- The proof-of-concept concept study represents the first successful attempt to counteract the aging clock in animals through epigenetic reprogramming.
- Scientists turned on fetal genes to reprogram mouse retina cells.
- Anti-glaucoma-induced eye damage in animals.
- The approach also restores age-related vision loss in older rats.
- Work spells that promise to use the same approach in other tissues, organs ahead of the eyes.
- Success sets the stage for the treatment of various age-related diseases in humans.
Scientists at Harvard Medical School have successfully restored vision in mice by turning the clock on aged eye cells in the retina to regain youthful gene function.
Team work described in Today (December 2, 2020) Nature, The first demonstration shows that complex tissues, such as the nerve cells of the eye, can be safely reprogrammed at an earlier age.
In addition to resetting the aging clock of cells, researchers have successfully reversed vision loss in animals with a condition that mimics human glaucoma, a leading cause of blindness worldwide.
The team said the first successful attempt to reverse glaucoma-induced vision loss was a success. If replicated by further studies, the approach could pave the way for therapy to promote tissue repair in various organs and to counteract aging and age-related diseases in humans.
“Our study shows that it is possible to safely reverse the age of complex tissues such as the retina and restore the biological function of its youth,” said David Sinclair, a senior author and professor of genetics at the Blevatnik Institute at Harvard Medical School. Glenn Center for Biology of Aging Research HMS and aging specialist.
Sinclair and colleagues cautioned that the findings before any human experiments would be replicated in further studies, including models of different animals. However, they added, the results present a proof and way of guiding the formulation of treatment for a range of age-related human diseases.
“If supported by further studies, these findings could be variable in the fields of care for age-related vision disorders such as glaucoma and biological and medical therapeutics for most diseases,” Sinclair said.
For their work, the team used a youth-related virus (AAV) as a vehicle to establish three youth-re-orning-established genes- into -x, Sox2 and KLF4 that are normally turned on during embryonic development. These three genes, together with the fourth, which were not used in this work, are collectively known as Yamanak factors.
The treatment had multiple beneficial effects on the eye. First, it promotes nerve regeneration following icoptic-nerve injury in rats with damaged optic nerves. Second, it can reverse vision loss in animals with a condition that mimics human glaucoma. And third, it can reverse vision loss in older animals without glaucoma.
The team’s approach is based on a new theory about why we age. Most cells in the body are identical DNA Atoms have a wide variety of functions. To achieve this degree of specialty, these cells must only read specific genes of their type. This regulatory function is the function of the epigenome, the system of turning on and off genes in a specific pattern without altering the underlying DNA sequence of the gene.
This theory postulates that epigenome mutations over time cause cells to read the wrong genes and defects that give rise to the diseases of old age. One of the most important changes in the epigenome is DNA methylation, a process by which methyl groups are taken over DNA. Examples of DNA methylation are placed to form different cell types during orbital development. Over time, youthful patterns of DNA methylation are lost, and the genes inside the cells are shut down and should be turned on, resulting in impaired cellular function. Some of these DNA methylation changes are predictable and are used to determine the biologic age of cells or tissues.
Yet, whether DNA methylation drives age-related changes within cells remains unclear. In the present study, the researchers speculated that if DNA methylation, in fact, controls aging, then erasing some of its steps could reverse the age of cells inside living organisms and restore them to their previous, more youthful state.
Past works have achieved this in cells grown in laboratory recipes, but have shown little effect in living organisms.
New findings show that the approach can also be used in animals.
Overcoming any significant obstacle
Leading study author, Yuancheng Lu, a HMS genetic research fellow and alumnus in Sinclair’s lab, developed a gene therapy that could safely reverse the age of cells in a living animal.
Lu’s work is based on the Nobel Prize-winning discovery of Shinya Yamanaka, who identified four transcription factors, 4KTO4, SOX2, KLF4, C-mic, which can erase the epigenetics markers on cells and their effects. Can, from where they can. Grow in any other cell.
Subsequent studies, however, showed two significant shocks. First, when used in adult rats, four Yamanaka factors can also induce tumor growth, making the approach unsafe. Second, factors can reset the cellular state to the most primitive cell state, thus completely erasing cell identity.
