By targeting a defective gene in stem cells, researchers opened a new possibility in correcting genetic disorders.
These days, cures are available for a great number of diseases. But are we stuck with our bad genes? Many hard-working scientists hope not. It has long been the dream of researchers to snip away a troubled gene in an afflicted patient and put in its place a gene with proper function.
There are numerous considerable challenges to be overcome. Is it possible to be precise enough such that only the gene of interest is targeted, leaving other genes unscathed? Can this be achieved without unintended harmful consequences?
Despite the roadblocks, researchers push ahead in the quest to find solutions to often untreatable genetic disorders. One such disorder is severe combined immunodeficiency (SCID), in which patients lack an adaptive immune system. Parents of young patients need the good fortune of finding a match for bone marrow transplantation. Readers may recall several children who made the news for suffering from this disorder, including “bubble boy” David Vetter.
Now, as a proof-of-efficacy approach, researchers have cured a form of SCID, SCID-X1, in lab studies, using stem cells to correct the culprit gene, IL2RG. Stem cells are tricky business. Nudge the stem cells too much, and they might transform into other types of cells – or program their own death. Unfortunately, stem cells need to be induced to divide to a certain extent in order for homologous recombination, a relatively less problematic form of gene insertion, to occur.
The researchers ultimately came up with the right conditions for introducing zinc finger nucleases, which introduced breaks in the stem cells’ DNA. A corrective DNA sequence was used to replace the excised gene. When placed into a mouse model of SCID-X1, hematopoietic stem cells that were modified produced healthy T-cells, effectively curing the disease. The scientists also applied their strategy to bone marrow cells taken from a four-month-old patient. Experiments showed that IL2RG was successfully targeted.
Researchers in this field must take care not to insert genes in a way that throws the genome off-balance and results in rapid cell division (cancer). The researchers here not only sidestepped the problem with their own work but demonstrated that, for other programs, genes may be introduced into regions called “genomic safe harbors,” where harming the genome is avoided.
Only a few percent of stem cells in this study exhibited gene correction. Those small number of cells could make up for the deficiency in this case, but for other diseases, higher percentages may be needed. Still, this work is an important step forward to the day when medical practitioners will use “genetic scalpels” to cut and mend uneasy genomes. At HemaCare, we provide stem cell products, including hematopoietic stem cells for treating specific human diseases.
 Genovese P et al. Targeted genome editing in human repopulating haematopoietic stem cells. Nature 2014 June 12;510:235-240.