New TDP-43-targeting antibodies may open a path for ALS treatment
Approach aims to spare healthy TDP-43 while targeting harmful clumps
- New antibodies selectively target abnormal TDP-43 protein clumps linked to ALS.
- In preclinical tests, they reduced the spread of TDP-43 clumps between cells
- The approach shows early promise for ALS and other neurodegenerative diseases.
Mindwalk Holdings has identified and validated antibodies that selectively target an abnormal form of the TDP-43 protein, which is found in about 97% of amyotrophic lateral sclerosis (ALS) cases and is also linked to other neurodegenerative diseases.
The candidates include antibodies that could potentially be given as a treatment, as well as intracellular antibodies, or intrabodies. These intrabodies are delivered using gene therapy, allowing cells to produce the antibodies from within and target harmful protein structures inside the cell.
Using its patented HYFT technology and LensAI platform, which use artificial intelligence to analyze large datasets, the company says it can identify promising parts of a protein to target and design new treatment candidates.
New tools target misfolded TDP-43 while sparing the healthy form
The new antibodies and intrabodies were designed to target misfolded TDP-43, the abnormal form that can clump inside cells in ALS and other neurological diseases, while sparing the healthy form of TDP-43.
“This discovery validates our platform strategy,” Jennifer Bath, president and CEO of Mindwalk, said in a company press release. “We are identifying disease-defining protein states and translating that insight into selective, validated assets with traceable biological evidence behind them.”
Using cellular models and patient-derived tissue samples, the company said it validated that the antibodies selectively bind abnormal TDP-43. In lab tests, some of the antibodies and intrabodies also reduced cell-to-cell transmission and inhibited “seeding,” a process that can trigger more abnormal clumps to form.
Results were shared in the preprint, “Rational Generation of Monoclonal Antibodies and Intrabodies Selective for Pathogenic TDP-43,” available in bioRxiv.
The results have not yet been peer-reviewed and should be interpreted with caution. Still, the researchers said the data provide proof-of-concept evidence that selectively targeting misfolded TDP-43 could be a potentially safe and effective strategy for ALS and other diseases.
Why TDP-43 clumps matter in ALS
Abnormal TDP-43 protein clumps are found in about 97% of ALS cases and are thought to contribute to nerve cell damage. Because of that, researchers see misfolded TDP-43 as a promising treatment target, though it remains unknown whether targeting it can slow disease in people.
TDP-43 clumps have also been reported in some cases of Alzheimer’s disease and in frontotemporal dementia, so researchers are also exploring whether targeting abnormal TDP-43 could help in other neurological diseases.
TDP-43 also plays important roles in healthy cells. That means any treatment would need to target the harmful form without disrupting the normal protein, a challenge that has made this approach difficult to pursue.
Mindwalk’s new monoclonal antibodies and intrabodies are designed to target a region of TDP-43 that is exposed only when the protein misfolds, but not when it is properly folded.
In a series of laboratory experiments, researchers showed the candidates could recognize misfolded TDP-43 in preclinical models. The antibodies selectively targeted TDP-43 clumps, not the normal form, in cell models and patient-derived tissue samples.
Early lab tests suggest antibodies may slow TDP-43 spread between cells
Researchers say there is evidence that misfolded TDP-43 may spread from one nerve cell to another, encouraging normal TDP-43 to misfold and potentially contributing to damage as disease progresses.
In laboratory experiments, the antibodies appeared to reduce the movement of TDP-43 clumps between cells and limit “seeding,” a process in which abnormal TDP-43 can trigger healthy TDP-43 to misfold and form new clumps.
Intrabodies also recognized TDP-43 clumps and accelerated their breakdown in cellular models.
Overall, the researchers wrote their findings “provide proof-of-concept evidence” supporting selective targeting of “misfolded toxic aggregates of TDP-43” as a potentially safe and effective treatment avenue for neurodegenerative diseases linked to TDP-43.
About the Author
