Scientists reverse age-related vision loss, eye damage from glaucoma in
mice

Date:
December 2, 2020
Source:
Harvard Medical School
Summary:
Researchers at Harvard Medical School have successfully reversed
age- related vision loss in animals as well as eye damage stemming
from with a condition mimicking human glaucoma, a leading cause
of blindness around the world.



FULL STORY ========================================================================== Harvard Medical School scientists have successfully restored vision
in mice by turning back the clock on aged eye cells in the retina to
recapture youthful gene function.


==========================================================================
The team's work, described Dec. 2 in Nature, represents the first
demonstration that it may be possible to safely reprogram complex tissues,
such as the nerve cells of the eye, to an earlier age.

In addition to resetting the cells' aging clock, the researchers
successfully reversed vision loss in animals with a condition mimicking
human glaucoma, a leading cause of blindness around the world.

The achievement represents the first successful attempt to reverse
glaucoma- induced vision loss, rather than merely stem its progression,
the team said. If replicated through further studies, the approach could
pave the way for therapies to promote tissue repair across various organs
and reverse aging and age-related diseases in humans.

"Our study demonstrates that it's possible to safely reverse the age of
complex tissues such as the retina and restore its youthful biological function," said senior author David Sinclair, professor of genetics in
the Blavatnik Institute at Harvard Medical School, co-director of the
Paul F. Glenn Center for Biology of Aging Research at HMS and an expert
on aging.

Sinclair and colleagues caution that the findings remain to be replicated
in further studies, including in different animal models, before any
human experiments. Nonetheless, they add, the results offer a proof of
concept and a pathway to designing treatments for a range of age-related
human diseases.



==========================================================================
"If affirmed through further studies, these findings could be
transformative for the care of age-related vision diseases like glaucoma
and to the fields of biology and medical therapeutics for disease at
large," Sinclair said.

For their work, the team used an adeno-associated virus (AAV) as a
vehicle to deliver into the retinas of mice three youth-restoring genes
-- Oct4, Sox2 and Klf4 -- that are normally switched on during embryonic development. The three genes, together with a fourth one, which was not
used in this work, are collectively known as Yamanaka factors.

The treatment had multiple beneficial effects on the eye. First, it
promoted nerve regeneration following optic-nerve injury in mice with
damaged optic nerves. Second, it reversed vision loss in animals with a condition mimicking human glaucoma. And third, it reversed vision loss
in aging animals without glaucoma.

The team's approach is based on a new theory about why we age. Most
cells in the body contain the same DNA molecules but have widely diverse functions. To achieve this degree of specialization, these cells must
read only genes specific to their type. This regulatory function is the
purview of the epigenome, a system of turning genes on and off in specific patterns without altering the basic underlying DNA sequence of the gene.

This theory postulates that changes to the epigenome over time cause
cells to read the wrong genes and malfunction -- giving rise to
diseases of aging. One of the most important changes to the epigenome
is DNA methylation, a process by which methyl groups are tacked
onto DNA. Patterns of DNA methylation are laid down during embryonic development to produce the various cell types. Over time, youthful
patterns of DNA methylation are lost, and genes inside cells that should
be switched on get turned off and vice versa, resulting in impaired
cellular function. Some of these DNA methylation changes are predictable
and have been used to determine the biologic age of a cell or tissue.



==========================================================================
Yet, whether DNA methylation drives age-related changes inside cells
has remained unclear. In the current study, the researchers hypothesized
that if DNA methylation does, indeed, control aging, then erasing some
of its footprints might reverse the age of cells inside living organisms
and restore them to their earlier, more youthful state.

Past work had achieved this feat in cells grown in laboratory dishes
but fell short of demonstrating the effect in living organisms.

The new findings demonstrate that the approach could be used in animals
as well.

Overcoming an important hurdle Lead study author, Yuancheng Lu, research
fellow in genetics at HMS and a former doctoral student in Sinclair's lab, developed a gene therapy that could safely reverse the age of cells in
a living animal.

Lu's work builds on the Nobel Prize winning discovery of Shinya Yamanaka,
who identified the four transcription factors, Oct4, Sox2, Klf4, c-Myc,
that could erase epigenetics markers on cells and return these cells
to their primitive embryonic state from which they can develop into any
other type of cell.

