Small Molecule Splicing Modulators For Reducing Aggregatable Prion Protein In Prion Diseases

SUMMARY

First-in-class small molecules to change how the PRNP gene is spliced, reducing harmful prion levels and offering a new treatment approach for prion diseases

The Unmet Need: Safe, effective, and deliverable therapies to reduce prion protein levels in the central nervous system

• Prion diseases, such as Creutzfeldt-Jakob Disease (CJD), are a group of rare, fatal neurodegenerative disorders characterized by the accumulation of misfolded prion proteins in the brain. These diseases progress rapidly and are currently untreatable, leading to severe cognitive decline and ultimately death. The prion protein (PrP), encoded by the PRNP gene, is central to disease pathology, as its misfolded form aggregates and propagates neurotoxicity. Given the devastating impact of prion diseases and the lack of effective therapies, there is a critical need for innovative strategies that can reduce the levels of aggregatable PrP in the brain. Recent research has highlighted that even modest reductions in PrP expression can significantly modify disease progression, making the modulation of PrP levels a promising therapeutic avenue.

• Current approaches to lowering PrP levels have significant limitations. Traditional methods, such as antisense oligonucleotides (ASOs) and RNA interference (RNAi), face challenges related to delivery across the blood-brain barrier, off-target effects, and the need for repeated invasive administration. Additionally, these approaches may not achieve sufficient or sustained reductions in PrP expression to impact disease progression meaningfully. Small molecule drugs that target prion aggregation or stability have also shown limited efficacy and specificity, often failing to prevent disease onset or progression in clinical settings. Thus, there remains a substantial unmet need for safe, effective, and easily deliverable therapies that can specifically and robustly reduce PrP levels in the central nervous system.

The Proposed Solution: Small molecule splicing modulators designed to treat prion diseases

• The faculty inventor developed a first-in-class small molecule splicing modulator designed to treat prion diseases such as Creutzfeldt-Jakob Disease (CJD) by targeting the PRNP gene. The approach involves altering the splicing pattern of the PRNP gene to reduce the expression of the aggregatable prion protein (PrP), which is implicated in neurodegenerative disease progression.

• This solution is differentiated by its precise and novel mechanism of action: it directly modulates the splicing of the PRNP gene rather than broadly suppressing gene expression or targeting downstream effects. Unlike existing splicing modulators developed for other diseases, this technology is the first to specifically target PRNP for prion disease therapy, offering a unique therapeutic strategy for a class of conditions with limited treatment options. The ability to induce a non-aggregatable PrP isoform through the introduction of a cryptic exon is a distinctive feature, providing both specificity and efficacy while minimizing toxicity. The modularity of the approach, demonstrated by the synergistic effects with other splicing enhancers, further sets it apart and supports its potential for clinical translation and patentability.

ADVANTAGES

ADVANTAGES

• First-in-class small molecule splicing modulator specifically targeting the PRNP gene for prion disease treatment

• Reduces expression of aggregatable prion protein (PrP), addressing the root cause of diseases like Creutzfeldt-Jakob Disease (CJD)

• Demonstrates efficacy without observed toxicity at effective doses

APPLICATIONS

• Creutzfeldt-Jakob Disease therapeutics

• Prion disease drug development

• Neurodegenerative disease research tools