National Institutes of Health (US) researchers have uncovered a key factor in
understanding the elevated cancer risk associated with gene therapy.
They conducted research on mice with a rare disease similar to one in
humans, hoping their findings may eventually help improve gene therapy
for humans.
Researchers at the National Human Genome Research Institute
(NHGRI), part of NIH, published their research in the Jan. 20, 2015,
online issue of the Journal of Clinical Investigation.
“Effective and safe gene therapies have the potential to
dramatically reverse diseases that are life-threatening for affected
children,” said NHGRI Scientific Director Dan Kastner, M.D., Ph.D.
“This study is an important step in developing gene therapies that can
be safely used to benefit patients.”
Toxic side effects actually are rarely observed by
researchers who have designed gene therapies using an adeno-associated
virus (AAV) as a vector to deliver the corrected gene to a specific
point in the cell’s DNA. AAVs are small viruses that infect humans but
do not cause disease. A vector is a DNA molecule of AAV used as a
vehicle to carry corrected genetic material into a cell. AAV viruses
are uniquely suited for gene therapy applications.
But one prior study did find an association between AAV
and the occurrence of liver cancer. The present research addresses this
problem in gene therapy for an inherited disease in children called
methylmalonic acidemia, or MMA.
For 10 years, NHGRI researchers have worked toward a
gene therapy to treat MMA. The condition affects as many as 1 in 67,000
children born in the United States. Affected children are unable to
properly metabolize certain amino acids consumed in their diet, which
can damage a number of organs and lead to kidney failure. MMA patients
also suffer from severe metabolic instability, failure to thrive,
intellectual and physical disabilities, pancreatitis, anemia, seizures,
vision loss and strokes. The most common therapy is a restrictive
diet, but doctors must resort to dialysis or kidney or liver
transplants when the disease progresses.
In prior MMA gene therapy studies, researchers showed
that mice bred to develop the condition could be restored to health by
AAV gene therapy injection shortly after birth. The mice in the study
survived into adulthood and were free from the effects of MMA.
“The corrected gene delivered by AAV is the most
effective therapy we have developed so far to treat MMA,” said Charles
Venditti, M.D., Ph.D., senior author and investigator in NHGRI’s
Genetic and Molecular Biology Branch. “However, we have identified an
important safety parameter related to the AAV gene therapy in our mouse
models that is critical to understand before we move to human patient
trials.”
Now, in a long-term follow-up of the treated mice — after
mice reached about two years of age — the researchers documented a
50-70 percent higher occurrence of liver cancer in AAV-treated mice
compared with a 10 percent liver cancer rate in untreated mice. Dr.
Venditti’s team determined that the AAV vector triggered the cancer.
The research team performed additional experiments to
detect where in the mouse genome the AAV vector delivered the corrected
gene and how that related to any cancer development. In many mice that
developed liver cancer, the AAV vector targeted a region of the mouse
genome called Rian, near a gene called Mir341 that codes for a microRNA
molecule. MicroRNAs are small, non-coding RNA molecules involved in
the regulation of gene expression. When the AAV was inserted near
Mir341, the vector caused elevated expression of the gene, which the
researchers believe contributed to the occurrence of liver cancer in
the mice. The authors note that Mir341 is found in the mouse genome,
however, it is not present in humans.
When the researchers used an alternate AAV vector to
deliver the corrected gene in a study of just 10 mice, that vector did
not insert where it would elevate the expression of nearby genes and it
did not cause liver cancer. The researchers found that this
modification was a safer gene therapy.
“These studies will help us move forward to develop safer
gene therapy for methylmalonic acidemia,” said Randy Chandler, Ph.D.,
lead author and NHGRI staff scientist. “Most of the AAV integrations
that caused liver cancer landed in a gene that is not found in the
human genome, which suggests that the cancers we observed after AAV gene
therapy may have been a mouse-specific phenomenon. However, these
studies do convincingly demonstrate that AAV can be a cancer-causing
agent, which argues for further studies.”
The researchers also observed that lower doses of AAV
resulted in reduced rates of liver cancer compared to a control group
of mice. Their data showed that the rate of cancer dropped in
proportion to the dose of the AAV.
Dr. Venditti hopes that methodologies described in his
team’s research will be used by others to study the toxicity of AAV
vectors in their preclinical trials.
NHGRI is one of the 27 institutes and centers at the
NIH, an agency of the Department of Health and Human Services. The
NHGRI Division of Intramural Research develops and implements
technology to understand, diagnose and treat genomic and genetic
diseases. Additional information about NHGRI can be found at its
website, http://www.genome.gov.
About the National Institutes of Health (NIH):
NIH, the nation's medical research agency, includes 27 Institutes and
Centers and is a component of the U.S. Department of Health and Human
Services. NIH is the primary federal agency conducting and supporting
basic, clinical, and translational medical research, and is
investigating the causes, treatments, and cures for both common and rare
diseases. For more information about NIH and its programs, visit www.nih.gov.