[GRG] No extra mutations in modified (gene edited) stem cells

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No extra mutations in modified stem cells, study finds
New results ease previous concerns that gene-editing
techniques—used to develop therapies for genetic diseases—could add
unwanted mutations to stem cells.
July 09, 2014Share on facebookShare on twitterShare on emailShare
on printMore Sharing Services5LA JOLLA—The ability to switch out
one gene for another in a line of living stem cells has only
crossed from science fiction to reality within this decade. As with
any new technology, it brings with it both promise—the hope of
fixing disease-causing genes in humans, for example—as well as
questions and safety concerns. Now, Salk scientists have put one of
those concerns to rest: using gene-editing techniques on stem cells
doesn’t increase the overall occurrence of mutations in the cells.
The new results were published July 3 in the journal Cell Stem
Cell.

“The ability to precisely modify the DNA of stem cells has greatly
accelerated research on human diseases and cell therapy,” says
senior author Juan Carlos Izpisua Belmonte, professor in Salk’s
Gene Expression Laboratory. “To successfully translate this
technology into the clinic, we first need to scrutinize the safety
of these modified stem cells, such as their genome stability and
mutational load.”

The new study shows that gene-editing technologies are specific to
their targets and do not introduce harmful mutations, clearing the
way for the development of safe therapies in the clinic. The left
panel shows misshapen nuclear envelopes (red) from induced
pluripotent stem cells derived from cells with Parkinson’s disease
(DNA in blue). The right panel shows similarly induced cells that
have been gene-edited to restore the cells.

Click here for a high-resolution image.

Image: Courtesy of the Salk Institute for Biological Studies
When scientists want to change the sequence of a stretch of DNA
inside cells—either for research purposes or to fix a genetic
mutation for therapeutic purposes—they have their choice of two
methods. They can use an engineered virus to deliver the new gene
to a cell; the cell then integrates the new DNA sequence in place
of the old one. Or scientists can use what’s known as custom
targeted nucleases, such as TALEN proteins, which cut DNA at any
desired location. Researchers can use the proteins to cut a gene
they want to replace, then add a new gene to the mix. The cell’s
natural repair mechanisms will paste the new gene in place.

Previously, Belmonte’s lab had pioneered the use of modified
viruses, called helper-dependent adenoviral vectors (HDAdVs) to
correct the gene mutation that causes sickle cell disease, one of
the most severe blood diseases in the world. He and his
collaborators used HDAdVs to replace the mutated gene in a line of
stem cells with a mutant-free version, creating stem cells that
could theoretically be infused into patients’ bone marrow so that
their bodies create healthy blood cells.

Before such technologies are applied to humans, though, researchers
like Belmonte wanted to know whether there were risks of editing
the genes in stem cells. Even though both common gene-editing
techniques have been shown to be accurate at altering the right
stretch of DNA, scientists worried that the process could make the
cells more unstable and prone to mutations in unrelated genes—such
as those that could cause cancer.

“As cells are being reprogrammed into stem cells, they tend to
accumulate many mutations,” says Mo Li, a postdoctoral fellow in
Belmonte’s lab and an author of the new paper. “So people naturally
worry that any process you perform with these cells in
vitro—including gene editing—might generate even more mutations.”

Juan Carlos Izpisua Belmonte, Keiichiro Suzuki and Mo Li of the
Gene Expression Laboratory
From left: Juan Carlos Izpisua Belmonte, Keiichiro Suzuki and Mo Li
of the Gene Expression Laboratory

Click here for a high-resolution image.

Image: Courtesy of the Salk Institute for Biological Studies

To find out whether this was the case, Belmonte’s group, in
collaboration with BGI and the Institute of Biophysics, Chinese
Academy of Sciences in China, turned to a line of stem cells
containing the mutated gene that causes sickle cell disease. They
edited the genes of some cells using one of two HDAdV designs,
edited others using one of two TALEN proteins, and kept the rest of
the cells in culture without editing them. Then, they fully
sequenced the entire genome of each cell from the four edits and
control experiment.

While all of the cells gained a low level of random gene mutations
during the experiments, the cells that had undergone gene-
editing—whether through HDAdV—or TALEN-based approaches—had no more
mutations than the cells kept in culture.

“We were pleasantly surprised by the results,” Keiichiro Suzuki, a
postdoctoral fellow in Belmonte’s lab and an author of the study,
says. “People have found thousands of mutations introduced during
iPSC reprogramming. We found less than a hundred single nucleotide
variants in all cases.”

The finding, Li adds, doesn’t necessarily mean that there are no
inherent risks to using stem cells with edited genes, but that the
editing process doesn’t make the stem cells any less safe.

“We concluded that the risk of mutation isn’t inherently connected
to gene editing,” he says. “These cells present the same risks as
using any other cells manipulated for cell or gene therapy.” He
adds that two other papers published in the same issue support
their results (one by Johns Hopkins University and one from Harvard
University and collaborators).

The Belmonte group is planning more studies to address whether gene-
repair in other cell types, using other approaches, or targeting
other genes could be more or less likely to cause unwanted
mutations. For now, they hope their findings encourage those in the
field to keep pursuing gene-editing techniques as a potential way
to treat genetic diseases in the future.

