Small molecules instead of gene therapy
Quite a lot of genes are known, mutations in which lead to certain diseases. It is quite logical that under these conditions, gene editing technologies are being actively developed. Most of the efforts are focused on improving the CRISPR/Cas9 system.
At the Scripps Research Institute in Florida, Professor Matthew Disney has chosen a different approach to creating a small molecule-based tool that acts on RNA by removing certain gene products.
It makes it possible to develop drugs that can be used as pills to correct genetic diseases – by destroying toxic products of pathological genes and chemical control of the body's defense mechanisms.
RNA is a group of molecules that read, regulate and translate proteins encoded in DNA. In cells, RNAs are constantly in motion: they are collected, perform their functions, and then decomposed for disposal by enzymes that destroy RNA.
Disney used a molecule that selectively binds to a specific RNA and combined it with an enzyme that catalyzes the degradation of RNA. This complex attaches to the product of an unwanted gene and destroys it. The author called the RIBOTAC technology – "ribonuclease-targeted chimeras" (ribonuclease-targeting chimeras).
Ribonuclease L, which is an important part of the antiviral immune response, was chosen as the RIBOTAC RNA-destroying enzyme. When a virus enters a cell, it activates and cleaves its RNA.
The second component of the RIBOTAC complex was targaprimir-96 , an RNA–targeting small molecule that was developed by the author in 2016 to bind an oncogene with microRNA that increases the proliferation of cancer cells, especially triple-negative breast cancer (miRNA-96). The destruction of the oncogene in that study led to the launch of a program to destroy cancer cells by increasing the activity of the FOXO1 gene.
By combining targaprimir-96 with ribonuclease L, the scientist was able to program RIBOTAC only against cells containing the oncogene miRNA-96. This led to the awakening of the FOXO1 gene and the selective destruction of tumor cells of triple-negative breast cancer.
RIBOTAC technology will allow you to fight not only cancer, but also hereditary diseases. RNA is a key factor in almost every one of them, so improving RIBOTAC technology is extremely important. Disney and his lab plan to focus on severe and incurable diseases with a poor prognosis, and perhaps someday they will be able to overcome them.
The article by M. G. Costales et al. Small Molecule Targeted Recruitment of a Nuclease to RNA is published in the Journal of the American Chemical Society.
Aminat Adzhieva, portal "Eternal Youth" http://vechnayamolodost.ru based on the materials of the Scripps Research Institute: Novel RNA-modifying tool corrects genetic diseases, including driver of triple-negative breast cancer.