Complement Yourself: Transcomplementation Rescues Partially Folded Mutant Proteins

Overview

Journal Biophys Rev

Publisher Springer

Specialty Biophysics

Date 2014 Jun 21

PMID 24949105

Citations 6

Authors

Liudmila Cebotaru

William B Guggino

Affiliations

Soon will be listed here.

Abstract

Cystic Fibrosis (CF) is an autosomal disease associated with malfunction in fluid and electrolyte transport across several mucosal membranes. The most common mutation in CF is an in-frame three-base pair deletion that removes a phenylalanine at position 508 in the first nucleotide-binding domain of the cystic fibrosis conductance regulator (CFTR) chloride channel. This mutation has been studied extensively and leads to biosynthetic arrest of the protein in the endoplasmic reticulum and severely reduced channel activity. This review discusses a novel method of rescuing ΔF508 with transcomplementation, which occurs when smaller fragments of CFTR containing the wild-type nucleotide binding domain are co-expressed with the ΔF508 deletion mutant. Transcomplementation rescues the processing and channel activity of ΔF508 and reduces its rate of degradation in airway epithelial cells. To apply transcomplementation as a therapy would require that the cDNA encoding the truncated CFTR be delivered to cells. We also discuss a gene therapeutic approach based on delivery of a truncated form of CFTR to airway cells using adeno-associated viral vectors.

Citing Articles

Amelioration of airway and GI disease in G551D-CF ferrets by AAV1 and AAV6.

Ciobanu C, Yanda M, Zeidan A, Izzi J, Guggino W, Cebotaru L Gene Ther. 2024; 31(9-10):499-510.

PMID: 39069560 DOI: 10.1038/s41434-024-00469-7.

Gene therapy for cystic fibrosis: Challenges and prospects.

Sui H, Xu X, Su Y, Gong Z, Yao M, Liu X Front Pharmacol. 2022; 13:1015926.

PMID: 36304167 PMC: 9592762. DOI: 10.3389/fphar.2022.1015926.

Short-Term Steroid Treatment of Rhesus Macaque Increases Transduction.

Yanda M, Tomar V, Cebotaru C, Guggino W, Cebotaru L Hum Gene Ther. 2021; 33(3-4):131-147.

PMID: 34806411 PMC: 8885436. DOI: 10.1089/hum.2021.239.

Transduction of Surface and Basal Cells in Rhesus Macaque Lung Following Repeat Dosing with AAV1CFTR.

Guggino W, Yanda M, Cebotaru C, Cebotaru L Hum Gene Ther. 2020; 31(17-18):1010-1023.

PMID: 32862701 PMC: 7495919. DOI: 10.1089/hum.2020.207.

Restoration of F508-del Function by Transcomplementation: The Partners Meet in the Endoplasmic Reticulum.

Bergbower E, Sabirzhanova I, Boinot C, Guggino W, Cebotaru L Cell Physiol Biochem. 2019; 52(6):1267-1279.

PMID: 31026390 PMC: 7097968. DOI: 10.33594/000000089.

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