Iron Chelators for the Treatment of Adult Neuronal Ceroid Lipofuscinosis

Background & Unmet Need

• Point mutations in cysteine string protein-α (CSPα) cause dominantly inherited adult-onset neuronal ceroid lipofuscinosis (ANCL), a rapidly progressing and lethal neurodegenerative disease
• There are currently no disease-specific treatments approved for ANCL
• ANCL mutations are proposed to trigger CSPα aggregation, but the mechanism of oligomer formation remains unclear
• Unmet Need: Novel therapeutic approaches that target CSPα to prevent disease progression

Technology Overview

• The Technology: Use of iron chelators to disrupt CSPα aggregation for the treatment of ANCL
• The Discovery: The normally palmitoylated cysteine string region of CSPα loses palmitoylation in ANCL mutants, enabling oligomerization via ectopic binding of iron-sulfur (Fe-S) clusters
• Pharmacological iron chelation with deferiprone (L1) and deferoxamine (Dfx) mitigates the oligomerization of mutant CSPα
• Iron chelation also led to partial rescue of downstream SNARE defects and the pathological hallmark of lipofuscin accumulation

Technology Applications

• Treatment of ANCL symptoms and prevention of disease progression

Technology Advantages

• The iron chelators L1 and Dfx are already approved for the treatment of iron overload, potentially leading to an accelerated development timeline
• L1 efficiently crosses the blood-brain barrier and is orally available
• Potential to be a disease-modifying therapy that slows disease progression, rather than simply treating symptoms