Oral Small Molecule Splicing Platform - PTC pioneered small molecule splicing therapies, with Evrysdi approved in over 100 countries and votoplam in development for Huntington's disease[21] - Small molecules enhance U1 interaction, increasing exon inclusion to generate distinct mRNA transcripts and modulate protein expression, exemplified by votoplam (PTC518)[22, 25, 29, 30] - PTC's PTSeek screening technology, leveraging learnings from SMA and HD programs, enables the discovery of novel sequence-selective 5' splice site enhancers for iExons[48, 96, 98] - PTC has discovered iExons throughout the entire transcriptome, covering a majority of genes, allowing for the targeting of splicing for novel small molecule enhancers[89, 90, 91] Splicing Platform Programs - MSH3 program targets nucleotide repeat disorders like Huntington's disease, with 30-50% MSH3 lowering stalling expansion in a human somatic expansion model[111, 129] - Spinocerebellar Ataxia 3 (SCA3) program aims to lower mutant ATXN3 protein production by inducing exon skipping[132, 141, 142] - Oncology program targets a key protein in cancer biology, with novel splicing modulators selectively inducing mRNA decay[147, 152] - Hemoglobinopathies program targets regulators of fetal hemoglobin (HbF) levels, with novel splicing modulators lowering a validated target of HbF induction[158, 163, 165] Inflammation & Ferroptosis Platform - PTC's inflammation and ferroptosis platform targets specialized enzyme hubs to regulate inflammation, energy production, and oxidative stress[179] - Parkinson's Disease program targets 15-LO to prevent ferroptosis-mediated cell death and alpha-synuclein aggregation[181, 183, 188] - PTC612, a highly selective NLRP3 inhibitor, demonstrates significant reduction in inflammatory cytokines and pathology across multiple preclinical models, with an IC50 of 099 nM in THP-1 cells[225, 227, 234]