# TDP-43 aggregation modulator

> A small molecule that engages the disordered low-complexity domain of TDP-43 to hold it in soluble states and interrupt the aggregation seen across ALS and frontotemporal dementia.

[View this page on Peptone](https://peptone.io/pipeline/tdp-43/)

## Program facts

- Target: TDP-43
- Modality: Small molecule
- Indication: TDP-43 proteinopathy in ALS and frontotemporal dementia
- Stage: Lead Optimization

## Target

TDP-43 is an RNA-binding protein with a long intrinsically disordered low-complexity domain. In disease it mislocalises from the nucleus and assembles into cytoplasmic aggregates, a pathology shared across most amyotrophic lateral sclerosis and a large fraction of frontotemporal dementia cases, which makes the disordered domain itself the object of therapeutic design.

## Approach

Peptone profiles the transient contacts within the low-complexity domain that drive phase separation and aggregation, then designs binders that favour soluble, assembly-incompetent states while preserving the protein's normal RNA-processing role.

## Preclinical

Biophysical and cellular assays confirm target engagement and read out reduced aggregation, guiding selection of a chemical series. Disease biology and mechanism-of-action studies are advanced with Prof. Leonard Petrucelli at Mayo Clinic.

## Development Plan

The program is in lead optimization, where the chemical series is being refined using collaboration-backed proteinopathy models ahead of candidate selection.

Peptone's TDP-43 program is advanced with Mayo Clinic and Prof. Leonard
Petrucelli. See Partnering and Collaborations on the pipeline page for detail.