This success tells us that it is
becoming practical to target specific DNA in a living human being in order to
first correct abnormalities and thenceforth to even induce beneficial
changes. Thus we discover that your
birth genetic package is no longer forever.
The mere fact that we can today
do the above agues that the full range of options that we can imagine will be
available to us during the next two decades and that this will even become a
huge research effort.
It is one thing to experiment on
the unborn, it is quite another to restrain the curious wishes and desires of
the wealthy in their pursuit of an improved body. It is not going to be denied and will surely begin
with improved sexual performance.
Genome Editing, a Next Step in Genetic Therapy, Corrects Hemophilia in
Animals
Released: 6/24/2011 2:45 PM EDT
Embargo expired: 6/26/2011 1:00 PM EDT
--Children’s Hospital
of Philadelphia Study Advances New Strategy
Newswise — Philadelphia, June 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 therapy—developing 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 liver—where 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.”
Support for this work came from the National Institutes of Health and
the Howard Hughes Medical Institute. High’s co-authors were from The Children’s
Hospital of Philadelphia, the University of Pennsylvania, and Sangamo
BioSciences, Inc. of Richmond, Calif.
“In vivo genome editing restores hemostasis in a mouse model of
hemophilia,” Nature, published online June 26, 2011. doi:
10.1038/nature10177
About the Center for Cellular and Molecular Therapeutics (CCMT) at The
Children’s Hospital of Philadelphia: The Children’s Hospital of Philadelphia
and the CCMT, directed by Dr. Katherine High, have pioneered the development of
clinically promising AAV-mediated gene therapies. Dr. High and her colleagues
conducted the first trial of recombinant AAV delivered to skeletal muscle, the
first trial of AAV directed to liver, and the first U.S.
About The Children’s Hospital
of Philadelphia : The Children’s Hospital of Philadelphia
