ELX-02: an investigational read-through agent for the treatment of nonsense mutation-related genetic disease

Kerem, Eitan

doi:10.1080/13543784.2020.1828862

Cited by 41 publications

(27 citation statements)

References 41 publications

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“…To overcome this problem, chemically modified AAGs with reduced toxicity were generated [ 20 , 21 ]. The most promising compound, NB124 (now known as ELX-02, Eloxx Pharmaceuticals), was effective in a series of cell- and animal-based experiments [ 19 , 22 ] and is presently being tested on CF patients in phase 2 clinical trials [ 23 ].…”

Section: Introductionmentioning

confidence: 99%

Comprehensive Analysis of Combinatorial Pharmacological Treatments to Correct Nonsense Mutations in the CFTR Gene

Venturini

Borrelli

Musante

et al. 2021

IJMS

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Cystic fibrosis (CF) is caused by loss of function of the CFTR chloride channel. A substantial number of CF patients carry nonsense mutations in the CFTR gene. These patients cannot directly benefit from pharmacological correctors and potentiators that have been developed for other types of CFTR mutations. We evaluated the efficacy of combinations of drugs targeting at various levels the effects of nonsense mutations: SMG1i to protect CFTR mRNA from nonsense-mediated decay (NMD), G418 and ELX-02 for readthrough, VX-809 and VX-445 to promote protein maturation and function, PTI-428 to enhance CFTR protein synthesis. We found that the extent of rescue and sensitivity to the various agents is largely dependent on the type of mutation, with W1282X and R553X being the mutations most and least sensitive to pharmacological treatments, respectively. In particular, W1282X-CFTR was highly responsive to NMD suppression by SMG1i but also required treatment with VX-445 corrector to show function. In contrast, G542X-CFTR required treatment with readthrough agents and VX-809. Importantly, we never found cooperativity between the NMD inhibitor and readthrough compounds. Our results indicate that treatment of CF patients with nonsense mutations requires a precision medicine approach with the design of specific drug combinations for each mutation.

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Section: Introductionmentioning

confidence: 99%

Comprehensive Analysis of Combinatorial Pharmacological Treatments to Correct Nonsense Mutations in the CFTR Gene

Venturini

Borrelli

Musante

et al. 2021

IJMS

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“…Studies in cystic fibrosis with PTC124 were disappointing, though a notable treatment effect was observed in individuals not receiving inhaled tobramycin [ 106 ]. ELX-02 was more recently described and shows promise based on in vitro data in human-derived intestinal organoids with G542X nonsense mutations and appeared safe based on phase 1 studies in healthy volunteers [ 107 ]. Currently, in vitro studies on PCD are being performed by Eloxx Pharmaceuticals (Waltham, United States of America, in collaboration with University Medical Center Utrecht (The Netherlands) and Amsterdam University Medical Center (The Netherlands).…”

Section: Future Treatments In Primary Ciliary Dyskinesiamentioning

confidence: 99%

Current and Future Treatments in Primary Ciliary Dyskinesia

Paff

Omran

Nielsen

et al. 2021

IJMS

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Primary ciliary dyskinesia (PCD) is a rare genetic ciliopathy in which mucociliary clearance is disturbed by the abnormal motion of cilia or there is a severe reduction in the generation of multiple motile cilia. Lung damage ensues due to recurrent airway infections, sometimes even resulting in respiratory failure. So far, no causative treatment is available and treatment efforts are primarily aimed at improving mucociliary clearance and early treatment of bacterial airway infections. Treatment guidelines are largely based on cystic fibrosis (CF) guidelines, as few studies have been performed on PCD. In this review, we give a detailed overview of the clinical studies performed investigating PCD to date, including three trials and several case reports. In addition, we explore precision medicine approaches in PCD, including gene therapy, mRNA transcript and read-through therapy.

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“…ELX-02 is a novel aminoglycoside analogue drug developed by Eloxx Pharmaceuticals that demonstrated read-through activity on CFTR PTC mutations. 48 In Phase I clinical studies (NCT02807961, NCT03292302, NCT03309605), 62 healthy volunteers were treated with ELX-02 and no serious adverse events or deaths were reported. 49 Two Phase II clinical studies have been initiated with 24 individuals with CF carrying the G542X mutation in at least one allele (NCT04126473, NCT04135495).…”

Section: Cftr Modulator Drugs and Personalized Medicinementioning

confidence: 99%

Pharmacological Modulation of Ion Channels for the Treatment of Cystic Fibrosis

Pinto¹,

Silva²,

Figueira³

et al. 2021

JEP

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Cystic fibrosis (CF) is a life-shortening monogenic disease caused by mutations in the gene encoding the CF transmembrane conductance regulator (CFTR) protein, an anion channel that transports chloride and bicarbonate across epithelia. Despite clinical progress in delaying disease progression with symptomatic therapies, these individuals still develop various chronic complications in lungs and other organs, which significantly restricts their life expectancy and quality of life. The development of high-throughput assays to screen drug-like compound libraries have enabled the discovery of highly effective CFTR modulator therapies. These novel therapies target the primary defect underlying CF and are now approved for clinical use for individuals with specific CF genotypes. However, the clinically approved modulators only partially reverse CFTR dysfunction and there is still a considerable number of individuals with CF carrying rare CFTR mutations who remain without any effective CFTR modulator therapy. Accordingly, additional efforts have been pursued to identify novel and more potent CFTR modulators that may benefit a larger CF population. The use of ex vivo individual-derived specimens has also become a powerful tool to evaluate novel drugs and predict their effectiveness in a personalized medicine approach. In addition to CFTR modulators, pro-drugs aiming at modulating alternative ion channels/transporters are under development to compensate for the lack of CFTR function. These therapies may restore normal mucociliary clearance through a mutation-agnostic approach (ie, independent of CFTR mutation) and include inhibitors of the epithelial sodium channel (ENaC), modulators of the calcium-activated channel transmembrane 16A (TMEM16, or anoctamin 1) or of the solute carrier family 26A member 9 (SLC26A9), and anionophores. The present review focuses on recent progress and challenges for the development of ion channel/transporter-modulating drugs for the treatment of CF.

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ELX-02: an investigational read-through agent for the treatment of nonsense mutation-related genetic disease

Cited by 41 publications

References 41 publications

Comprehensive Analysis of Combinatorial Pharmacological Treatments to Correct Nonsense Mutations in the CFTR Gene

Comprehensive Analysis of Combinatorial Pharmacological Treatments to Correct Nonsense Mutations in the CFTR Gene

Current and Future Treatments in Primary Ciliary Dyskinesia

Pharmacological Modulation of Ion Channels for the Treatment of Cystic Fibrosis

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