Navigation Links
Genome editing, a next step in genetic therapy, corrects hemophilia in animals
Date:6/26/2011

Using an innovative gene therapy technique called genome editing that hones in on the precise location of mutated DNA, scientists have treated the blood clotting disorder hemophilia in mice. This is the first time that genome editing, which precisely targets and repairs a genetic defect, has been done in a living animal and achieved clinically meaningful results.

As such, it represents an important step forward in the decades-long scientific progression of gene therapydeveloping treatments by correcting a disease-causing DNA sequence. In this new study, researchers used two versions of a genetically engineered virus (adeno-associated virus, or AAV)one carrying enzymes that cut DNA in an exact spot and one carrying a replacement gene to be copied into the DNA sequence. All of this occurred in the liver cells of living mice.

"Our research raises the possibility that genome editing can correct a genetic defect at a clinically meaningful level after in vivo delivery of the zinc finger nucleases," said the study leader, Katherine A. High, M.D., a hematologist and gene therapy expert at The Children's Hospital of Philadelphia. High, a Howard Hughes Medical Institute Investigator, directs the Center for Cellular and Molecular Therapeutics at Children's Hospital, and has investigated gene therapy for hemophilia for more than a decade.

The study appeared online today in Nature.

High's research, a collaboration with scientists at Sangamo BioSciences, Inc., makes use of genetically engineered enzymes called zinc finger nucleases (ZFNs) that act as molecular word processors, editing mutated sequences of DNA. Scientists have learned how to design ZFNs custom-matched to a specific gene location. ZFNs specific for the factor 9 gene (F9) were designed and used in conjunction with a DNA sequence that restored normal gene function lost in hemophilia.

By precisely targeting a specific site along a chromosome, ZFNs have an advantage over conventional gene therapy techniques that may randomly deliver a replacement gene into an unfavorable location, bypassing normal biological regulatory components controlling the gene. This imprecise targeting carries a risk of "insertional mutagenesis," in which the corrective gene causes an unexpected alteration, such as triggering leukemia.

In hemophilia, an inherited single-gene mutation impairs a patient's ability to produce a blood-clotting protein, leading to spontaneous, sometimes life-threatening bleeding episodes. The two major forms of the disease, which occurs almost solely in males, are hemophilia A and hemophilia B, caused respectively by a lack of clotting factor VIII and clotting factor IX. Patients are treated with frequent infusions of clotting proteins, which are expensive and sometimes stimulate the body to produce antibodies that negate the benefits of treatment.

In the current study, the researchers used genetic engineering to produce mice with hemophilia B, modeling the disease in people. Before treatment, the mice had no detectable levels of clotting factor IX.

Previous studies by other researchers had shown that ZFNs could accomplish genome editing in cultured stem cells that were then injected into mice to treat sickle cell disease. However, this ex vivo approach is not feasible for many human genetic diseases, which affect whole organ systems. Therefore the current study tested whether genome editing was effective when directly performed in vivo (in a living animal).

High and colleagues designed two versions of a vector, or gene delivery vehicle, using adeno-associated virus (AAV). One AAV vector carried ZFNs to perform the editing, the other delivered a correctly functioning version of the F9 gene. Because different mutations in the same gene may cause hemophilia, the process replaced seven different coding sequences, covering 95 percent of the disease-carrying mutations in hemophilia B.

The researchers injected mice with the gene therapy vector, which was designed to travel to the liverwhere clotting factors are produced. The mice that received the ZFN/gene combination then produced enough clotting factor to reduce blood clotting times to nearly normal levels. Control mice receiving vectors lacking the ZFNs or the F9 minigene had no significant improvements in circulating factor or in clotting times.

The improvements persisted over the eight months of the study, and showed no toxic effects on growth, weight gain or liver function, clues that the treatment was well-tolerated.

"We established a proof of concept that we can perform genome editing in vivo, to produce stable and clinically meaningful results," said High. "We need to perform further studies to translate this finding into safe, effective treatments for hemophilia and other single-gene diseases in humans, but this is a promising strategy for gene therapy." She continued, "The clinical translation of genetic therapies from mouse models to humans has been a lengthy process, nearly two decades, but we are now seeing positive results in a range of diseases from inherited retinal disorders to hemophilia. In vivo genome editing will require time to mature as a therapeutic, but it represents the next goal in the development of genetic therapies."


'/>"/>

Contact: John Ascenzi
ascenzi@email.chop.edu
267-426-6055
Children's Hospital of Philadelphia
Source:Eurekalert  

Related biology news :

1. The human genome -- now on an iPad near you
2. The complete map of the Germany E. coli O104 genome released
3. Entomologists launch the 5,000 Insect Genome Project (i5k)
4. Genome offers clue to functions of destructive wheat fungus
5. Genome sequence could reveal Achilles heels of important wheat disease
6. Gerry A. Higgins, Ph.D. Joins GenomeQuest to Foster Development of Whole Genome Diagnostics
7. Einstein offers easy-to-use genome analyzer to scientific community
8. BGI releases a complete de novo E. coli O104 genome and details of their detection kit
9. BGI sequences genome of the deadly E. coli in Germany and reveals new super-toxic strain
10. Of mice and men: UNC-led team solves mouse genome dilemma
11. Comparison of genomes of plant parasites provides solid clues for response
Post Your Comments:
*Name:
*Comment:
*Email:
Related Image:
Genome editing, a next step in genetic therapy, corrects hemophilia in animals
(Date:2/3/2016)... India , February 3, 2016 ... the new market research report "Automated Fingerprint Identification System ... Search, Latent Search), Application (Banking & Finance, Government, Healthcare, ... published by MarketsandMarkets, the market is expected to be ... CAGR of 21.0% between 2015 and 2020. The transformation ...
(Date:2/2/2016)... , Feb. 2, 2016  BioMEMS devices ... primarily focused on medical screening and diagnostic ... parameters. Wearable devices that facilitate and assure ... of movement are being bolstered through new ... biomedical signal acquisition coupled with wireless connectivity ...
(Date:2/2/2016)... NEW YORK , Feb. 2, 2016 Technology ... service presents an analysis of the digital and computed ... Malaysia , and Indonesia ... current trends and market size, as well as regional ... by country and discusses market penetration and market attractiveness, ...
Breaking Biology News(10 mins):
(Date:2/4/2016)... CA (PRWEB) , ... February 04, 2016 , ... ... enterprise talent development and compliance training, today announced an interactive FDA compliance ... Playbook™. The RAPS (Regulatory Affairs Professional Society) accredited interactive course on Morf ...
(Date:2/4/2016)... (PRWEB) , ... February 04, ... ... conference presented by Bloomsburg University’s Digital Forensics Club, takes place February 5-6 ... two-day event features 20+ speakers and activities such as workshops and competitions ...
(Date:2/4/2016)... --> --> Q BioMed ... provide the following update on recent corporate developments. ... months we have significantly increased our cash position through several ... result, we have positioned ourselves to execute on the initial ... that development to continue on schedule. --> ...
(Date:2/4/2016)... ... February 04, 2016 , ... ... leading supplier of Semantic Graph Database technology has been recognized As “ Best ... by Corporate America Magazine. , “At Corporate America, it’s our priority to showcase ...
Breaking Biology Technology: