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<a href="http://dewpointx.com">Dewpoint Therapeutics</a> has received a grant from the <a href="https://www.targetals.org/">Target ALS Foundation</a> to advance the development of small molecules called c-mods, which will target the TDP-43 condensates thought to drive most cases of <a href="https://alsnewstoday.com/what-is-als/">amyotrophic lateral sclerosis</a> (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 <a href="https://www.globenewswire.com/news-release/2024/01/16/2809938/0/en/Dewpoint-Therapeutics-Awarded-Target-ALS-Grant-for-Development-of-C-mods-for-ALS.html">company press release</a>.
“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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<h3>Grant to support proof-of-concept study using mouse model of ALS</h3>
The in-kind grant, awarded in collaboration with the <a href="https://www.als.org">ALS Association</a> and <a href="https://www.jax.org/">The Jackson Laboratory</a>, 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 <a href="https://alsnewstoday.com/symptoms-of-als/">symptoms</a>.
“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 <a href="https://www.frontiersin.org/articles/10.3389/fmolb.2022.1007744/full">dubbed c-mods</a> (from condensate-modifying drugs), are expected to rescue damage to nerve cells and ease symptoms.
In cell models of ALS, the company has demonstrated <a href="https://dewpointx.com/modulation-of-tdp-43-condensates-rescues-als-ftd-disease-phenotypes-in-multi-stressor-paradigms-presented-at-icgeb-conference-on-tdp-43-function-and-dysfunction-in-disease/">c-mods can reverse some of the cellular changes</a> 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 <a href="https://alsnewstoday.com/forms-of-als-familial-als/">familial</a> and <a href="https://alsnewstoday.com/sporadic-als/">sporadic ALS</a>.
“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 <a href="https://alsnewstoday.com/causes-of-als/#Genetics_of_ALS">genetic cause of ALS</a>,” 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 <a href="https://www.globenewswire.com/news-release/2024/01/07/2805015/0/en/Dewpoint-Therapeutics-Filed-Multiple-Patent-Applications-with-the-US-Patent-Office-on-Novel-Composition-of-Matter-for-the-Treatment-of-ALS.html">press release</a>.

Tag: small molecules

Dewpoint wins grant to develop its condensate-modifying therapies