ELX-02 Generates Protein via Premature Stop Codon Read-Through without Inducing Native Stop Codon Read-Through Proteins

Crawford, Daniel K.; Alroy, Iris; Sharpe, Neal; Goddeeris, Matthew M.; Williams, Greg

doi:10.1124/jpet.120.265595

Cited by 40 publications

(25 citation statements)

References 35 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…ELX-02 is a eukaryotic ribosomal selective glycoside which displays preferential binding to the eukaryotic ribosome and promotes premature stop codon read-through [3] . Evidence of native stop codon read-through has not been detected [4] , consistent with conserved cis-element factors that improve native stop codon fidelity. ELX-02 has been evaluated in Phase 1 clinical trials, where it was found to be well tolerated with pharmacokinetic properties consistent with preclinical evaluations [5] .…”

Section: Introductionmentioning

confidence: 86%

Targeting G542X CFTR nonsense alleles with ELX-02 restores CFTR function in human-derived intestinal organoids

Crawford

Mullenders²,

Pott³

et al. 2021

Journal of Cystic Fibrosis

Self Cite

View full text Add to dashboard Cite

Background: Promoting full-length protein production is a requisite step to address some of the remaining unmet medical need for those with Cystic Fibrosis (CF) nonsense alleles. ELX-02 promotes readthrough of mRNA transcripts bearing nonsense mutations, including the most common CF nonsense allele G542X , in several different preclinical models including human bronchial epithelial cells. Here we evaluate ELX-02 mediated read-through using the CFTR-dependent Forskolin-induced swelling (FIS) assay across a selection of G542X genotype patient derived organoids (PDOs). Methods: CFTR functional restoration was evaluated in ELX-02 treated G542X homozygous and heterozygous PDOs in the CFTR-dependent FIS assay. CFTR mRNA abundance and integrity were evaluated by qPCR and Nanostring analysis while PDO protein was detected by capillary based size-exclusion chromatography. Results: PDOs homozygous for G542X or heterozygous with a second minimally functional allele had significantly increased CFTR activity with ELX-02 in a dose-dependent fashion across a variety of forskolin induction concentrations. The functional increases are similar to those obtained with tezacaftor/ivacaftor in F508del homozygous PDOs. Increased CFTR C-and B-band protein was observed in accordance with increased function. In addition, ELX-02 treatment of a G542X/G542X PDO results in a 5-fold increase in CFTR mRNA compared with vehicle treated, resulting in normalization of CFTR mRNA as measured via Nanostring. Conclusions: These data with ELX-02 in PDOs are consistent with previous G542X model evaluations. These results also support the ongoing clinical evaluation of ELX-02 as a read-through agent for CF caused by the G542X allele.

show abstract

Section: Introductionmentioning

confidence: 86%

Targeting G542X CFTR nonsense alleles with ELX-02 restores CFTR function in human-derived intestinal organoids

Crawford

Mullenders²,

Pott³

et al. 2021

Journal of Cystic Fibrosis

Self Cite

View full text Add to dashboard Cite

show abstract

“…This selectivity profile Figure 3 was hypothesized to improve nonsense mutation read-through while mitigating drug-induced tolerability attributed to binding to the mitochondrial ribosome. Optimization led to ELX-02 and other similar molecules showing greater read-through activity in a plasmid-based dual-luciferase assay and restoration of full length, functional protein by ELX-02 in cellular assays while simultaneously demonstrating improved cellular tolerability [20,23,24]. Normally, ribosomes translate mRNA to produce full-length protein and that mRNA transcript is then still available for additional rounds of translation.…”

Section: Chemistrymentioning

confidence: 99%

“…In an exemplar nonsense mutation model system, ELX-02 produced significant read-through of the premature stop codon found in TP53 mRNA in DMS-114 cells, resulting in increased p53 protein expression and an increased mRNA content that is consistent with decreased NMD [24]. Native stop codon read-through protein products were not observed in either DMS-114 cells or in clinical samples from subjects dosed with ELX-02 in studies EL-001 or EL-006 (as described in Section 3 below).…”

