Dewpoint wins grant to develop its condensate-modifying therapies

C-mods are small molecules to target TDP-43 condensates thought to drive ALS

Margarida Maia, PhD avatar

by Margarida Maia, PhD |

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Dewpoint Therapeutics has received a grant from the Target ALS Foundation to advance the development of small molecules called c-mods, which will target the TDP-43 condensates thought to drive most cases of amyotrophic lateral sclerosis (ALS).

Condensates are borderless compartments in cells that can cause cellular processes to go awry, leading to a so-called condensatopathy. In ALS, TDP-43 condensates are linked to multiple markers of disease.

“Receiving the Target ALS grant is a tremendous honor and a significant validation for Dewpoint’s novel, therapeutic approach to target condensatopathies,” Ameet Nathwani, MD, Dewpoint’s CEO, said in a company press release.

“This grant will propel our research efforts and accelerate the development of our ALS-targeted c-mods towards becoming the first molecules to address the underlying pathology [disease mechanism] in most ALS patients,” Nathwani said.

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Grant to support proof-of-concept study using mouse model of ALS

The in-kind grant, awarded in collaboration with the ALS Association and The Jackson Laboratory, will support an in vivo proof-of-concept study of the company’s c-mods in a mouse model of ALS.

The TDP-43 protein normally resides in the nucleus, the cells’ control center that harbors most of the genetic material. In ALS, however, TDP-43 moves outside the nucleus and clumps into toxic condensates that prevent nerve cells from working properly, causing symptoms.

“Cellular mislocalization [incorrect or faulty localization] and aggregation of TDP-43 is the pathological hallmark of 97% of ALS cases, however, no marketed drugs target TDP-43 directly,” said Amy Easton, PhD, Target ALS Foundation’s senior director of scientific programs.

Dewpoint identified small molecules that can move mislocalized TDP-43 back into the nucleus. These small molecules, which the company dubbed c-mods (from condensate-modifying drugs), are expected to rescue damage to nerve cells and ease symptoms.

In cell models of ALS, the company has demonstrated c-mods can reverse some of the cellular changes induced by the aberrant TDP-43 protein clumps, including alterations in gene activity and stress-induced damage.

With support from the grant, Dewpoint will now test whether c-mods can similarly ease disease processes in a mouse model of ALS. This model carries a repeat expansion of a short DNA sequence in the C9orf72 gene, the most common genetic mutation in familial and sporadic ALS.

“Dewpoint’s research proposal, reviewed by the Target ALS Independent Review Committee, included a high-quality preliminary data package, sufficient to trigger in vivo studies in a disease model,” Easton said.

“Dewpoint’s study is one of the first to test whether reducing TDP-43 condensates is beneficial in the context of a C9orf72 repeat expansion, the most common genetic cause of ALS,” Easton added.

The company also recently filed multiple patent applications to cover c-mods and their use in ALS and other TDP-43-mediated conditions. Over the next few years, it is expected to produce multiple additional c-mods to target a number of other conditions, according to another company press release.