Dewpoint’s new drug candidate targets ALS protein clumps
Novel small molecule shown to restore TDP-43 function in early studies
- Dewpoint developed a drug candidate for ALS.
- It targets abnormal TDP-43 protein clumps that cause nerve cell death.
- Preclinical studies show it restores TDP-43 function; human trials are next.
Dewpoint Therapeutics has selected a novel small molecule designed to prevent the formation of abnormal TDP-43 protein clumps that drive nerve cell death in amyotrophic lateral sclerosis (ALS) and other related conditions.
The candidate is specifically designed to target condensates, or membrane-less structures that concentrate specific molecules to facilitate certain biochemical processes.
In ALS and other diseases, the TDP-43 protein is abnormally included in condensates in the cytoplasm, the liquid that fills the inside of cells. This prevents the protein from exerting its normal functions in the nucleus, where DNA is housed. These condensates are intermediate, reversible structures, but they can progress to irreversible protein clumps that are toxic to nerve cells.
Dewpoint’s candidate condensate-modifying drug is designed to disassemble TDP-43 condensates and prevent their formation, allowing the protein to return to the nucleus and resume its normal function.
“This announcement reflects more than a single program milestone, it validates an emerging therapeutic approach and modality we are pursuing at Dewpoint,” Ameet Nathwani, MD, CEO of Dewpoint, said in a company press release.
Candidate’s selection based on promising preclinical data
The selection was based on extensive preclinical data showing the molecule restored TDP-43 location and function in cell models and reduced markers of neurodegeneration in animal models.
The company is now planning to advance into late-stage preclinical studies that are expected to support a future investigational new drug application, which is a formal request to the U.S. Food and Drug Administration to test the candidate in human trials.
“This development candidate represents the first time anyone has achieved full restoration of TDP-43 function in preclinical models by directly correcting the pathologic condensates that underlie ALS. We believe this approach has the potential to deliver disease-modifying outcomes for patients,” said Isaac Klein, MD, PhD, chief scientific officer of Dewpoint.
TDP-43 protein clumps — a hallmark of ALS — are present in nerve cells in about 97% of all ALS patients. They are also seen in several other neurodegenerative diseases, such as frontotemporal dementia, traumatic brain injury, and Alzheimer’s disease.
This development candidate represents the first time anyone has achieved full restoration of TDP-43 function in preclinical models by directly correcting the pathologic condensates that underlie ALS. We believe this approach has the potential to deliver disease-modifying outcomes for patients.
In a poster presented last year at the Target ALS Annual Meeting, Dewpoint demonstrated that its condensate-modifying candidate selectively inhibits the formation of TDP-43 condensates, restores TDP-43 function, and extends the survival of nerve cells derived from ALS patients.
In animal studies, the candidate also reduced abnormal TDP-43 aggregation in mouse models of ALS and lowered levels of neurofilament light chain, a blood biomarker associated with nerve cell death. The molecule also showed potential applicability to other TDP-43-associated disorders, including traumatic brain injury.
“Our condensate biology platform has enabled what has not been possible before: direct, mechanistic restoration of TDP-43 function, one of the most important and historically inaccessible targets in neurodegeneration,” said Nathwani. “Advancing this program underscores our conviction that condensate-modulating therapeutics can redefine what is achievable in neurology.”
About the Author