Section: Pharmacodynamicsmentioning

confidence: 99%

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

Kerem

2020

Expert Opinion on Investigational Drugs

View full text Add to dashboard Cite

Introduction: ELX-02, an investigational compound that is structurally an aminoglycoside analog, induces read-through of nonsense mutations through interaction with the ribosome, through which full-length functional proteins can be produced. It is being developed as a therapy for genetic diseases caused by nonsense mutations such as cystic fibrosis (CF) and nephropathic cystinosis. In Phase 1 clinical trials, 105 volunteers were exposed to ELX-02. To date, ELX-02 is well tolerated and there has been no reported treatment-related serious adverse events or deaths. Areas Covered: The development of this molecule, from its pharmacology to the ongoing Phase 2 clinical trials is discussed. Expert Opinion: Globally, nonsense mutations account for ~11% of all described gene lesions causing inherited monogenetic diseases. In CF and nephropathic cystinosis, they comprise from 10% to 12% of the disease-causative alleles. ELX-02 is in development as a therapeutic for patients with these alleles as in vitro and in vivo data demonstrated dose-dependent read-through of nonsense mutations to produce full-length, functional proteins. Since read-through efficiency varies between alleles and mRNA context, careful consideration of target patient populations is required. The results to date support the ongoing Phase 2 clinical evaluations of ELX-02 as a read-through agent.

show abstract

“…ELX-02 can restore the expression of nonsense mutated CFTR in CF models by interfering with the NMD process and/or stabilizing the mRNA. ELX-02 exerts its nonsense suppressor activity with improved efficacy and a 100-fold lower antibiotic activity compared with first generation aminoglycosides [186,212]. ELX-02 showed a ten-fold improved PTC-readthrough efficacy compared with gentamicin in restoring nonsense mutated CFTR gene in vitro and in vivo [213].…”

Section: Aminoglycoside Derivativesmentioning

confidence: 99%

Nonsense Suppression Therapy: New Hypothesis for the Treatment of Inherited Bone Marrow Failure Syndromes

Bezzerri

Api

Allegri

et al. 2020

IJMS

View full text Add to dashboard Cite

Inherited bone marrow failure syndromes (IBMFS) are a group of cancer-prone genetic diseases characterized by hypocellular bone marrow with impairment in one or more hematopoietic lineages. The pathogenesis of IBMFS involves mutations in several genes which encode for proteins involved in DNA repair, telomere biology and ribosome biogenesis. The classical IBMFS include Shwachman–Diamond syndrome (SDS), Diamond–Blackfan anemia (DBA), Fanconi anemia (FA), dyskeratosis congenita (DC), and severe congenital neutropenia (SCN). IBMFS are associated with high risk of myelodysplastic syndrome (MDS), acute myeloid leukemia (AML), and solid tumors. Unfortunately, no specific pharmacological therapies have been highly effective for IBMFS. Hematopoietic stem cell transplantation provides a cure for aplastic or myeloid neoplastic complications. However, it does not affect the risk of solid tumors. Since approximately 28% of FA, 24% of SCN, 21% of DBA, 20% of SDS, and 17% of DC patients harbor nonsense mutations in the respective IBMFS-related genes, we discuss the use of the nonsense suppression therapy in these diseases. We recently described the beneficial effect of ataluren, a nonsense suppressor drug, in SDS bone marrow hematopoietic cells ex vivo. A similar approach could be therefore designed for treating other IBMFS. In this review we explain in detail the new generation of nonsense suppressor molecules and their mechanistic roles. Furthermore, we will discuss strengths and limitations of these molecules which are emerging from preclinical and clinical studies. Finally we discuss the state-of-the-art of preclinical and clinical therapeutic studies carried out for IBMFS.

show abstract

ELX-02 Generates Protein via Premature Stop Codon Read-Through without Inducing Native Stop Codon Read-Through Proteins

Cited by 40 publications

References 35 publications

Targeting G542X CFTR nonsense alleles with ELX-02 restores CFTR function in human-derived intestinal organoids

Targeting G542X CFTR nonsense alleles with ELX-02 restores CFTR function in human-derived intestinal organoids

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

Nonsense Suppression Therapy: New Hypothesis for the Treatment of Inherited Bone Marrow Failure Syndromes

Contact Info

Product

Resources

About