Targeting TDP-43 Protein in Sporadic Amyotrophic Lateral Sclerosis: A Novel Approach Using Oligonucleotide Therapeutics

Background

Amyotrophic lateral sclerosis (ALS) is a progressive and intractable motor neuron disease marked by systemic muscle atrophy and weakness. In over 95% of sporadic and familial ALS cases, cytoplasmic aggregates of the 43-kDa TAR DNA-binding protein (TDP-43) are found in neurons. Mutations in the TARDBP gene, which encodes TDP-43, further highlight its central role in ALS pathogenesis. However, there are currently no efficient therapies that directly target TDP-43. While nucleic acid-based disease-modifying therapies (DMTs) are advancing for familial ALS, developing DMTs for sporadic ALS ‑ the majority of cases ‑ remains profoundly challenging. This is partly due to the essential and tightly regulated functions of TDP-43, an RNA-binding protein involved in RNA splicing. Its suppression causes loss of function, while overexpression leads to toxicity.

Technology Overview

To overcome this, the Institute of Science Tokyo are developing a novel therapeutic approach called “protein-binding (pb) RNA,” designed to modulate TDP-43 aggregation without altering its expression levels.

• Key discovery: The mechanism suppressing TDP-43 protein aggregation lies in its “binding to RNA”.
• Innovative approach: Researchers developed an oligonucleotide, a “pbRNA,” mimicking the role of this binding RNA.
• Precise modulation of TDP-43 oligomerization: The pbRNA effectively modulates the oligomerization of TDP-43 protein, powerfully inhibiting subsequent aggregation.
• Ensured target specificity and avoidance of off-target effects: Through unique chemical modifications, pbRNA significantly minimizes non-specific binding to other intracellular RNA/DNA, achieving high target specificity.
• Optimized intracellular localization: Optimized pbRNA design enables precise localization within the cytoplasm, the primary site of TDP-43 aggregation.
• Engineered for superior stability and persistence: The highly engineered pbRNA features advanced chemical modifications that confer significantly improved stability and high resistance to degradation within the body.

Benefits

• High efficacy: Created a pbRNA that binds to TDP-43 and effectively inhibits its aggregation through optimized RNA sequence and chemical modifications.
• Safety considerations: Ensures efficacy and localization in the cytoplasm while exhibiting low toxicity.
• Promising therapeutic strategy: A drug candidate with the potential to become a completely new treatment for neurodegenerative diseases like ALS by inhibiting protein aggregation.
• Potential first disease-modifying therapy for sporadic ALS.
• As the first oligonucleotide therapeutic targeting the TDP-43 protein, it successfully extended survival, suppressed weight loss, and mitigated motor function decline in an ALS model mouse.
• No concern about off-target effects, such as cleaving sequences similar to the target sequence, which is often a concern with antisense oligonucleotides.

Applications

• A pharmaceutical company developing drugs to treat neurodegenerative disease.
• The global amyotrophic lateral sclerosis (ALS) treatment market was valued at USD 1.01 billion in 2023 and is projected to grow to USD 1.8 billion by 2032, exhibiting a CAGR of 11.3%.