ALS research has focused on TDP-43, a protein present in the neuropathology of approximately 97% of all ALS patients. First identified as the predominant protein in ALS neuropathologic inclusions roughly 20 years ago, TDP-43 has since been established as a major regulator of RNA metabolism. At ALS Nexus, a dedicated session brought together leading experts to break down what TDP-43 is and why it may be key to making ALS livable.
Robert Bowser, PhD, is Chief Scientific Officer, Professor, and Chair of the Department of Translational Neuroscience at Barrow Neurological Institute in Phoenix, Arizona. He was among the speakers at ALS Nexus presenting on TDP-43 and the basics behind its biology. Bowser’s research is focused on biomarker discovery and disease mechanisms in ALS and other neurodegenerative diseases.
TDP-43 Mechanism and Rationale
Bowser explained that TDP-43 was initially identified as an RNA/DNA-binding protein relevant in how viruses hijack RNA processing events in cells. It was later found to be a major player in RNA metabolism, involved in the splicing, assembly, and location of messenger RNAs within cells. The loss of function of TDP-43 in the nucleus drives a cascade of downstream consequences that contribute to motor neuron death.
The development of TDP-43-targeted agents is exciting, with several companies developing small molecules to break up TDP-43 aggregates and eliminate toxic species. Other approaches include using antibodies or nanobodies to target pathologic species of TDP-43, and gene therapy to deliver nanobodies directly into cells. Bowser noted that CRISPR approaches are also being explored to gene edit and fix mutations in individuals with genetic alterations of the TDP-43 gene.
Bowser discussed the biggest unanswered questions about TDP-43, including the development of biomarkers related to its loss of function. Several groups have identified cryptic peptides that are produced when TDP-43 loss of function occurs, which could serve as biomarkers in clinical trials. However, more work is needed to develop improved assays to detect these peptides in biofluids.
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Future of TDP-43-Targeted Therapies
He envisions combination therapies that target TDP-43, as well as other mechanisms that contribute to the onset and progression of ALS. TDP-43 pathology also exists in other neurodegenerative diseases, such as Alzheimer’s disease, Parkinson’s disease, and frontotemporal dementia, making it a promising target for therapies that could benefit multiple diseases.
Bowser noted that the outlook for using TDP-43-targeted therapies in combination or sequenced with other targets for ALS is promising. He sees combination therapies as the main route for treating ALS more effectively, and believes that biomarkers will play a significant role in identifying the best approaches for individual patients. The development of biomarkers related to TDP-43 loss of function, such as cryptic peptides, will add another layer of input into clinical trials, allowing for more informed decisions about which therapies to pursue.
As biomarker development matures, Bowser expects that clinical trials will evolve to incorporate multiple biomarkers that target different mechanisms of action. This will enable researchers to quickly identify which therapies are effective and which are not, allowing for more efficient drug development and better outcomes for patients. The goal is to enable patients to participate in multiple trials, increasing their chances of receiving effective treatments.
The use of neurofilament light chain as a biomarker has already shown promise, and Bowser believes that the development of additional biomarkers, such as those related to TDP-43 loss of function, will further enhance clinical trial design. By incorporating multiple biomarkers and targeting different mechanisms of action, researchers can develop more effective treatments for ALS and improve patient outcomes. According to Bowser, the development of TDP-43-targeted therapies is a major component of combination approaches moving forward, and will likely play a key role in the treatment of ALS in the years to come, with TDP-43 being a primary target for therapy development.
Implications for Future Research
The development of TDP-43-targeted therapies has significant implications for future research in ALS and other neurodegenerative diseases. As TDP-43 pathology exists in several other diseases, including Alzheimer’s disease, Parkinson’s disease, and frontotemporal dementia, therapies developed for TDP-43 in ALS patients may have broader applications. Researchers are eager to explore the potential of TDP-43-targeted therapies in these diseases, with the hope of developing treatments that can benefit multiple patient populations.