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Gene Therapy and Small Molecules Used in the Treatment of Cystic Fibrosis
Published in Yashwant Pathak, Gene Delivery, 2022
Manish P. Patel, Uma G. Daryai, Mansi N. Athalye, Praful D. Bharadia, Jayvadan Patel
Since the CFTR gene mutation causes hyperactivation of the epithelial sodium channel (ENaC), the absorption of Na+ ions is enhanced and the lung airway mucus becomes dehydrated. Hence, the inhibition of ENaC expression could serve as a promising therapeutic approach for the treatment of cystic fibrosis. One method for the inhibiting the expression of ENaC-encoding genes (SCNN1A, SCNN1B, SCNN1G, and SCNN1D encoding α, β, γ, and δ ENaC subunits, respectively) involves the use of a single strand nucleic acid known as antisense oligonucleotide (ASO) (Almughem et al., 2020). When this oligonucleotide is hybridized to mRNA, RNase H is triggered to slice the hybridized mRNA. Targeting the α-subunit of ENaC in the respiratory organ, using ASO might inhibit the cationic channel activity (Almughem et al., 2020). Another study showed the possibility of using aerosolized ENaC antisense oligonucleotide containing wing modifications to inhibit ENaC mRNA in CF-like mice models (Hajj and Whitehead, 2017). This aerosolized ENaC antisense oligonucleotide helped to cure various cystic fibrosis symptoms, like airway hyper-responsiveness and inflammation (Crosby et al., 2017).
Genetic Basis of Blood Pressure and Hypertension
Published in Giuseppe Mancia, Guido Grassi, Konstantinos P. Tsioufis, Anna F. Dominiczak, Enrico Agabiti Rosei, Manual of Hypertension of the European Society of Hypertension, 2019
Sandosh Padmanabhan, Alisha Aman, Anna F. Dominiczak
Na+ reabsorption is controlled by mineralocorticoid active steroid hormones in both the distal convoluted tubule and the collecting duct (Figure 7.1). The amiloride-sensitive epithelial Na+ channel (ENaC; SCNN1A, SCNN1B, SCNN1G, SCNN1D) is found predominantly in principal cells of the collecting duct and the thiazide-sensitive sodium chloride cotransporter (NCC; SLC12A3) in the distal convoluted tubule. In addition, basolateral sodium-potassium adenosine triphosphate (ATP1A1-3, ATP1B1-4) and the luminal renal outer medulla K+ channel (ROMK; KCNJ1) are responsible for Na+ and K+ homeostasis. Aldosterone binds to the cytosolic mineralocorticoid receptor (MR; NR3C2) and leads to increased activity of the apical Na+ transporter, ENaC. Deoxycorticosterone and deoxycortisol and their metabolites are alternative agonists of the MR, with cortisol being the most important one. The 11β-hydroxysteroid dehydrogenase type 2 enzyme (HSD11B2), which converts active cortisol to the inactive cortisone, protects the MR from cortisol, an alternative agonist of the MR, thus establishing the aldosterone specificity of the MR. Additional regulatory elements that are involved include, but are not limited to, WNK (with no lysine) kinases – a family of large serine/threonine protein kinases (WNK1 and WNK4) (52). While WNK1 is widely expressed, WNK4 is expressed primarily in the kidney, localized to tight junctions. WNK4 is responsible for tonic inhibition of the thiazide-sensitive Na+ channel (SLC12A3), while WNK1 is a negative regulator of WNK4. WNK1 also activates NCC (SLC12A3), ENaC (SCNN1A, SCNN1B, SCNN1G, SCNN1D), and inhibits the renal K+ channel ROMK (KCNJ1) (52,53). Under hyperosmotic or hypotonic low-Cl− conditions, WNK isoforms are activated, and subsequently phosphorylate and activate the related protein kinases SPAK (STK39) and OSR1 (OXSR1) (54). SPAK and OSR1 phosphorylate and activate ion cotransporters that include NCC, NKCC1 (SLC12A2) and NKCC2 (SLC12A1), which are targets for the commonly thiazide-diuretic and loop-diuretic drugs, the former being an excellent antihypertensive drug (55).
