A naturally occurring genetic mutation that benefits a small number of people afflicted with sickle cell anemia has been introduced by means of genomic editing. Thus far, the mutation has been deliberately introduced only under special circumstances, in the laboratory, where erythroid cells, or red blood cell precursors, were altered by means of transcription activator-like effector nucleases (TALENs), proteins that can cut DNA at selected points, enabling the insertion of supplied DNA. The supplied DNA in this case made possible a point mutation, one associated with elevated fetal globin.

The introduction of the beneficial mutation was accomplished by scientists at the University of New South Wales (UNSW). These scientists reported that their genomic editing technique succeeded increasing fetal globin expression, an achievement, they asserted, that provides “proof of concept” that changing just one letter of DNA in a gene can alleviate the symptoms of sickle cell anemia and thalassemia.

The scientists anticipate that their genomic editing approach could be shown to work effectively in blood stem cells. If this advance were to be achieved, the genomic editing approach would offer significant advantages over other approaches, such as conventional gene therapy, in which viruses are used to ferry healthy genes into a cell to replace the defective ones. Also, the genetic changes to cells would not be inherited, making the approach very different to recent controversial Chinese research in which the DNA of human embryos was altered.

The current results were published May 14 in Nature Communications, in an article entitled, “Editing the genome to introduce a beneficial naturally occurring mutation associated with increased fetal globin.” The article described how the naturally occurring Hereditary Persistence of Fetal Hemoglobin (HPFH) −175T>C point mutation associated with elevated fetal γ-globin was introduced into erythroid cell lines.

“We show,” wrote the article’s authors, “that this mutation increases fetal globin expression through de novo recruitment of the activator TAL1 to promote chromatin looping of distal enhancers to the modified γ-globin promoter.”

The USNW team was led by Merlin Crossley, Ph.D. According to Dr. Crossley, his team’s approach should be effective and safe because the good genetic mutation that was introduced already exists in nature. This good mutation can help people afflicted with sickle cell anemia to keep their fetal hemoglobin gene “switched on,” even though it is usually “switched off” in adults. Fetal hemoglobin, if it remains present in sufficient quantity, can compensate for the faulty adult hemoglobin that causes sickle cell.

The USNW team’s genomic editing technique, noted Dr. Crossley, exploited natural DNA repair mechanisms: “Breaks in DNA can be lethal to cells, so they have in-built machinery to repair any nicks as soon as possible, by grabbing any spare DNA that seems to match—much like you might darn a red sock with any spare red wool lying around. When our genome editing protein cuts the DNA, the cell quickly replaces it with the donor DNA that we have also provided.”

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