Recovering vision in people who have lost it due to different diseases, such as glaucoma or macular or retinal degeneration is one of the frontiers that scientific research has barely reached. Progress is slow, but in recent days two new studies seem to have taken a new step.
The first of these is published today in “Nature” and its authors claim to have reversed age-related vision loss, at least in mice. How?.
Researchers have used an innovative way to achieve it. They have reprogrammed the neurons of the mice to a more youthful state in which they regain the ability to regenerate and restore vision. The research is especially significant because it represents the first demonstration that complex tissues, such as nerve cells in the eye, can be safely reprogrammed for delivery at an earlier age.
In addition, it sheds light on the mechanisms of aging and identifies new therapeutic targets, potential for age-related neural diseases, such as glaucoma.
By resetting the aging clock of cells, the researchers successfully reversed vision loss in animals with a condition that mimics human glaucoma, one of the leading causes of blindness worldwide.
The achievement represents the first successful attempt to reverse glaucoma-induced vision loss, rather than simply stopping its progression, the team said. If replicated through additional studies, the approach could pave the way for therapies to promote tissue repair in various organs and reverse aging and age-related diseases in humans.
“Our study shows that complex tissues such as the retina can be safely re-aged and their biological function restored to a more early stage,” says the lead author. David Sinclair, from the Blavatnik Institute of Harvard Medical School (USA).
Although these findings need to be replicated in further studies, including in different animal models, before designing a human study, they consider that this ‘proof of concept’ opens a way to design treatments for a variety of age-related human diseases, such as Alzheimer’s.
“If confirmed, these findings could be transformative for the care of age-related eye diseases like glaucoma and for other diseases,” says Sinclair.
The lead author of the study, Yuancheng Lu, developed a gene therapy that could safely reverse the age of cells in a living animal.
His work is based on the discovery of Yamanaka, who identified the four transcription factors, Oct4, Sox2, Klf4, c-Myc. However, later studies showed that, when these factors are used in adult mice, they also could induce tumor growth, making the focus unsafe. Second, these factors could restore the cellular state to the most primitive cellular state, thus completely erasing the identity of a cell.
To get around these obstacles, they slightly modified the approach. They skipped the c-Myc gene and delivered only the three remaining Yamanaka genes, Oct4, Sox2, and Klf4. The modified approach successfully reversed cellular aging without stimulating tumor growth or losing its identity.
In the current study, the researchers focused on cells central nervous system because it is the first part of the body affected by aging. After birth, the ability of the central nervous system to regenerate rapidly diminishes.
To test whether the regenerative capacity of the young animals could be imparted to adult mice, the researchers administered the modified combination of three genes via an AAV into retinal ganglion cells of adult mice with optic nerve injury.
The technique they describe in their work used an adeno-associated virus (AAV) as a vehicle to deliver three youth-restoring genes (Oct4, Sox2 and Klf4) into the retinas of mice, which are normally activated during embryonic development. The three genes, along with a fourth, which was not used in this work, are collectively known as Yamanaka factors (the Japanese Shinya Yamanaka discovered that it was possible to reverse the clock of cells and get them to revert to a state similar to the embryonic work for which he received the Nobel Prize in Medicine in 2006).
The treatment had multiple beneficial effects on the eye. First, promoted nerve regeneration after optic nerve injury in mice with damaged optic nerves. Additionally, it reversed vision loss in animals with a condition that mimicked human glaucoma. And finally, 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 they have very different functions. To achieve this degree of specialization, these cells must read only specific genes of their type.
This regulatory function is the responsibility of the epigenoma, 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 in the epigenome over time cause cells to read the wrong genes and thus malfunction, leading to diseases of aging. One of the most important changes in the epigenome is DNA methylation, a process by which methyl groups are added to DNA. DNA methylation patterns are established during embryonic development to produce the various types of cells.
Over time, youthful DNA methylation patterns are lost and genes within cells that should be turned on are turned off and vice versa, resulting in impaired cell function. Some of these DNA methylation changes are predictable and have been used to determine the biological age of a cell or tissue.
However, it is not clear whether DNA methylation generates age-related changes within cells. In the current study, the researchers hypothesized that if DNA methylation does control aging, erasing some of its fingerprints could reverse the age of cells within living organisms and restore them to their earlier, more youthful state.
Previous work had accomplished this feat in cells grown in laboratory plates, but failed to demonstrate the effect in living organisms. The new findings show that the approach could also be used in animals.
Does this mean that it could also be reversed in humans and that it could be applied in humans? In News & Views, Andrew Huberman of the Stanford University School of Medicine (USA) believes that, although the effects of the transcription factors described here have not yet been tested in humans, the results suggest that they can reprogram brain neurons in all the species.
“What this tells us is that the clock doesn’t just represent time, it is time,” says Sinclair. “If you turn back the hands of the clock, time also goes back.”
In another work, published in the magazine «Molecular Therapy», Spanish researchers describe how dying retinal cells send a rescue signal to stem cells to repair eye damage.
The findings open up new treatment avenues in the field of vision recovery, such as, for example, transplantation of modified stem cells that are sensitive to this signal.
This team from the Center for Genomic Regulation (CRG) identified two cellular signals – known as Ccr5 and Cxcr6 – in models of retinal degeneration in humans and mice. He then modified the stem cells to express an abundance of receptors for Ccr5 and Cxcr6.
After transplanting these stem cells into the models used, the team found that they were more likely to move into dying retinal cells, rescuing them from death and preserving their function.
“One of the main obstacles in the use of stem cells to treat vision loss is their low capacity for migration and cellular integration in the retina,” he says. Pia Cosma, lead author of the study. Here, he notes, “we have found a way to facilitate this process using bone marrow stem cells, but in principle any type of cell can be used.”
Retinal degeneration is incurable and inevitably causes visual impairment and, in the vast majority of cases, blindness. With a growing and aging population, the number of people affected by damage to the retina is expected to increase substantially in the coming decades.
Stem cell therapies are a great idea for treating degenerative retinal conditions. The stem cells can be transplanted into the eye, releasing therapeutic molecules with neuroprotective and anti-inflammatory properties that promote the survival, proliferation and automatic repair of retinal cells. And they can also generate new retinal cells, to replace those that have been lost or damaged.
In this case, mesenchymal stem cells were used, which come from the bone marrow and can differentiate into many types of cells, including retinal cells that respond to light. They can also be easily grown outside of an organism, providing abundant starting material for transplantation, compared to other cellular sources, such as hematopoietic stem cells.
The researchers modified them using a lentivirus, but the team believes that using other methods, such as the adeno-associated virus (AAV) vector, can also express these receptors.
‘AAV is gaining popularity as the ideal therapeutic vector in Europe and the US Regulators have already approved commercial uses of AAV-based therapies in patients. Although much work remains to be done, our findings could make stem cell transplants a viable and realistic option for treating visual impairment and restoring vision, ”Cosma concludes.