CATALYSTS
E ( Figure 3 ). As a prerequisite , healthy cells have no such RNA motif and the nuclease should remain silent . In this context , G-dase E represents a completely new class of drugs .
Significant progress has been made in the development of cancer drugs , but there is still room for improvement . Cancer cells are known to develop resistance mechanisms that cause certain treatments to fail . Furthermore , current cancer drugs often have off-target effects that can affect treatment response and quality of life .
In addition , cancer is a complex disease with multiple molecular and genetic alterations leading to extensive heterogeneity - a challenge for conventional treatments . Finally , therapeutic approaches with greater flexibility and rapid adaptation to new tumour markers make it possible to envisage personalised medicine , where treatment is tailored to individual patients based on their specific tumour characteristics and genetic profile .
The current gold standards in the field of guided toxicity are antibodydrug conjugates and cell therapies like CAR-T : highly toxic and specific , but with a target range limited to cell surface markers or displayed epitopes . A major drawback is a lack of flexibility to address a new target . A complete drug development programme must be initiated for each new marker or indication .
Other CRISPR-like nucleases provide high specificity and flexibility , but are not toxic enough to kill cells . G-dase E offers the combination of specificity , toxicity and flexibility . Due to the molecular mechanism of target recognition , this nuclease is extremely precise and at the same time highly toxic to cancer cells .
Targeting RNAs directly
Direct cell killing by DNA degradation may have a chance to overcome some of the escape mechanisms of cancer cells since G-dase E uses new biomarkers and does not rely on the typical pathways to kill cells . This
Figure 3 - Addressable molecular target space for cytotoxic nuclease G-dase E
is why there is enormous potential , especially in combination with established therapeutic approaches .
G-dase E has the potential to target cancer-specific RNAs directly , ranging from mRNAs of viral oncogenes to fusions or mutations and noncoding RNAs , which to the best of our knowledge have not been targeted like this in cancer therapy . 4 For this reason , it should have the potential to treat previously untreatable types of cancer .
Finally , in theory G-dase E can be easily programmed to the next biomarker - and thus the next indication - by simply adapting 21 base pairs of the guide RNA , providing its platform technology capability . Like probably other Cas nucleases , G-dase E has the potential to be used in personalised medicine in the future .
Next steps
The efficient delivery of G-dase E into cancer cells is currently under development . The toxic nuclease requires a suitable delivery system for use in upcoming proof-of-concept studies for anti-tumour efficacy and later in clinical studies and treatment .
Fortunately , G-dase E technology can benefit from a wide range of technologies that have been established in recent years for various active ingredients as so called payloads . Advantageously , G-dase E as a payload itself should be highly specific and tightly regulated by the RNA biomarker interaction .
Nevertheless , delivery remains a challenge . Since no available system is suited to target all cancer types , and G-dase E is to be used as a platform , we are looking for partners who are interested in combining their delivery system with a next generation payload . In addition , we are looking for strategic partners for the development of new cancer therapies . ●
* - G-Dase E is a registered trademark of BRAIN Biotech
Dr Dirk Sombroek
HEAD OF STRATEGIC PARTNERSHIPS
AKRIBION GENOMICS k + 49 6251 9331-0 J dis @ akribion-genomics . com j www . akribion-genomics . com
28 SPECIALITY CHEMICALS MAGAZINE ESTABLISHED 1981