ALS, Alzheimer’s and other diseases driven by TDP-43 pathology

ALS and Alzheimer’s Disease: Devastating diseases with few meaningful treatment options

Amyotrophic Lateral Sclerosis (ALS) and Alzheimer’s Disease (AD) are two of the most prevalent and devastating neurodegenerative diseases. Despite years of research, both remain largely untreatable, with available therapies offering only modest symptomatic relief—and no meaningful impact on disease progression for most patients.

• ALS is a rapidly progressive, fatal disease that causes degeneration of motor neurons in the brain and spinal cord, leading to muscle weakness, paralysis, and death. It affects 2–6 in 100,000 people globally. Most patients are diagnosed in their 40s to 60s, with a median survival time of just 2–5 years. Roughly 90% of ALS cases are sporadic, with no known genetic cause, and over 95% show accumulation of TDP-43 protein in neurons.
• Alzheimer’s Disease is the most common cause of dementia, affecting over 55 million people worldwide. While some anti-amyloid therapies have recently been approved, their effect is modest and limited to specific patient populations. A growing body of research has identified TDP-43 pathology in up to 50% of AD cases, where it contributes to neurodegeneration independent of amyloid and tau.

In both diseases, TDP-43 mislocalisation from the nucleus to the cytoplasm has emerged as a key pathological event—one that is not addressed by any currently approved therapy.

TDP-43 mislocalisation is a unifying driver of neurodegeneration — yet remains unaddressed

TDP-43 is a DNA/RNA-binding protein essential for healthy neuronal function. In over 95% of ALS cases and a significant subset of Alzheimer’s disease (AD) cases, TDP-43 mislocalises from the nucleus to the cytoplasm, where it forms aggregates. This shift drives cellular dysfunction by both toxic gain-of-function (aggregate formation) and loss-of-function (nuclear depletion), ultimately leading to neurodegeneration.

Yet, there are currently no approved therapies that address the root cause of this pathology.

Harness is targeting the restoration of TDP-43 function through nuclear remobilisation

Our second lead program focuses on upregulating a nuclear import receptor, a critical protein capable of relocating misfolded TDP-43 from the cytoplasm back to the nucleus—restoring its native function and preventing downstream toxicity.

This innovative approach offers several advantages:

• First-in-class target inaccessible to traditional gene or protein replacement therapies
• Intervenes upstream, remobilising TDP-43 rather than attempting to compensate for its loss downstream.
• Mechanism-driven restoration of TDP-43 function, avoiding the loss-of-function risks associated with degradation-based approaches.
• Broad potential impact across sporadic ALS and TDP-43-positive Alzheimer’s, which together represent a substantial proportion of all neurodegenerative disease

Please contact us for further information about our TDP-43Programme.