Not to darn, but to change the whole
CRBR gene therapy promises to treat any mutations without risks
Svetlana Maslova, Hi-tech+
The CRBR (Co-opting Regulation Bypass Repair) technology takes advantage of CRISPR/Cas9, however, it has lower error risks and is not limited to correcting defects in only one genetic sequence. Instead, a new fully functional copy of the gene is inserted to replace the mutated one. According to the authors, this opens up new opportunities in the treatment of cystic fibrosis, sickle cell anemia and other genetic diseases, including rare ones.
The proof of the prospects of the new approach was presented by scientists from University of Pennsylvania. They sought to expand the possibilities of CRISPR/Cas9 gene therapy to simultaneously correct various mutations in one gene, but at the same time do it faster and cheaper.
Article by Hu et al. Co-opting regulation bypass repair as a gene correction strategy for monogenic diseases is published in the journal Molecular Therapy – VM.
CRISPR/Cas9 works on the principle of genetic scissors, cutting DNA in a certain place for point editing. In addition to the fact that this process requires the presence of certain proteins, which are available only during cell division, another disadvantage remains the limitations of the manipulations performed.
Even if the disease is caused by a defect in one gene, it can be triggered by many different mutations in it. To use CRISPR/Cas9, it is necessary to develop and test a strategy for each of the potential mutations, and CRBR works comprehensively.
CRBR takes advantage of CRISPR/Cas9 and a cell repair pathway called "non-homologous end connection" to insert a genetic sequence between the promoter region of the mutated gene (the genetic sequence that controls when and where the gene functions) and the mutated part of the gene. The newly inserted sequence contains a compressed version of the normal gene, which is used instead of the mutated one.
The first important advantage of CRBR is the independence of the proteins necessary for repair, so the approach can be used in all types of adult tissues. The second advantage is to guarantee that the inserted gene will be expressed at the same time and at the same level as the replaced one.
First, scientists tested CRBR on mice with a mutation in the PERK gene that leads to a rare disease — Woolcott-Rallison syndrome. This syndrome occurs when both inherited copies of a gene have mutations. The gene edited with CRBR could restore the PERK function. Further experiments with human cells have shown the potential of CRBR for gene repair in humans as well.
To develop the use of CRBR, it is necessary to improve delivery systems to the cells of interest, but the approach has great potential for the treatment of genetic diseases in humans, the researchers concluded.
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