11 July 2014

Modification of the stem cell genome does not cause unwanted mutations

The ability to replace one gene with another in the DNA of living cells appeared to specialists only a few years ago. Like any new technology, the editing of genetic material is associated with both high hopes for the cure of genetic diseases and safety issues.

The results obtained by scientists of the Institute of Biomedical Research named after Salk, working under the guidance of Professor Juan Belmonte (Juan Carlos Izpisua Belmonte), point to the groundlessness of one of these questions. The authors demonstrated that the use of the most popular gene modification techniques does not increase the number of mutations occurring in stem cells.

To date, there are two main methods of modifying the DNA sequence: the use of a viral vector or so–called TALEN proteins, nuclease enzymes that cut DNA, to deliver a new gene to the cell.

As part of earlier work, the researchers first used the so-called helper-dependent adenoviral vectors (HDAdVs) as a DNA modification tool. With their help, they corrected a mutation in the genome of bone marrow stem cells that causes sickle cell anemia. Theoretically, the introduction of cells obtained by this method into the patient's bone marrow can alleviate his condition.

However, before using such technologies in the clinic, it is necessary to obtain convincing evidence of their safety. To do this, the authors used a line of human induced pluripotent stem cells (CHIPSCS) with a mutation that causes sickle cell anemia. They divided the cells into three populations, one of which was modified with HDAdVs, the second with TALEN, and the third, intact, was used as a control.

Subsequent complete sequencing of the cell genome showed that only a slight accumulation of random mutations occurred in the DNA of cells of all populations. In all cases, they were represented by single nucleotide polymorphisms randomly scattered throughout the genome and unique for each cell clone, the number of which did not exceed 100.

Diagram from an article in Cell Stem Cell

The authors note that the results obtained do not mean that the use of stem cells with altered genes is safe, they only indicate that making modifications to the genome of cells is not associated with additional risks.

They have also developed a combined (hybrid) TALEN-HDAdV vector that provides a significant increase in the efficiency of genome modification, and in the near future they plan to study the effect of genetic modifications introduced using these techniques on the risk of unwanted mutations in other types of cells.

Article by Keiichiro Suzuki et al. Targeted Gene Correction Minimally Impacts Whole-Genome Mutational Load in Human-Disease-Specific Induced Pluripotent Stem Cell Clones published in the journal Cell Stem Cell.

Evgeniya Ryabtseva
Portal "Eternal youth" http://vechnayamolodost.ru based on the materials of the Salk Institute for Biological Studies:
No extra mutations in modified stem cells, study finds


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