Dewpoint’s TDP-43-targeted ALS therapy gains further support
Target ALS Foundation grant will let company test c-mod in preclinical studies
Dewpoint Therapeutics has won a second grant from Target ALS Foundation to advance preclinical studies of its experimental TDP-43-targeted therapy for amyotrophic lateral sclerosis (ALS).
TDP-43 is a protein that often gets mislocalized within cells in ALS and forms into toxic clumps that contribute to neurodegeneration. Dewpoint’s treatment candidate is designed to move early, nontoxic TDP-43 aggregates, called condensates, back to their normal location, preventing toxic clumps from forming.
“This alliance will accelerate the path to the clinic for Dewpoint’s revolutionary [TDP-43 condensate-modifying compound], which we believe holds great promise for patients,” Isaac Klein, MD PhD, Dewpoint’s chief scientific officer, said in a company press release.
“Target ALS is thrilled to have the opportunity to help advance Dewpoint’s mission to deliver a novel, effective treatment to ALS patients,” said Amy Easton, PhD, senior director of scientific programs at Target ALS.
The second in-kind grant, this one provided in collaboration with Biospective, will let Dewpoint test its candidate in a mouse model of slow-progressing ALS that mimics TDP-43 mislocalization, neurodegeneration, and motor deficits in ALS patients.
Validating this model will complement Dewpoint’s ongoing preclinical research in a different ALS mouse model associated with the most common genetic cause of ALS. That model was supported by a previous in-kind grant from Target ALS.
Targeting the TDP-43 protein
ALS is marked by the progressive death of motor neurons that control voluntary movement. While its cause remains largely unknown, a range of underlying mechanisms have been identified, involving alterations in specific genes and modifications in protein function.
Treating ALS consists mainly of medications to manage specific symptoms and therapies that target disease-specific mechanisms. An urgent need for more effective therapies remains, however.
Dewpoint Therapeutics’ approach targets a feature in more than 97% of ALS cases: the mislocalization of the TDP-43 protein. The protein usually resides inside the cell’s nucleus, where DNA is housed and where the protein exerts its function, but TDP-43 erroneously relocates outside the nucleus in most ALS cases.
When it’s outside its usual location, TDP-43 cannot work normally and clumps with other proteins, forming intermediate structures known as condensates. Over time, these condensates undergo modifications that transform them into toxic clumps. The lack of working TDP-43 in the nucleus and the accumulation of toxic TDP-43 aggregates outside it are thought to contribute to neurodegeneration.
Dewpoint’s lead TDP-43 condensate-modifying compound (c-mod) was selected from a battery of small molecules that were able to move mislocalized TDP-43 back into the nucleus. By addressing this “condensatopathy,” the therapy should help slow the disease’s progression.
“Their molecule will be one of the first to test a central hypothesis regarding the role of TDP-43 in motor neuron degeneration and may have the potential to treat both sporadic and familial forms of ALS,” Easton said.
Preclinical data presented by the company this month showed TDP-43 c-mod effectively lowers the number of TDP-43 condensates outside the cell nucleus and restores TDP-43 function in lab-grown patient-derived motor neurons. The molecule also lowered toxic TDP-43 clumps in a mouse model of ALS and was shown to rescue neuroinflammation and neurodegeneration markers in a mouse model of traumatic brain injury.
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