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Gene therapy techniques restore
vision damage from age and glaucoma in miceJanuary 21, 2021
While eyesight often dims with age,
a novel mouse study provides intriguing evidence that innovative gene therapy
techniques could someday roll back the biological clock for our vision. The
research was conducted with NIA and the National Eye Institute support by a
Harvard Medical School team and published recently in Nature.
The teamfs approach involved
epigenetics, a field of science that studies heritable changes that can
activate or deactivate genes without any change in the underlying DNA sequence
of these genes. The word epigenetics is of Greek origin and literally means
over and above (epi) the genome.
Their experiments refined a technique that won a Nobel prize in 2012. The
basic idea is that by using a harmless virus to introduce just a few genes,
called Yamanaka factors after the researcher who discovered them, scientists
can reprogram the DNA of mature cells of different types to transform back
into young (pluripotent) stem cells. These can then regenerate function
lost to age, illness, or injury. The virusf payload is turned on or off
via injection of a selective inducer molecule.
This cell reprogramming method
could lead to future disease therapies, but previous studies showed it is tough
to safely rein in the rapid cell growth and tumor development triggered by
Yamanaka factors. The Harvard team found a way to keep the beneficial effects
and weed out the dangerous ones by leaving out one of the four factor genes,
called MYC, that is closely related to cancer and can shorten the lifespan of
mice when it is expressed.
First working in lab cell cultures,
the team was able to rejuvenate damage to retinal ganglion cells, a type of
neuron found at the rear of the eye. Later in a mouse model, the same
techniques seemed to protect some optic nerve cells from damage and caused
others to grow fresh connections to the brain. A third experiment had similar
success reversing some vision damage in a mouse model of glaucoma, a leading
cause of age-related blindness in humans.
In lab tests, the glaucoma model
mice who received the injection treatment gained back roughly half of their
previously lost visual ability. In other experiments, middle-aged mice who
received the injection scored similar to younger mice in visual tests, plus
their DNA showed expression and methylation (epigenetic patterns of common
chemical groups that attach to DNA at different life stages) signatures that
resembled the genetic material of younger mice. They have also found that these
recovered functions require two DNA methylation enzymes that could be
responsible for these epigenetic changes during the reprograming.
While the researchers are
encouraged by this progress, they caution that epigenetic reprogramming
techniques are still very complex and still harbor risk of abnormal cell growth
or cancer. They plan to conduct many further studies to test the gene therapy
technologies in larger animals, explore how the restorative factors impact
other types of cells and tissues, and verify that the youthful changes seen are
not fleeting.
This research was funded by NIA
grants R01AG019719, R37AG028730, R01AG067782, R01AG065403, K99AG068303, and
T32AG023480.
Reference: Lu Y, et al. Reprogramming to recover youthful epigenetic information
and restore vision.
Nature. 2020;588(7836):124-129. doi:10.1038/s41586-020-2975-4
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