Scientists have successfully restored vision in mice by turning back the clock to recapture the youthful function of the genes in their eyes, an advance which may set the stage for the treatment of various age-related diseases in humans. The proof-of-concept research, published in the journal Nature, also successfully reversed age-related vision loss in mice with a condition mimicking human glaucoma, a leading cause of blindness around the world.
According to the scientists, the study 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. ”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 study senior author David Sinclair, professor of genetics at Harvard Medical School in the US.
If replicated in further studies, the researchers believe the approach could pave the way for novel therapies to reverse aging and age-related diseases in humans. In the study, the scientists 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. They said these three genes, together with a fourth one, which was not used in this work, are collectively known as Yamanaka factors.
The novel treatment, based on an emerging understanding of why animals age, promoted nerve regeneration in mice with damaged optic nerves, and also reversed vision loss in the rodents which had a condition mimicking human glaucoma, the study noted. While most cells in the body contain the same DNA molecules, they have widely diverse functions by reading out only genes specific to their type.
This regulatory function, the researchers explained, is based on a system of turning genes ”on and off” in specific patterns without altering the basic underlying DNA sequence of the gene — also known as the epigenome. They believe changes to this epigenome system, such as when methyl chemical groups in the body are tacked onto DNA, cause cells to read the wrong genes and malfunction over time — giving rise to diseases of aging. Although patterns of DNA methylation are laid down during embryonic development to produce the various cell types, the researchers said these systems may be lost over time. When this happens, the scientists said genes inside cells that should be switched on get turned off, and vice versa, resulting in impaired cellular function.
In the current study, the researchers assessed if erasing some of the footprints of DNA methylation might reverse the age of cells. Earlier studies had pointed that the genes Oct4, Sox2, and Klf4 could help erase epigenetics markers, and return these cells to their primitive embryonic state from which they can develop into any other type of cell.
In the current research, they delivered the modified three-gene combination via an AAV into retinal ganglion cells of adult mice with optic nerve injury. According to the scientists, 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.
”Our results suggest this method is safe and could potentially revolutionise the treatment of the eye, and many other organs affected by aging,” said study lead author Yuancheng Lu from Harvard Medical School. Following the results, the scientists planned two sets of experiments — one to test whether the three-gene cocktail could restore vision loss caused by glaucoma, and another to see if the approach could reverse aging-related blindness.
In a mouse model, they said the treatment led to increased nerve cell electrical activity, and a notable increase in visual acuity measured by the animals’ ability to see moving vertical lines on a screen — even after the glaucoma-induced vision loss had already occurred. ”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,” said Bruce Ksander, another co-author of the study.
When the scientists analysed molecular changes in the treated cells, they found reversed patterns of DNA methylation — an observation suggesting that DNA methylation is not a mere marker in the aging process, but rather an driving force. ”What this tells us is the clock doesn’t just represent time — it is time. If you wind the hands of the clock back, time also goes backward,” Sinclair added.