Other researchers on the study were Jing Qu, April Goebl, Emi
Aizawa, Rupa Devi Soligalla, Jessica Kim, Na Young Kim, Hsin-Kai
Liao, Chris Benner, and Concepcion Rodriguez Esteban of the Salk
Institute for Biological Studies; Chang Yu, Xiaotian Yao, Senwei
Tang, Fan Zhang, Feng Chen, Yabin Jin, and Yingrui Li of BGI; and
Jing Qu,Tingting Yuan, Ruotong Ren, Xiuling Xu, and Guang-Hui Liu
of the Institute of Biophysics, Chinese Academy of Sciences.

The work was supported by the G. Harold and Leila Y. Mathers
Charitable Foundation, the Leona M. and Harry B. Helmsley
Charitable Trust, the Glenn Foundation, the California Institute of
Regenerative Medicine, the National Institutes of Health, the
Chinese Academy of Sciences, the Beijing Natural Science
Foundation, and the Thousand Young Talents program of China.

About the Salk Institute for Biological Studies:
The Salk Institute for Biological Studies is one of the world’s
preeminent basic research institutions, where internationally
renowned faculty probes fundamental life science questions in a
unique, collaborative and creative environment. Focused both on
discovery and on mentoring future generations of researchers, Salk
scientists make groundbreaking contributions to our understanding
of cancer, aging, Alzheimer’s, diabetes and infectious diseases by
studying neuroscience, genetics, cell and plant biology, and
related disciplines.

Faculty achievements have been recognized with numerous honors,
including Nobel Prizes and memberships in the National Academy of
Sciences. Founded in 1960 by polio vaccine pioneer Jonas Salk, MD,
the Institute is an independent nonprofit organization and
architectural landmark.

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About Johnny Adams

My full-time commitment is to slow and ultimately reverse age related functional decline to increase healthy years of life. I’ve been active in this area since the 1970s, steadily building skills and accomplishments. I have a good basic understanding of the science of aging, and have many skills that complement those of scientists so they can focus on science to advance our shared mission. Broad experience Top skills: administration, management, information technology (data and programming), communications, writing, marketing, market research and analysis, public speaking, forging ethical win-win outcomes among stakeholders (i.e. high level "selling"). Knowledge in grant writing, fundraising, finance. Like most skilled professionals, I’m best described as a guy who defines an end point, then figures out how to get there. I enjoy the conception, design, execution and successful completion of a grand plan. Executive Director Gerontology Research Group (GRG). Manages Email discussion forum, web site, meetings and oversees supercentenarian (oldest humans, 110+ years) research. CEO / Executive Director Carl I. Bourhenne Medical Research Foundation (Aging Intervention Foundation), an IRS approved 501(c)(3) nonprofit. http://www.AgingIntervention.org Early contributor to Supercentenarian Research Foundation. Co-Founder Geroscience Healthspan Forum. Active contributor to numerous initiatives to increase healthy years of life. Co-authored book on conventional, practical methods available today to slow the processes of aging – nutrition, exercise, behavior modification and motivation, stress reduction, proper supplementation, damage caused by improper programs, risk reduction and others. Fundamental understanding of, and experience in the genomics of longevity (internship analyzing and curating longevity gene papers). Biological and technical includes information technology, software development and computer programming, bioinformatics and protein informatics, online education, training programs, regulatory, clinical trials software, medical devices (CAT scanners and related), hospital electrical equipment testing program. Interpersonal skills – good communication, honest, well liked, works well in teams or alone. Real world experience collaborating in interdisciplinary teams in fast paced organizations. Uses technology to advance our shared mission. Education: MBA 1985 University of Southern California -- Deans List, Albert Quon Community Service Award (for volunteering with the American Longevity Association and helping an elderly lady every other week), George S. May Scholarship, CA State Fellowship. BA psychology, psychobiology emphasis 1983 California State University Fullerton Physiological courses as well as core courses (developmental, abnormal etc). UCLA Psychobiology 1978, one brief but fast moving and fulfilling quarter. Main interest was the electrochemical basis of consciousness. Also seminars at the NeuroPsychiatric Institute. Other: Ongoing conferences, meetings and continuing education. Aging, computer software and information technology. Some molecular biology, biotech, bio and protein informatics, computer aided drug design, clinical medical devices, electronics, HIPAA, fundraising through the Assoc. of Fundraising Professionals. Previous careers include: Marketing Increasing skill set and successes in virtually all phases, with valuable experience in locating people and companies with the greatest need and interest in a product or service, and sitting across the table with decision makers and working out agreements favorable to all. Information Technology: Management, data analysis and programming in commercial and clinical trials systems, and bioinformatics and protein informatics. As IT Director at Newport Beach, CA based technology organization Success Family of Continuing Education Companies, provided online software solutions for insurance and financial professionals in small to Fortune 500 size companies. We were successful with lean team organization (the slower moving competition was unable to create similar software systems). Medical devices: At Omnimedical in Paramount CA developed and managed quality assurance dept. and training depts. for engineers, physicians and technicians. Designed hospital equipment testing program for hospital services division. In my early 20’s I was a musician, and studied psychology and music. Interned with the intention of becoming a music therapist. These experiences helped develop valuable skills used today to advance our shared mission of creating aging solutions.
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