Nonsense pathogenic genetic variants lead to premature termination codon (PTC) and subsequent truncated protein translation, which is normally degraded by nonsense-mediated decay. Thus, enhanced stop-codon read-through is a potential strategy for treating diseases caused by nonsense mutations. CD BioSciences offers specialized stop-codon read-through enhancement solutions for lysosomal storage disorders (LSDs).
Background of Stop-Codon Read-Through Enhancement for LSDs
An extensive meta-analysis based on a database of human mutations showed that 12% of all described genetic damage causing human genetic disorders is caused by PTC mutations (also known as "nonsense mutations"). These mutations introduce PTCs into protein-coding gene sequences by changing the amino acid-coding triplet to a stop codon. In many LSDs, a nonsense mutation in one or both alleles of the gene encoding the lysosomal enzyme produces a PTC. Premature stop codon mutations are often associated with a more severe clinical phenotype, as the truncated messenger RNA (mRNA) or protein is usually eliminated, resulting in ineffective or minimal net enzyme activity in the cell. Certain low molecular weight drugs (e.g., gentamicin) are known to induce premature stop-codon read-through and restore the production of full-length proteins with less than normal or even normal enzymatic activity. In addition, enhanced termination codon read-through can be used as a treatment for different genetic diseases, including Duchenne muscular dystrophy and cystic fibrosis.
Fig. 1. Premature termination codon read-through process. (Dabrowski M, et al., 2018)
Solutions
PTC in the mRNA coding region of LSDs leads to incorrect termination of translation and generation of non-functional truncated proteins. Based on our understanding of the translation read-through mechanism and the natural phenomenon of stop codon repression, our team of experts has made many efforts to develop therapeutic strategies that counteract the negative effects of PTC.
As an ideal partner for drug development for LSDs, CD BioSciences is committed to developing enhanced stop-codon read-through drug discovery solutions to restore defective protein function through nonsense inhibition.
Preclinical Development of Enhanced Premature Stop-Codon Read-Through Drugs
Translation read-through of PTC induced by pharmaceutical compounds is a promising approach to restore functional protein expression and reduce disease symptoms without affecting the genome or transcriptome of patients with LSDs. We develop low molecular weight drugs to stimulate translational machinery to recode PTC to treat nonsense mutations in genes associated with LSDs. Based on our reliable high-throughput drug screening platform to identify low-molecular-weight lead compounds that inhibit nonsense-mediated mRNA decay, including but not limited to:
❖ Aminoglycoside antibiotics.
❖ Non-aminoglycoside antibiotics.
❖ Macrolide antibiotics.
❖ Other non-aminoglycoside compounds.
Assessment of the Therapeutic Potential of Enhanced Premature Stop-Codon Read-Through Drugs
We focus on studies investigating the ability of the above drugs to inhibit PTC and restore protein function. We provide our clients with multiple models of in vitro transcriptional and translational systems to test the therapeutic potential of the above drugs as PTC read-through stimulating compounds, such as dual reporters in cell lines, LSDs patient-derived cells and LSDs mouse models.
Alternative Approaches to Enhance Premature Stop-Codon Read-Through
In addition to pharmacological suppression of PTC, we work closely with genetic biologists to explore other approaches to suppress PTC (or enhance its suppression) as following:
❖ Nonsense suppression of tRNA.
❖ Pseudo-uridylation recoding.
❖ Inhibition of nonsense-mediated mRNA decay.
Strategies for Improving Aminoglycoside Inhibition Therapy
Aminoglycosides restore a significant amount of protein function, but are limited to a small subset of patients with nonsense mutations. In addition, due to the toxic side effects of conventional aminoglycosides, including hearing loss and kidney damage. We offer several strategies to reduce the toxicity of aminoglycosides.
❖ Encapsulation of aminoglycosides into liposomes.
❖ Development of aminoglycoside derivatives with enhanced nonsense inhibition efficiency and reduced toxicity.
Why Choose Us
- Aminoglycosides are not specific for stop codons.
- Can restore a large number of protein functions.
- We have suitable animal models carrying nonsense mutations.
- Develop phenotypic endpoints that are well correlated with therapeutic efficacy in cells, animals and patients
We are very innovative in the development phase to achieve each client's individual goals. We are ready to explore the value of stop-codon read-through enhancement to meet the requirements of novel LSDs treatment strategies. For more information, please feel free to contact us.
Reference
- Dabrowski M, Bukowy-Bieryllo Z, Zietkiewicz E. (2018) Advances in therapeutic use of a drug-stimulated translational readthrough of premature termination codons[J]. Molecular medicine. 24(1): 1-15.