Development of a Splicing Modulator for the treatment of Creutzfeldt-Jakob Disease
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PROJECT SUMMARY Creutzfeldt-Jakob Disease (CJD) is a rapidly progressive and invariably fatal neurodegenerative disorder caused by misfolding and aggregation of the prion protein (PrP). CJD remains untreatable, with no FDA-approved therapies capable of modifying disease progression. Robust preclinical evidence demonstrates that therapeutic reduction of cellular PrP, encoded by the PRNP gene, can extend survival and delay disease onset in animal models. However, current approaches, such as antisense oligonucleotides and gene editing, require intrathecal administration and are still in early development. There remains a critical unmet need for an effective, non- invasive therapeutic strategy. We propose to enter the Discovery Phase of the NIH Blueprint Neurotherapeutics (BPN) program to develop first-in-class, orally bioavailable small-molecule modulators of PRNP RNA splicing. Our lead compound, CP3, acts via a novel molecular glue mechanism that promotes inclusion of a cryptic “poison” exon in PRNP pre- mRNA, leading to nonsense-mediated decay and substantial reduction in PrP levels. CP3 reduces PrP protein by ~70% in human cells with a favorable toxicity profile and readily crosses the blood-brain barrier. Preliminary pharmacokinetics and structure-activity relationship (SAR) studies support further lead optimization. During the UG3 phase, we will validate in vivo activity of CP3 and analogs using a transgenic mouse model expressing the full-length human PRNP gene and perform targeted SAR and pharmacokinetics profiling to identify preliminary leads. The UH3 phase will focus on refining drug-like properties through expanded medicinal chemistry, evaluating long-term PrP suppression, and testing survival benefit in prion-infected mice challenged with various human prion strains. This project will establish a new class of small-molecule splicing modulators for prion disease and serve as a broadly applicable platform for RNA-targeted drug discovery, particularly for neurodegenerative diseases involving prion-like protein dysfunctions. 1
