For the first time, scientists have successfully managed to shuttle
gene-stimulating molecules into specific target cells of a living
animal. Alongside being a long-sought-after achievement, the team was
also able to use their novel technique to drive the production of
protective proteins in the livers of mice, rescuing them from
drug-induced liver damage. Although much more research is needed before
this revolutionary method finds itself in the clinic, this encouraging
work raises the possibility that it could one day achieve similar
therapeutic feats in humans. The study has been published in Nature Materials.
Our genetic material, DNA, contains the biological instructions
needed to create the components of the cell, or more specifically
proteins. When a protein needs to be made, DNA is used to generate a
blueprint, called mRNA, which contains the necessary codes for its
production. This process is known as transcription and can be ramped up
or dampened by molecules known as transcription factors. These proteins stick to specific bits of DNA and consequently promote or block the action of molecules that drive the reading of genes, thus controlling which are switched on or off.
Since transcription factors control every major physiological process within the cell,
and hold the ability to correct the causes of a significant range of
diseases, they have huge therapeutic potential. For example, the
transcription factor Nrf2 drives production of proteins, such as
antioxidants, that reduce cellular stress and inflammation and can hence
protect against various inflammatory diseases, like drug-induced liver
failure and Alzheimer’s.
While this all sounds great on paper, researchers are faced with a
problem: When they try to get these helpful molecules inside the cell,
they get automatically directed
towards an acidic compartment known as a lysosome, which causes them to
break down. Scientists therefore endeavored to find a way to prevent
this from happening without altering the transcription factor itself—and
back in 2011, a group from UCLA started to make significant progress.
They discovered
that attaching the molecules to a string of DNA that matches the
transcription factor’s target sequence, alongside cocooning it inside a
positively charged molecule, helped it traverse the cell’s negatively
charged membrane. This allowed the researchers to get the transcription
factors inside human cells in a dish. Now, taking this one step further,
the scientists have added further features to the complex that not only
target it to specific cells, but also help prevent its degradation by
the lysosome.
This involved linking certain chemicals to the DNA that puncture the
lysosome’s membrane, allowing the transcription factor to escape once
inside. They also added specific sugar molecules to these chemicals that
bind to receptors found on the surface of liver cells, thus
facilitating targeted delivery of the molecules. The researchers called
this final complex DART, or DNA assembled recombinant transcription
factors.
To test it out, they created a complex with the aforementioned
transcription factor Nrf2 and tried it out on mice that had been given a
very high dose of the pain-relief medication acetaminophen, or
paracetamol, which would normally cause liver damage. Next, they
injected DART into half of the mice and assessed their outcomes.
They found that DART was predominantly taken up by liver cells and
boosted the expression of genes known to protect against cellular
stress. Furthermore, mice that had been given DART had livers that
closely resembled those of healthy mice, whereas the controls
experienced liver damage.
These early results are certainly promising, but it remains to be
seen whether other tissues could be targeted, which would obviously
widen clinical applications. Furthermore, this kind of therapy would be extremely extensive, which may limit its use.
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