is challenging to diagnose pre-symptomatically. In the case of ALS evidence implies that TDP-43 is the core pathogenic pathway of the disease hence a reliable detection of which would have fundamental roles in diagnosis, stratification, and as a pharmacodynamic biomarker. The neuropathological characteristics of TDP-43 proteinopathy in ALS include nuclear to cytoplasmic mislocalization, post-translational modifications such as ubiquitination and phosphorylation, aggregation and importantly N-Terminal truncation of TDP-43 resulting in smaller C-terminal TDP-43 fragments.

Problem(s) addressed

ALS is primarily diagnosed based on detailed history of the symptoms and signs observed by a physician during physical examination along with a series of tests over a period of time to rule out other mimicking diseases, causing a big burden to the health care system. There are attempts using antibodies against TDP-43 and its phosphorylated form to measure pathological TDP-43 by ELISA, however the results have been contradicting because of the lower amounts of pathological TDP-43 present in a complex matrix such as biofluids, and more importantly the commercially available TDP-43 antibodies are non-specific and bind other proteins such as immunoglobulins. Specific antibodies that selectively bind different isoforms of brain-derived TDP-43 and/or a definitive diagnostic test are not available in the current clinical setting. A sensitive and reliable assay for pathological TDP-43, which has been designated one of the top priorities for facilitating therapeutic advances in ALS and FTD. It will also be important in any future personalized medicine approach to AD therapy.

Oxford's Solution

To address the above problem, researchers from the University of Oxford have developed a technology for absolute quantification of TDP-43 and its truncated isoforms by an antibody-independent technique. By determining the ratio between specific C- and N-Terminal TDP-43 peptides, which has been found specifically increase in ALS, discrimination of ALS from other neurodegenerative diseases becomes possible. Patients will be benefit from the definitive diagnosis and better management of the disease, that will subsequently reduce the burden of our health care system.

Commercial Opportunity

A patent application has been filed for the invention; the technology is available for licensing.

Development Status

Further studies indicated that the pathological peptides can be detected in body fluid samples such as CSF, more samples are being tested and will be available in 2021.

Patent Situation

A patent application has been filed for the invention; the technology is available for licensing.

Further Reading


Amyotrophic Lateral Sclerosis "ALS" Diagnosis