Restore age-related vision loss through epigenetic reprogramming

  • The proof-of-concept study represents the first successful attempt to reverse the clock of aging in animals through epigenetic reprogramming.
  • Scientists turned on the embryonic genes to regenerate the cells of the mouse retinus.
  • Approach cataract-induced eye damage in animals.
  • The approach also restored age-related vision loss in elderly mice.
  • Karya mantras promise to use the same approach in other tissues, organs beyond 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 back on aged eye cells in the retina to regain young gene function.

The team’s work, described today (December 2, 2020) Nature, Represents the first demonstration that it may already be possible to safely reconstruct complex tissues, such as the nerve cells of the eye, until an age.

In addition to resetting the cells’ aging clock, the researchers successfully reversed the animal’s vision to a condition mimicking human glaucoma, a major cause of blindness worldwide.

The team said the achievement represents the first successful attempt to overcome glaucoma-induced vision loss, rather than to halt its progress. If replicated through further studies, this approach may pave the way for treatment to promote tissue repair in various organs and to reverse aging and age-related diseases in humans.

“Our study suggests that it is possible to safely remove the age of complex tissues such as the retina and restore its young biological function,” said senior author David Sinclair, co-director of the Blavatnik Institute at Harvard Medical School, Pro . Paul F. in HMS Glenn Center for Biology of Aging Research and an expert on aging.

Sinclair and colleagues cautioned that the findings remain to be replicated in other studies, including various animal models, before any human experiments. Nevertheless, they add, the results provide proof of concept and design treatments for a range of age-related human diseases.

“If confirmed through further study, these findings could be transformative for the fields of biology and medical treatment for age-related vision diseases such as glaucoma and for large-scale disease,” Sinclair said .

For their work, the team used an adeno-associated virus (AAV) as a vehicle to transport the three young-genes of mice — Oct4, Sox2, and Colf4 — into the retina, that is, the embryo Are normally turned on during development. Three genes, with a fourth, which were not used in this work, are collectively known as Yamanaka factors.

The treatment had several beneficial effects on the eye. First, it promoted nerve regeneration after optic nerve injury in mice with damaged optic nerves. Second, it reverses vision loss in animals with conditions that mimic human glaucoma. And third, it reverses vision loss in aging animals without glaucoma.

The team’s approach is based on a new theory of why we are of age. This happens in most cells of the body DNA Molecular but widely diverse functions. To achieve this degree of specialization, these cells must only study genes specific to their type. This regulatory function is a system of switching genes on and off in specific patterns without altering the original underlying DNA sequence of the genome.

This theory suggests that the change in epigemin over time causes cells to read the wrong genes and malfunctions – leading to diseases of aging. One of the most important changes in the epigenome is DNA methylation, a process by which methyl groups are disposed on DNA. Patterns of DNA methylation are determined during embryonic development to produce different cell types. Over time, young patterns of DNA methylation are lost, and genes inside cells that must be switched on and vice versa, resulting in cellular function. Some of these DNA methylation changes are predictable and have been used to determine the biological age of a cell or tissue.

Nevertheless, whether DNA methylation elucidates age-related changes inside cells. In the current study, researchers hypothesized that if DNA methylation, in fact, controls aging, some of its footprints can reverse the age of cells inside living organisms and make them look younger, earlier. Can restore to state.

Previous work achieved this feat in cells developed in laboratory dishes, but fell short of demonstrating the effect in living organisms.

New findings suggest that this approach may also be used in animals.

Overcome an important obstacle

The lead study author, Yuancheng Lu, a research fellow in genetics at HMS and a former doctoral student in Sinclair’s laboratory, developed a gene therapy that can safely reverse the lifespan of cells in living animals.

Lu’s work builds on the Nobel Prize-winning discovery of Shinya Yamanaka, who has identified four transcription factors, Oct4, Sox2, Culf4, c-Myc, that can erase epigenetics markers on cells and allow these cells to Primitive embryos can revert from the stage by which they can develop into another type of cell.

However, later studies showed two significant failures. First, when used in adult mice, four Yamanaka factors can induce tumor growth, rendering the approach unsafe. Second, factors can reset the cellular state to the most primitive cell state, thus completely erasing cell identity.