Clinical and genetic characteristics of the patients with hypertension and hypokalemia carrying a novel SCNN1A mutation
Published in Scandinavian Journal of Clinical and Laboratory Investigation, 2022
Mengzi Chen, Xi Lv, Jiwu Li, Manli Guo, Shaogang Ma
We performed WES combined with Sanger sequencing to identify disease-causing mutations in this Chinese family. After filtering the results based on the frequencies in the HGMD, 1000 Genomes Project and dbSNP databases, we found that the proband carried a compound heterozygous mutation in SCNN1A (a novel heterozygous mutation c.1130T > G, inherited from the father and a previously characterized heterozygous polymorphism c.1987A > G, inherited from the mother) (Figure 1). Mutations in SCNN1A gene of seven family members are shown in Table 5. In II 2, the individual carried the c.1987A > G homozygous mutation. In I 1 and II 1, the genotypes were heterozygous and both individuals carried the c.1130T > G mutation. In I 3, I 4 and III 2, the genotypes were heterozygous and the individuals the c.1987A > G mutation. A comparison of mutant amino acid sequences with normal amino acid sequences of different species is presented in Table 6. The predicted structural changes in the SCNN1A protein are shown in Figure 2.
Fluoride effects on cell viability and ENaC expression in kidney epithelial cells
Published in Toxicology Mechanisms and Methods, 2021
Mariana R. Santesso, Flávia A. Oliveira, Cintia K. Tokuhara, Gabriela S. N. Oliveira, Flávia M. Levy, Lígia S. Antonio, Marília A. R. Buzalaf, Rodrigo C. Oliveira
Gene expression analysis revealed upregulation of the Scnn1a (αENaC) gene in cells treated with 100 or 200 µM NaF for 24 h (p < 0.05) (Figure 2(A)). At a higher concentration (400 µM), NaF downregulated Scnn1a within 48 h of exposure (p < 0.05). The Scnn1b (βENaC) gene was downregulated when cells were exposed to 400 µM NaF for either 24 or 48 h (p < 0.05) (Figure 2(B)). In contrast, the Scnn1g (γENaC) gene was upregulated after exposure to 100 or 200 µM NaF for 24 or 48 h but downregulated in response to 400 µM NaF treatment at both time points (p < 0.05) (Figure 2(C)).
The epithelial sodium channel (ENaC) as a therapeutic target for cystic fibrosis lung disease
Published in Expert Opinion on Therapeutic Targets, 2018
Patrick J. Moore, Robert Tarran
Finally, a number of mutations that lead to increased ENaC activity have been found in patients with atypical CF which are summarized below: Sheridan et al. identified 20 patients out of a cohort of 185 who had elevated sweat chloride concentrations and pulmonary disease without CFTR mutations. It was revealed that two patients contained heterozygous mutations in SCNN1B: one patient exhibited a missense mutation (P26L) while the other patient had a splice mutation and two missense mutations (G294S and E539K). Both P26L and E539K mutants demonstrated decreased activity while G294S mutation increased activity [97]. In a multicenter European study, 30 ENaC mutations were found in 76 patients with atypical CF. In two of the patients sampled, the CF-like disease could be explained by mutations in SCNN1A (F61L and V114I) that lead to an alteration in function [98]. Furthermore, an additional mutation (W293R) in SCNN1A demonstrated a fourfold increase in amiloride-sensitive currents compared to wild type ENaC when expressed in X. laevis oocytes [98]. Similarly, a mutation in the β-ENaC subunit, V348M, was identified which increased ENaC PO by destabilizing the closed channel state [99]. Another study of atypical CF phenotypes detected three missense variants in SCNN1A (R204W, A357T, C641F) and one missense in SCNN1B (R543Q). The authors of this study suggested that these variants that appear at a higher incidence in patients with atypical CF may be responsible for the observed CF-like symptoms [100]. More recently, a mutation in the δ subunit reduced ENaC activity indicating δENaC as a potential genetic CF disease modifier [101]. SPLUNC1 has also been shown to be a potential gene modifier and CF patients who have a polymorphism on the G allele of rs1078761 had decreased SPLUNC1 expression and increased disease severity [102]. Taken together, these data suggest that increased ENaC activity and/or a failure of SPLUNC1 to regulate ENaC might contribute to the development of CF lung disease.