DNA-Snipping Enzymes Cure Hemophilia in Mice

By Veronique Greenwood | June 27, 2011 2:44 pm


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

CATEGORIZED UNDER: Health & Medicine
  • http://www.facebook.com/pages/The-Science-News/183084708403986 Science news – Facebook page

    Conventional gene therapy techniques suffer from the problem that they can randomly deliver a replacement gene into an unfavorable location, bypassing the normal biological regulatory components controlling the gene.

  • http://www.facebook.com gian


  • http://smilingdoom.com Doomsayer General

    My stepson has hemophilia (A) and he won’t “rapidly bleed to death from even small cuts.” He doesn’t clot but he doesn’t bleed *more* than the average person. So unless that small cut is to an artery or something, I don’t see how he’d bleed to death even if he didn’t get his Factor 8 shots. I’m used to hearing these sorts of “bleeder” stereotypes from people who don’t know jack, but from Discovery? Come on guys.

  • http://smilingdoom.com Doomsayer General

    Not to belabor the point, but my stepson also still has platelets that do a decent job of knitting surface wounds without factor. The bleeding is more of an internal issue. Especially in the joints.

    You should correct your mistake so as not to spread further misinformation.

  • Laura Snyder

    Not sure I’d want to sign up my 2 boys with Type A with inhibitors for something that is trusted to a virus. If we knew more about virus patterns and their particulars, a good chunk of our diseases would be cured. And I second the ‘rapidly bleed to death’ misnomer-Hemophilia 101 basic info disproves that myth.

  • Samuell Price

    I have hemophilia and this sounds great, but I have heard this for years. I will be convinced once it is on the shelves and available to anyone that needs the treatment or “cure”. I am also a biologist and have worked in a lab environment. I know how we can “demonstrate” a potential cure and it be only 1 out of 1000 specimens that survived the cure. I want to see the long term results of the cure to the animal over its lifetime. What happens to the next generation of the mouse? Is its genes also affected or mutated worse? Please don’t brag about a ‘cure’ until it has been tested and proven by many separate labs.

    As for the article it self, Guys get your facts right about the symptoms. I have had many cuts in my life and NEVER bleed to death. In fact some were deep enough to require many stitches. Like Doomsayer General says, it is the joints that the bleeding is most harmful not the surface cuts. Other wise we would of all bleed to death every time we got our factor injection.

  • Molly

    As a new mother of son who has Hemophilia I was also disgusted with the opening line about cuts and bleeding to death. That is exactly the type of generalization and uneducated statements the hemophilia community is trying to avoid. My son will live a full life and be as normal as any other child. When he gets a cut, we will put a band aid on it.

    I am happy to hear about new breakthroughs and hope there will one day be a cure which will lead to cures of other diseases, but just like Samuell points out, we are not there from one mouse. But fingers crossed!

  • Sarah

    The stereotype in the first paragraph aside, I think the most important and interesting aspect of this article is that there is truly meaningful and exciting research being done by bright people who want to cure this disorder. While I realize the odds of being able to look my son square in the eye and tell him one day that he is cured from this disorder, research like this at least gives me hope…especially on the tough days.

  • mom

    KEEP GOING KEEP GOING!! as a new mother of a child with severe hemophilia A i think any news of successful ongoing trials is exciting. i am hopeful that someday some smart scientist somewhere will find the cure and it be available to everyone. we put people on the moon for crying out loud, we will have the cure for hemophilia. just a matter of when, and i hope soon! staying positive and having hope is the only way i can accept this right now. i dont know what to expect, and the thought of my precious baby boys future being filled with pain, is a heartbreak beyond coping with.

  • Dan

    I have a 4 year old son with hemophilia. When you tell someone that he has hemophilia the conversation inevitably goes to uncontrollable bleeding (even from a minor cut) or AIDs (due to Ryan White). The uncontrollable bleeding from a minor injury is very much a fallacy, and the AIDs belief is no longer an issue for children born nowadays thanks to synthetic factor that is not a blood product. I’m surprised that a scientific publication would run with one of the most innane rumors about hemophilia. At least with the AIDs implication there was a time where that was true.

  • Veronique Greenwood

    To everyone who commented, I’m glad to hear that you and your family members with hemophilia are doing relatively well!

    To address your comments, the modern treatments that manage to keep the disease more or less at bay are recent developments. For most of human history, hemophilia was quite a bit more dangerous than it is now (though it’s certainly no picnic today). Before the clotting factor injections became available, through the first half of the 20th century, hemophiliacs regularly did not reach adulthood. A family friend of mine lost her brother to a fairly minor wound when he was a child, before the injections were available.

    Simply because most hemophiliacs, with treatment, can avoid catastrophic bleeding, doesn’t mean that it’s wrong to say that it’s possible. But thank goodness none of you have had that experience!


Discover's Newsletter

Sign up to get the latest science news delivered weekly right to your inbox!


80beats is DISCOVER's news aggregator, weaving together the choicest tidbits from the best articles covering the day's most compelling topics.

See More

Collapse bottom bar