Subsequent studies, however, showed two important setbacks. First, when
used in adult mice, the four Yamanaka factors could also induce tumor
growth, rendering the approach unsafe. Second, the factors could reset
the cellular state to the most primitive cell state, thus completely
erasing a cell's identity.

Lu and colleagues circumvented these hurdles by slightly modifying the approach. They dropped the gene c-Myc and delivered only the remaining
three Yamanaka genes, Oct4, Sox2 and Klf4. The modified approach
successfully reversed cellular aging without fueling tumor growth or
losing their identity.

Gene therapy applied to optic nerve regeneration In the current study,
the researchers targeted cells in the central nervous system because it
is the first part of body affected by aging. After birth, the ability
of the central nervous system to regenerate declines rapidly.

To test whether the regenerative capacity of young animals could be
imparted to adult mice, the researchers delivered the modified three-gene combination via an AAV into retinal ganglion cells of adult mice with
optic nerve injury.

For the work, Lu and Sinclair partnered with Zhigang He, HMS professor
of neurology and of ophthalmology at Boston Children's Hospital, who
studies optic nerve and spinal cord neuro-regeneration.

The treatment resulted in a two-fold increase in the number of surviving retinal ganglion cells after the injury and a five-fold increase in
nerve regrowth.

"At the beginning of this project, many of our colleagues said our
approach would fail or would be too dangerous to ever be used," said
Lu. "Our results suggest this method is safe and could potentially revolutionize the treatment of the eye and many other organs affected
by aging." Reversal of glaucoma and age-related vision loss Following the encouraging findings in mice with optic nerve injuries, the team partnered
with colleagues at Schepens Eye Research Institute of Massachusetts Eye
and Ear Bruce Ksander, HMS associate professor of ophthalmology, and
Meredith Gregory-Ksander, HMS assistant professor of ophthalmology. They planned two sets of experiments: one to test whether the three-gene
cocktail could restore vision loss due to glaucoma and another to see
whether the approach could reverse vision loss stemming from normal aging.

In a mouse model of glaucoma, the treatment led to increased nerve
cell electrical activity and a notable increase in visual acuity,
as measured by the animals' ability to see moving vertical lines on a
screen. Remarkably, it did so after the glaucoma-induced vision loss
had already occurred.

"Regaining visual function after the injury occurred has rarely been demonstrated by scientists," Ksander said. "This new approach, which successfully reverses multiple causes of vision loss in mice without the
need for a retinal transplant, represents a new treatment modality in regenerative medicine." The treatment worked similarly well in elderly, 12-month-old mice with diminishing vision due to normal aging. Following treatment of the elderly mice, the gene expression patterns and electrical signals of the optic nerve cells were similar to young mice, and vision
was restored. When the researchers analyzed molecular changes in treated
cells, they found reversed patterns of DNA methylation -- an observation suggesting that DNA methylation is not a mere marker or a bystander in
the aging process, but rather an active agent driving it.

"What this tells us is the clock doesn't just represent time -- it is
time," said Sinclair. "If you wind the hands of the clock back, time
also goes backward." The researchers said that if their findings are
confirmed in further animal work, they could initiate clinical trials
within two years to test the efficacy of the approach in people with
glaucoma. Thus far, the findings are encouraging, researchers said. In
the current study, a one-year, whole-body treatment of mice with the
three-gene approach showed no negative side effects.


========================================================================== Story Source: Materials provided by Harvard_Medical_School. Original
written by Ryan Jaslow.

Note: Content may be edited for style and length.


========================================================================== Journal Reference:
1. Yuancheng Lu, Benedikt Brommer, Xiao Tian, Anitha Krishnan,
Margarita
Meer, Chen Wang, Daniel L. Vera, Qiurui Zeng, Doudou Yu, Michael S.

Bonkowski, Jae-Hyun Yang, Songlin Zhou, Emma M. Hoffmann,
Margarete M.

Karg, Michael B. Schultz, Alice E. Kane, Noah Davidsohn, Ekaterina
Korobkina, Karolina Chwalek, Luis A. Rajman, George M. Church,
Konrad Hochedlinger, Vadim N. Gladyshev, Steve Horvath, Morgan
E. Levine, Meredith S. Gregory-Ksander, Bruce R. Ksander, Zhigang
He, David A.

Sinclair. Reprogramming to recover youthful epigenetic
information and restore vision. Nature, 2020; 588 (7836): 124 DOI:
10.1038/s41586-020- 2975-4 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2020/12/201202114531.htm

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