What's the News:Hemophilia
is perhaps best known as a disease of nineteenth-century royalty (specifically, of the oft-intermarried Hapsburgs
), but it has evaded our efforts at a cure for thousands of years. And its effects are gruesome: mutations in the gene for a crucial clotting factor mean that victims can rapidly bleed to death from even small cuts. Now, researchers working with hemophiliac mice have demonstrated a simple and apparently safe technique
to swap in a functioning gene, giving hope for a future respite for sufferers of the disease. How the Heck:
Gene therapy usually involves removing cells from a patient, repairing their damaged genes in a Petri dish, reinserting them, and hoping that they'll take, a fraught, expensive process. These researchers performed the whole procedure within their mouse subjects, sending in enzymes to snip out the defective gene and a virus carrying a normal gene to replace it.
The mice had been engineered to carry a human gene for hemophilia, and the enzymes and virus had been specifically engineered as well: the enzymes would cut only certain sequences of DNA, patterns that were known to appear on either side of the defective gene, and the virus, which naturally infects the liver cells where the clotting factor is made, would swap in an unmutated gene, instead of the viral genes it would carry in nature.
The treated mice bled for a significantly shorter time than untreated mice and made 3-7% of the normal level of the clotting factor, a level that would result in only mild bleeding in humans. What's more, even after part of the liver had been removed and allowed to regenerate, the mice continued to produce clotting factor, a sign that the modified cells were passing the normal gene down to their daughter cells.
What's the Context:
Because the genetic cause of hemophilia is clear, it's a prime candidate for gene therapy, the process of altering damaged or abnormal DNA to restore normal function.
Gene therapy has shown promise in the lab for treating HIV, Parkinson's, and even color blindness. Despite early, serious setbacks for gene therapy, clinical trials are now under way for treating a wide variety of genetic diseases.
The type of hemophilia treated here happens to be hemophilia B, which accounts for about 20% cases. But because the therapy replaces the entire gene, it seems likely it would work for the more common hemophilia A as well, which is a mutation in another clotting factor.
Not So Fast:
A serious concern about gene therapy is that enzymes could clip healthy parts of the genome, leading to cancer and other diseases or reactions---researchers have proceeded with utmost caution since children receiving gene therapy for X-linked severe combined immunodeficiency (also known as bubble boy syndrome) developed leukemia as a result of their treatment. One of the reasons scientists perform gene therapy in a Petri dish is so they can check for this by sequencing the genomes of the cells they plan to reinject, as well as watch them for signs of abnormality before putting them back in their patients.
Obviously, it would be much easier if therapy that bypassed this process could be relied upon to not harm the patient, and the fact that the mice have experienced no ill effects over the eight-month period since the treatment is a good sign, as is the fact that the enzymes seem to have snipped only one site beyond than their intended target. But this is a known danger with gene therapy, and researchers will have to show that they can prove the treatment doesn't cause damage to the rest of the genome.
The Future Holds: This finding is just the first step on a long road to developing a genetic treatment for hemophilia. But it's a very tidy study, and should prompt much future research into gene therapy. Reference: Hojun Li, Virginia Haurigot, Yannick Doyon, Tianjian Li, Sunnie Y. Wong, Anand S. Bhagwat, Nirav Malani, Xavier M. Anguela, Rajiv Sharma, Lacramiora Ivanciu, Samuel L. Murphy, Jonathan D. Finn, Fayaz R. Khazi, Shangzhen Zhou, David E. Paschon, Edward J. Rebar, Frederic D. Bushman, Philip D. Gregory, Michael C. Holmes, Katherine A. High. In vivo genome editing restores haemostasis in a mouse model of haemophilia. Nature, 2011; DOI: 10.1038/nature10177
Image credit: Wikimedia Commons