OrPro Therapeutics is targeting the functional mucus abnormalities which link genetic CFTR ion-transport defects to the obstruction, infection and inflammation responsible for most CF morbidity and mortality. Impaired mucus transport and lack of clearance largely precede the onset of these symptoms, making abnormal mucus a potentially disease-modifying target, unlike the viscous DNA associated with purulent airway infections commonly treated symptomatically with inhaled DNase (Pulmozyme®). The first CF treatment to be derived from an airway enzyme1, our development candidate ORP100S is an inhaled protein disulfide reductase that preferentially targets abnormal linkages in CF mucus proteins associated with increased viscosity and stiffness2. In contrast to non-selective mucolytic drugs, ORP100S does not promiscuously attack all mucus bonds. Instead, it relaxes mucus gels without disrupting the polymeric structure essential for normal mucus clearance, and retains activity across a broad airway pH range3. This potency and selectivity, along with the long duration of activity conferred by its stability and target-binding mechanism, gives ORP100S unique properties as a natural mucus modulator4 that sets it apart from other approaches. We anticipate that ORP100S, as a supplement of native thioredoxin activity that may be deficient in CF5, will help CFTR modulators reach the level of lung function improvement required to slow the advance to pulmonary failure, and as a stand-alone drug may have the potential to modify airway disease progression in patients who are not candidates for modulator therapy.
1 Rancourt, R.C., Tai, S., King, M., Heltshe, S.L., Penvari, C., Accurso, F.J., and White, C.W. (2004). Thioredoxin liquefies and decreases the viscoelasticity of cystic fibrosis sputum. Am J Physiol Lung Cell Mol Physiol 286, L931-938
2 Heifetz, P.B., Rancourt, R.C., and Nichols, D. (2014). A novel inhaled mucus normalizing therapy for cystic fibrosis. Pediatric Pulmonology 49, S307
3 Heifetz, P.B., Moskowitz, H., Nichols, D., and Rancourt, R.C. (2015). pH dependency of mucolytic agents: the case for protein-drug mucus normalization. Pediatric Pulmonology 50, S235
4 Falk Libby, E., Fortinberry, H., Birket, S., Moskowitz, H., Hill, D.B., Tearney, G.J., Rowe, S.M., and Heifetz, P.B. (2016). Theradux™, a novel biologic derived from optimized Thioredoxin-1, improves mucociliary transport in situ. Pediatric Pulmonology 51, S292-293
5 Rauniyar, N., Gupta, V., Balch, W.E., and Yates, J.R. (2014). Quantitative Proteomic Profiling Reveals Differentially Regulated Proteins in Cystic Fibrosis Cells. Journal of Proteome Research 13, 4668-4675