Ribosomes form the translation machinery that generates functional proteins from genetic sequences; modulating the ribosome subunits provides a therapeutic approach to addressing a number of diseases.
Although the ribosome provides a rich target, the development of disease-specific ribosome modulators has been a challenge. We’re rising to this challenge.
Nonsense mutations implicated in many rare diseases
Ribosomal mutations driving cancer
A nonsense mutation is a mutation in the mRNA that substitutes a stop codon for one that specifies for an amino acid. This terminates translation and results in a shortened, nonfunctional protein.Nonsense mutations are the cause of many rare diseases and cancers.
Ribosomal mutations may be associated with cellular transformation and tumor progression.
A nonsense mutation is a mutation in the mRNA that substitutes a stop codon for one that specifies for an amino acid. This terminates translation and results in a shortened, nonfunctional protein. Nonsense mutations are the cause of many rare diseases and cancers.
TURBO-ZM™ and Ribosome Modulating Agents (RMAs)
Eukaryotic Ribosomal Selective Glycosides (ERSGs)
TURBO-ZM™ technology allows rapid synthesis of novel oral Ribosome Modulating Agents (RMAs) and has potential to fully unlock macrolide activity. Macrolides have been shown to modulate the ribosome but have limitations such as moderate activity and safety and tolerability concerns.
TURBO-ZM™ allows us to synthesize RMAs that are optimized vs traditional macrolides with lower molecular weight and higher water solubility.
Alport Syndrome
Recessive dystrophic epidermolysis bullosa (RDEB)/ junctional epidermolysis bullosa (JEB)
Familial adenomatous polyposis (FAP)
Our lead program is in Alport Syndrome with ELX-02
Clinical data shows that the macrolide and aminoglycoside classes have activity in many rare diseases and cancers, yet are not able to fulfill clinical promise because of limitations. Our platforms allow us to overcome these limitations.
Clinical results for macrolides and aminoglycosides are reported in more than 36 rare diseases.2-7
Macrolides and aminoglycosides have significant limitiations that our therapies are designed to overcome.
References: 1. Kandasamy J, Atia-Glikin D, Shulman E, et al. Increased selectivity toward cytoplasmic versus mitochondrial ribosome confers improved efficiency of synthetic aminoglycosides in fixing damaged genes: a strategy for treatment of genetic diseases caused by nonsense mutations. J Med Chem. 2012;55(23):10630-10643. 2. Kariv R, Fliss-Isacov N, Caspi M, et al. Erythromycin readthrough of APC nonsense stop codon mutation in familial adenomatous polyposis. Ann Oncol. 2018;29(suppl 3)III39. 3. Sermet-Gaudelus I, Renouil M, Fajac A, et al. In vitro prediction of stop-codon suppression by intravenous gentamicin in patients with cystic fibrosis: a pilt study. BMC Med. 2007;5(5): doi10.1186/1741-7015-5-5. 4. Malik V, Rodino-Klapac, Viollet L, et al. Aminoglycoside-induced mutation suppression) stop codon readthrough) as a therapeutic strategy for Duchenne muscular dystrophy. Ther Adv Neurol Disord. 2010;3(6):379-389. 5. Woodley DT, Cogan J, Hou Y. Gentamicin induces functional type VII collagen in recessive dystrophic epidermolysis bullosa patients. J Clin Invest. 2017;127(8):3028-3038. 6. Caspi M, Firsow A, Rajkumar R. A flow cytometry-based reporter assay identifies macrolide antibiotics as nonsense mutation read-through agents. J Mol Med. 2016;94(4):469-482. 7. Goldmann T, Overlack N, Wolfrum U, et al. PTC124- medicated translational readthrough of a nonsense mutation causing Usher syndrome type 1C. Hum Gene Ther. 2011;22(5):537-547.
Class 1 cystic fibrosis (CF)
Clinical data shows that the macrolide and aminoglycoside classes have activity in many rare diseases and cancers, yet are not able to fulfill clinical promise because of limitations.Our platforms allow us to overcome these limitations.