- Arthritis or joint inflammation is a painful condition that
restricts mobility and physical activity, and affects the quality of life.
- Current drugs that target the pro-inflammatory molecule, namely
tumor necrosis factor-alpha (TNF-α), are given systemically with potential
- Modified stem cells termed SMART cells (Stem
cells Modified for Autonomous Regenerative Therapy), created using gene editing technology
delivers targeted biological anti-inflammatory drug locally within the
joint only when required.
rewired stem cells or SMART cells can become a possible future therapy for
joint inflammation due to arthritis
. The remarkable feature of these stem cells is their ability to form healthy
to replace damaged cartilage in arthritis, while at the same time delivering a biological
to combat the tissue damage associated with chronic
These SMART cells were developed at
Washington University School of Medicine in St. Louis and Shriners Hospitals
for Children-St. Louis, in collaboration with investigators at Duke University
and Cytex Therapeutics Inc., both in Durham, N.C.
‘Using a combination of pluripotent stem cells to create desired tissue, and CRISPR gene editing technology to modify genes, opens up endless possibilities for treating a wide variety of disorders including arthritis.’
Aim of The Research
drugs for arthritis such as Etanercept
(Humira) and Infliximab
(Remicade) that target the pro-inflammatory molecule TNF-α are
administered systemically rather than locally, making the individual prone to
side-effects such as increased risk of infections.
research team aimed to overcome the
limitations of current forms of treatment and create a stem cell-based
that could be given directly
into the joints
"Our goal is to package the rewired
stem cells as a vaccine for arthritis, which would deliver an anti-inflammatory drug to an arthritic
joint but only when it is needed," said Farshid Guilak, PhD, the paper's
senior author and a professor of orthopedic surgery at Washington University
School of Medicine.
of the Research
team of scientists proceeded to create SMART cells (Stem
cells Modified for Autonomous Regenerative Therapy) for local injection within
- Using skin cells taken from the
tails of mice, the scientists converted them into stem cells in the lab.
- Using CRISPR gene editing
technology, the team removed stem cell genes that encode for the production
of the inflammatory molecule (TNF-alpha) and replaced with genes that
induce production of a TNF-α inhibitor.
- The scientists then directed these stem cells to become cartilage
cells that produce cartilage tissue.
- Advanced tools of synthetic biology and regenerative medicine
enabled them to control the response so that these modified stem cells
would release the anti-inflammatory drug at the appropriate time when
there was an exacerbation of joint pain and swelling.
- Additionally, the research team incorporated genes into the stem
cells that caused them to light up in response to inflammation enabling
them to monitor the stem cell response.
tools from synthetic biology, we found we could re-code the program that stem
cells use to orchestrate their response to inflammation," said Jonathan
Brunger, PhD, the paper's first author and a postdoctoral fellow in cellular
and molecular pharmacology at the University of California, San Francisco.
went on to add that in essence, they had hijacked an inflammatory response
pathway to instead produce a protective anti-inflammatory drug.
Results of the Research
research team observed that the synthetic
cartilage produced by these modified cells was protected from inflammation
What is CRISPR Technology?
CRISPR-Cas9 is a novel technology that
allows scientists to edit the genome, by deleting, replacing, or adding to
parts of the DNA sequence. It consists of two key components namely the enzyme Cas-9
and a guide RNA (gRNA) that guides the molecular scissors to the right part of
the genome to be removed or replaced.
Future Research and Expansion of Current Research
Guilak's team have already begun testing the modified stem cells in
mouse models of rheumatoid arthritis and other inflammatory diseases
Should the therapy be reproducible in
other animals and developed into clinical treatment, the synthetic cartilage
produced from the stem cells in response to inflammation would also release a
biological TNF-alpha inhibitor protecting it from inflammation and damage. In
certain joints, the natural cartilage would also be protected.
"When these cells see TNF-alpha,
they rapidly activate a therapy that reduces inflammation," Guilak
explained. "We believe this
strategy also may work for other systems that depend on a feedback loop
diabetes, for example, it's possible we could make stem cells that would sense
glucose and turn on insulin in response.
In conclusion, the potent combination of
pluripotent stem cells and CRISPR
gene editing technology, throws up innumerable
possibilities to treat a wide range of disorders.
With an eye toward further applications
of this approach, Brunger added, "The ability to build living tissues from
'smart' stem cells that precisely respond to their environment opens up
exciting possibilities for investigation in regenerative medicine."
- Jonathan M. Brunger, Ananya Zutshi, Vincent P. Willard, Charles A. Gersbach, Farshid Guilak. Genome Engineering of Stem Cells for Autonomously Regulated, Closed-Loop Delivery of Biologic Drugs. Stem Cell Reports, 2017; DOI: 10.1016/j.stemcr.2017.03.022
- What is CRISPR-Cas9? - (http://www.yourgenome.org/facts/what-is-crispr-cas9)