Using an experimental gene therapy, Harvard scientists have successfully restored vision to mice suffering glaucoma by effectively rewinding the aging process in their cells. While still in the early stages, the team says the research is a proof of concept for slowing the symptoms of aging with epigenetics.
To turn back the clock, the researchers delivered three key genes into the retinas of several groups of mice with different eye problems. In mice with optic nerve injuries, the treatment helped the nerves regenerate. The therapy also helped reverse vision loss in mice with a condition similar to glaucoma, as well as those with more general age-related impairment.
“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,” says David Sinclair, senior author of the study. “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.”
The team's research involves targeting the epigenome. The contents of our DNA isn’t the only way information is passed down through generations – the field of epigenetics explores how the expression of genes is turned on and off. One of the main epigenetic changes is DNA methylation, where patterns of molecules “tag” genes to control how they’re expressed without changing the underlying DNA sequence.
These methylation patterns are laid down during embryonic development, essentially helping different cell types only read the DNA sequences that are relevant to them. DNA methylation patterns are thought to become somewhat scrambled as we age, which changes gene expression and, in turn, impairs the function of cells. Ultimately, that results in the symptoms of aging that we all know too well.
So, the researchers on the new study set out to investigate whether restoring these patterns to a more youthful state could reverse damage to cells. They loaded three specific genes into a viral vehicle and introduced the package to the retinas of mice.
The genes in question – Oct4, Sox2 and Klf4 – are three of the four Yamanaka factors, a group of genes that are used to turn cells into induced pluriopotent stem cells, ready to become whatever cells are needed.
By only using three of the factors, the team didn’t rewind the clock right back to the stem cell stage – just far enough to return the cells to a healthier, more youthful state. Plus, it prevents the method from inducing tumor growth, which is a known pitfall.
And the treatment had promising results in the animal tests. In the mice with optic nerve damage, the treatment doubled the number of surviving retinal ganglion cells, and regrew the nerves five times better than the control.
In those with glaucoma or age-related vision loss, gene expression patterns and electrical signals in optic nerve cells increased to levels normally seen in young, healthy mice. The animals also performed better in visual acuity tests.
“Regaining visual function after the injury occurred has rarely been demonstrated by scientists,” says Meredith Gregory-Ksander, an author of the study. “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 team says that if the findings can be validated in further animal studies, human clinical trials could begin in glaucoma patients within two years.
The research was published in the journal Nature.
Source: Harvard Medical School