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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
Amplifiers are modulators that increase CFTR expression (Mijnders, Kleizen, and Braakman, 2017). PTI-428 is an amplifier that increases the amount of CFTR mRNA and protein loaded on to the endoplasmic reticulum. The amplifier is usually combined, either with a corrector or potentiator modulator. These modulators play an important role in the treatment of most CFTR class mutations except class I mutation, owing to a premature termination codon mutation that leads to defective protein production. To overcome this drawback, a combination of an aminoglycoside antibiotic, like gentamicin or tobramycin, and PTC124 (Ataluren) is employed (Almughem et al., 2020). A small molecule HDAC7 inhibitor SAHA1 not only amplifies F508del-CFTR expression, but also promotes significant transport of F508del-CFTR to the cell surface by reshaping CFTR’s proteostasis network (Mijnders, Kleizen, and Braakman, 2017).
Current and future CFTR therapeutics
Published in Anthony J. Hickey, Heidi M. Mansour, Inhalation Aerosols, 2019
Marne C. Hagemeijer, Gimano D. Amatngalim, Jeffrey M. Beekman
Ataluren (PTC124, Translarna™) is an oxadiazole of which the chemical structure is depicted in Figure 14.4. The drug is taken as an oral suspension and is metabolized by uridine diphosphate glucuronosyltransferase (UGT) enzymes in the liver into ataluren-O-1β-acyl glucuronide with (i) a tissue half-life of 2–6 hours, (ii) peak plasma levels being reached around 1.5 hours after administration, and (iii) 99.6% bound to plasma proteins (53). Ataluren was initially developed to treat Duchene muscular dystrophy (DMD) (54), for which it has been authorized in the European Union (53), but also seemed to be effective in clinical studies in individuals with CFTR premature termination mutations (55–57). The mechanism of action of Ataluren is not completely understood. It promotes translational read-through by stimulating insertion of near-cognate tRNAs at the premature termination codon with specific codon-anticodon preference for amino acid substitutions, for which direct binding to ribosomes seems to be required (58). The sequence surrounding the premature termination codon also seems to be important for this selection (59).
SCN1A as a therapeutic target for Dravet syndrome
Published in Expert Opinion on Therapeutic Targets, 2023
Ataluren, also known as PTC124, is a drug designed to increase protein expression in patients with nonsense pathogenic variants. A nonsense pathogenic variant is a nucleotide change that results in a ‘stop codon,’ which leads to one of UAA, UAG, or UGA in the mRNA coding sequence. Normally, a stop codon triggers premature termination of translation, and the truncated polypeptide is degraded. However, certain agents, such as aminoglycoside antibiotics, have been shown to promote read-through of nonsense codons, allowing continued translation and ultimately production of a full-length protein product [62]. Gentamicin has been trialed in Duchenne muscular dystrophy and cystic fibrosis due to nonsense pathogenic variants, albeit with limited clinical benefit and concern for side effects such as ototoxicity and nephrotoxicity [63–66].
Emerging medicines to improve the basic defect in cystic fibrosis
Published in Expert Opinion on Emerging Drugs, 2022
Isabelle Fajac, Isabelle Sermet-Gaudelus
The best-characterized drugs active against PTCs are aminoglycoside antibiotics, including gentamicin [66]. In short clinical studies, no aminoglycoside studied restored enough functional CFTR protein to allow a prolonged clinical benefit [67,68]. Moreover, their strong oto- and nephrotoxicity prevent their long-term use in patients. Ataluren is a readthrough agent which failed to show in vivo efficacy on respiratory function in phase 3 trials in CF [69]. ELX-02[6’-(R)-Methyl-5-O-(5-amino-5,6-dideoxy-α-L-talofuranosyl)-paromamine sulfate], previously referred to as NB124, is an aminoglycoside derivative with decreased toxicity that has been evaluated in vitro with two frequent PTCs: G542X [70] and W1282X [71] and three rare PTCs: W679X, Q250X, and R1162X [71]. ELX-02 is currently being investigated in phase 2 trials in patients with CF (NCT04135495, NCT04126473). Several other readthrough molecules are in preclinical stage development (Table 1).
Developing DMD therapeutics: a review of the effectiveness of small molecules, stop-codon readthrough, dystrophin gene replacement, and exon-skipping therapies
Published in Expert Opinion on Investigational Drugs, 2021
Current investigational drugs for DMD – especially steroids and other small molecule drugs, stop codon readthrough, exon-skipping, and gene replacement therapy – are promising strategies to limit loss of skeletal and cardiac muscle function. Vamorolone potentially inhibits disease progression with fewer adverse effects compared to conventional steroids [35]. Ataluren has indicated potential in treating patients with nonsense mutations [121] despite failing to demonstrate dystrophin production. Meanwhile, the field of exon-skipping therapies for DMD is buoyed by the accelerated approval of eteplirsen and golodirsen by the FDA and the clinical investigation of several other exon-skipping strategies. Viltolarsen, in particular, received approval in Japan and the United States in 2020 . Based on this regulatory progress, exon-skipping therapies demonstrate great momentum in the quest to treat DMD. Alongside exon-skipping therapies, the more permanent strategy of microdystrophin gene replacement therapy is delivering encouraging results and is poised to enter Phase III trials soon. For gene therapy to be successful, however, serious consequences requiring intensive treatment or leading to death must be preemptively addressed.