Scientists take step forward in "editing" human genetic mutations

Chuck Bednar for redOrbit.com – Your Universe Online
In a new “proof of concept” experiment, scientists have managed to edit the genome of sperm-producing adult stem cells, creating a break in the DNA strands of a mutant gene in mouse cells then repairing it by replacing flawed segments with corrected ones.
The process utilized in the study is known as homologous recombination, and researchers from Indiana University, Stanford University and the University of Texas used spermatogonial stem cells (the building blocks for the production of sperm and the only adult stem cells that contribute genetic information to the next generation) to demonstrate their technique.
By repairing flaws in these cells, the study authors said that experts could prevent mutations from being passed onto to future generations. The technique, which is detailed in a recent edition of the journal PLOS One, has tremendous potential for gene therapy as well as basic research.
“We showed a way to introduce genetic material into spermatogonial stem cells that was greatly improved from what had been previously demonstrated,” co-author Christina Dann, an associate scientist in the Indiana University (IU) Department of Chemistry, said in a statement Monday. “This technique corrects the mutation, theoretically leaving no other mark on the genome.”
Dann, lead author and former IU research associate Danielle Fanslow, and their colleagues had to overcome a number of difficulties in their research – including the fact that spermatogonial stem cells are difficult to isolate, culture and work with. They were only able to create the correct conditions in which to maintain and propagate the cells following years worth of work by scientists at multiple laboratories.
“A primary hurdle was to find a way to make specific, targeted modifications to the mutant mouse gene without the risk of disease caused by random introduction of genetic material,” the university explained. “The researchers used specially designed enzymes, called zinc finger nucleases and transcription activator-like effector nucleases, to create a double strand break in the DNA and bring about the repair of the gene.”
Stem cells that were modified in the laboratory were then transplanted into the testes of sterile mice where they grew or colonized, indicating that the stem cells were viable. However, the researchers were unable to breed the mice, though they are do not know if it was abnormalities in the transplanted cells or the recipient testes led to the rodents’ failure to produce sperm.
“We demonstrated that gene-corrected cells maintained several properties of spermatogonial stem/progenitor cells including the ability to colonize following testicular transplantation,” the study authors wrote. “This proof of concept for genome editing… impacts both cell therapy and basic research given the potential for GS [germline stem] cells to be propagated in vitro, contribute to the germline in vivo following testicular transplantation or become reprogrammed to pluripotency in vitro.”
“This research is a first step to allowing men carrying potentially harmful mutations, such as cystic fibrosis or Huntington disease, to have children naturally without concern about passing on their disease to their offspring,” said Dr. James West, a researcher Vanderbilt University who is also conducting similar experiments. “The methodology they are using guarantees no harmful side effects elsewhere in the genome, and so if it is going to be done therapeutically, the method they are using is the best bet.”
In related research published earlier this month, scientists from multiple institutions in China used a different technique in order to edit a faulty gene in spermatogonial stem cells of mice. In that study, the rodents were able to successfully reproduce following transplantation of cells carrying the corrected gene.
“The research developments could open doors for better understanding of stem cells and advances in gene therapy,” Indiana University explained. “The ability to edit the genome could facilitate analysis of gene function and the processes by which sperm cells divide and differentiate. The techniques could be used, for instance, to test the functional importance of a genetic mutation implicated in reproductive failure.”
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