Lu and colleagues overcame these obstacles by making a slight change in approach. They released the C-myc gene and distributed the remaining three Yamnaka genes, 4cto4, Sox2 and KLF4. The modified approach successfully reversed cellular aging without increasing tumor growth or losing their identity.
Gene therapy applied to optic nerve regeneration
In the current study, researchers targeted cells of the central nervous system because they are the first part of the body to be affected by aging. After birth, the central nervous system’s ability to regenerate rapidly decreases.
To test whether the regenerative capacity of young animals could be given to adult mice, the researchers delivered three gene modifications modified by AAV in the retinal ganglion cells of adult mice with aptic nerve injury.
For the work, Lu and Sinclair partnered with Zigang Hee, HMS professor of neurology and ophthalmology at Boston Children’s Hospital, who studies icopic nerve and spinal neuro-regeneration.
Treatment resulted in a two-fold increase in the number of living retinal ganglion cells after injury and a five-fold increase in nerve growth.
“At the beginning of this project, many of our colleagues said our approach would fail or it would be dangerous to never use it,” Lou said. “Our results suggest that this method is safe and could revolutionize the treatment of the eye and many other organs affected by aging.”
Glaucoma contrast and age-related vision loss
Following encouraging findings in rats with icoptic nerve injuries, the team partnered with Massachusetts Eye and Ear Bruce Cassander, HMS Associate Professor of Ophthalmology, and HMS Assistant Professor of Ophthalmology Meredith Gregory-Casender. They plan to conduct two experiments: one to test whether a three-gen cocktail can restore vision loss due to glaucoma and another to see if the approach can counteract vision loss arising from normal aging.
In the mouse model of glaucoma, the treatment resulted in an increase in the electrical activity of the nerve cell and a significant increase in visual acuity, as measured by the animal’s ability to move vertic lines on the screen. Significantly, glaucoma-induced vision loss had already occurred, after which he did so.
“Recovering visual function after an injury has rarely been demonstrated by scientists,” Ksender said. “This new approach, which successfully counteracts many of the causes of vision loss in rats without the need for retinal transplants, introduces a new treatment condition in regenerative drugs.”
The treatment works similarly in old age, in old age, in 12-month-old mice with reduced vision due to normal aging. After treatment of older mice, patterns of gene expression and electrical signals of optic nerve cells were similar to those of young mice, and vision was restored. When researchers analyzed molecular mutations in treated cells, they found patterns of DNA methylation – observations suggesting that DNA methylation is not just a marker or bystander in aging, but the active agent that drives it.
“What this tells us is that the clock doesn’t just represent time – it’s time,” Sinclair said. “If you wind the clock back, time goes back too.”
The researchers said that if their findings were confirmed in the next work of the animals, they would be able to start a clinical trial in two years to test the effectiveness of the approach in people with glaucoma. So far, the findings are encouraging, the researchers said. In the current study, one year of mice with a three-gene approach, no negative side effects were found in whole-body treatment.
Ref: 2 December 2020, Nature.
DOI: 10.1038 / s41586-020-2975-4
Other authors on the paper include Benedict Bromer, Shio Tian, Anita Krishnan, Margarita Mer, Chen Wang, Daniel Vera, Kurui Zheng, Daudou Yu, Michael Bonkowski, J-Hyun Yang, Songlin Zhou, Emma Hoffman, Margalit, Margaret , Noah Davidson, Ekaterina Korobkina, Carolina Chwalek, Lewis Rajman, George Church, Conrad Hochedlinger, Vadim Gladyshev, Steve Horvath and Morgan Levine.
The work of Harvard Medical School epijenetiksa Seed Grant and Development Grant, Glenn Foundation, Edward fees, the National Institutes for Health (R01AG019719, R37AG028730, R01A026939, R01EY021526, R0010130115, R01A01301, R01A01301, R-001301 for Medical Research, 01, 0101301, 010130153), R24EY028767 And R21EY030276), and the St. Vincent de Paul Foundation.
Related Disclosures: David Sinclair is a board member of Edu’s Therapeutics and inventor of licensed patents for equity owner, an epigenetic reprogramming therapy developed life bioscience company and an unpaid consultant to Zimo Research, an epigenetic tools company. Yuancheng Lu, Luis Rajman and Steve Horvath are the equity owners of Idu’s Therapeutics. George Church and Noah Davidson are co-founders of Navjivan Bio.
