Nonclinical safety assessment of SPX-101, a novel peptide promoter of epithelial sodium channel internalization for the treatment of cystic fibrosis

Walker, Matthew P.; Cowlen, Matt; Christensen, Dale J.; Miyamoto, Mutsumi; Barley, Phillip; Crowder, Timothy

doi:10.1080/08958378.2017.1366602

Cited by 11 publications

(5 citation statements)

References 11 publications

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“…For instance, the P2Y 2 receptor agonist denufosol failed to show replicable results in phase III clinical trials [52], and to the best of our knowledge, there are, at the moment, no chemical compounds in clinical trials that target purine metabolism. Third, compounds associated with SPLUNC1, while in the early stages of clinical tests, have been producing positive results [27,53,54]; correspondingly, we focused on the relationships between ENaC, ASL, SPLUNC1 and PI(4,5)P 2 . Fourth, our results indicate that the components used in our model are sufficient to capture the phenomena of interest here.…”

Section: Discussionmentioning

confidence: 99%

Thickness of the airway surface liquid layer in the lung is affected in cystic fibrosis by compromised synergistic regulation of the ENaC ion channel

Olivença

Fonseca

Voit

et al. 2019

J. R. Soc. Interface.

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The lung epithelium is lined with a layer of airway surface liquid (ASL) that is crucial for healthy lung function. ASL thickness is controlled by two ion channels: epithelium sodium channel (ENaC) and cystic fibrosis (CF) transmembrane conductance regulator (CFTR). Here, we present a minimal mathematical model of ENaC, CFTR and ASL regulation that sheds light on the control of ENaC by the short palate lung and nasal epithelial clone 1 (SPLUNC1) protein and by phosphatidylinositol 4,5-biphosphate (PI(4,5)P 2 ). The model, despite its simplicity, yields a good fit to experimental observations and is an effective tool for exploring the interplay between ENaC, CFTR and ASL. Steady-state data and dynamic information constrain the model's parameters without ambiguities. Testing the hypothesis that PI(4,5)P 2 protects ENaC from ubiquitination suggests that this protection does not improve the model results and that the control of the ENaC opening probability by PI(4,5)P 2 is sufficient to explain all available data. The model analysis further demonstrates that ASL at the steady state is sensitive to small changes in PI(4,5)P 2 abundance, particularly in CF conditions, which suggests that manipulation of phosphoinositide metabolism may promote therapeutic benefits for CF patients.

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Section: Discussionmentioning

confidence: 99%

Thickness of the airway surface liquid layer in the lung is affected in cystic fibrosis by compromised synergistic regulation of the ENaC ion channel

Olivença

Fonseca

Voit

et al. 2019

J. R. Soc. Interface.

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“…Administration of SPX-101 to neonatal transgenic mice overexpressing the β-subunit of ENaC (one of the most widely used models of CF lung disease) improved survival from roughly 45% to 92% at the most efficacious dose. Importantly, safety data in murine and canine models did not demonstrate any adverse events, even in doses up to the maximum feasible dose [73]. At therapeutically meaningful doses, SPX-101 did not produce hyperkalemia, alter body weight, urinalysis measures, or blood chemistry, as peptide delivery to the lung offers some tissue specificity.…”

Section: Enac Inhibitors In Developmentmentioning

confidence: 99%

The epithelial sodium channel (ENaC) as a therapeutic target for cystic fibrosis

Shei

Peabody

Kaza

et al. 2018

Current Opinion in Pharmacology

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Cystic fibrosis (CF) is a monogenic disease caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. CFTR dysfunction is characterized by abnormal mucociliary transport due to a dehydrated airway surface liquid (ASL) and hyperviscous mucus, among other pathologies of host defense. ASL depletion is caused by the absence of CFTR medicated chloride secretion along with continued activity of the epithelial sodium channel (ENaC) activity, which can also be affected by CFTR mediated anion conductance. Therefore, ENaC has been proposed as a therapeutic target to ameliorate ASL dehydration and improve mucus transport. Inhibition of ENaC has been shown to restore ASL hydration and enhance mucociliary transport in induced models of CF lung disease. To date, no therapy inhibiting ENaC has successfully translated to clinical efficacy, in part due to concerns regarding off-target effects, systemic exposure, durability of effect, and adverse effects. Recent efforts have been made to develop novel, rationally designed therapeutics to produce specific, long-lasting inhibition of ENaC activity in the airways while simultaneously minimizing off target fluid transport effects, systemic exposure and side effects. Such approaches comprise next-generation small molecule direct inhibitors, indirect channel-activating protease inhibitors, synthetic peptide analogs, and oligonucleotide-based therapies. These novel therapeutics represent an exciting step forward in the development of ENaC-directed therapies for CF.

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“…This is because these small molecule inhibitors of ENaC enter the systemic circulation where they engage ENaC in the kidney thereby inducing potassium-sparing diuresis. Nebulized SPX-101 was tested in toxicology trials in rats and dogs and found to have no impact on serum potassium concentrations and was rapidly removed from systemic circulation [18,39]. Moreover, in clinical trials in healthy volunteers and adult patients with cystic fibrosis SPX-101 was not associated with any relevant changes in serum or urinary potassium (manuscripts in preparation).…”

Section: Discussionmentioning

confidence: 99%

SPX-101 is stable in and retains function after exposure to cystic fibrosis sputum

Sesma

Stuhlmiller

et al. 2019

Journal of Cystic Fibrosis

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Nonclinical safety assessment of SPX-101, a novel peptide promoter of epithelial sodium channel internalization for the treatment of cystic fibrosis

Cited by 11 publications

References 11 publications

Thickness of the airway surface liquid layer in the lung is affected in cystic fibrosis by compromised synergistic regulation of the ENaC ion channel

Thickness of the airway surface liquid layer in the lung is affected in cystic fibrosis by compromised synergistic regulation of the ENaC ion channel

The epithelial sodium channel (ENaC) as a therapeutic target for cystic fibrosis

SPX-101 is stable in and retains function after exposure to cystic fibrosis sputum

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