Lu and colleagues slightly modified these approaches to circumvent these barriers. They dropped Jean C-Mike and distributed only the remaining three Yamanaka genes, October 4, Sox 2 and Kolf 4. The modified approach successfully reversed cellular aging without reducing tumor growth or losing its identity.

Gene therapy applied for optic nerve regeneration

In the current study, researchers targeted cells in the 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.

To test whether the regenerative potential of young animals could be conferred on adult mice, the researchers distributed three gene combinations modified via AAV to the retinal ganglion cells of adult mice with optic nerve injury.

For the work, Lu and Sinclair partnered with HMS Professor of Neurology and Xeyang He of Ophthalmology at Boston Children’s Hospital to study neuro-regeneration of the optic nerve and spinal cord.

Treatment involves a twofold increase in the number of living retinal ganglion cells after injury and a fivefold increase in nerve regrowth.

“At the beginning of this project, many of our colleagues said that our approach would fail or be too dangerous to ever use,” Lu said. “Our results suggest that this method is safe and can potentially revolutionize the treatment of aging affected eye and many other organs.”

Cataract and age-related vision loss reversal

Following encouraging findings in mice with optic nerve injuries, the team partnered with the Shepens Eye Research Institute of Massachusetts Eye and colleagues of Kan Bruce Saffron, HMS Associate Professor of Ophthalmology, and Meredith Gregory-Casander, HMS Assistant Professor of Ophthalmology . He planned two sets of experiments: one to test whether a three-gene cocktail could restore vision loss due to glaucoma, and another to see if the approach could reverse vision loss from normal aging is.

In a mouse model of glaucoma, treatment increased nerve cell electrical activity and significantly increased visual acuity, as measured by animals’ ability to see vertical lines on the screen. Remarkably, this was done after glaucoma-induced vision loss.

“Achieving visual function after an injury has rarely been demonstrated by scientists,” Saffron said. “This new approach, which successfully reverses several causes of vision loss in mice without the need for retinal transplantation, represents a new treatment modality in regenerative medicine.”

The treatment worked equally well in elderly, 12-month-old mice with decreased vision as they aged. After treatment with elderly mice, gene expression patterns and electrical signals of optic nerve cells were similar to those of younger mice, and vision was restored. When researchers analyzed the molecular changes in the treated cells, they found the reversed pattern of DNA methylation – an observation suggesting that DNA methylation is not a mere marker or a bypasser in the aging process, but an active agent driving it. Used to be.

“That which tells us that the clock doesn’t just represent time — it’s time,” Sinclair said. “If you wind the hands of the clock, time also goes backward.”

Researchers said that if their findings were confirmed in further animal work, they could begin clinical trials within two years to test the efficacy of the approach in people suffering from glaucoma. Thus, the findings so far are encouraging, the researchers said. In the current study, whole-body treatment of mice with a one-year, three-gene approach showed no negative side effects.

Reference: 2 December 2020, Nature.
DOI: 10.1038 / s41586-020-2975-4

Other authors on the paper include Benedict Bromer, Xiao Tian, ​​Anitha Krishnan, Margarita Mir, Chen Wang, Daniel Vera, Kiurui Zeng, Dodou Yu, Michael Bonkowski, Jae-hyun Yang, Songlin Zhou, Emma Hoffman, Margaret Carr, Michael Schulz, Huh. Alice Kane, Noah Davidshaw, Ekaterina Korobkina, Karolina Chavalek, Luis Rajman, George Church, Konrad Hockedlinger, Vadim Gladyshev, Steve Horvath and Morgan Levine.

This work was supported by a Harvard Medical School Epigenetics Seed Grant and Development Grant, The Glenn Foundation for Medical Research, Edward Shulak, National Institutes of Health (grant R01AG019719, R37AG028730, R01EY026939, R01EY021526, R01AG06778282, R01AG06778282). , R24EY028767 and R21EY030276), and the St. Vincent de Paul Foundation.

Relevant Revelations: David Sinclair is a consultant, a licensed patent inventor, board member and equity owner of Iduna Therapeutics, a life biosciences company developing epigenetic reprogramming therapy, and an epigenetic tool company Unpaid for Zimo Research Is a consultant. Yuancheng Lu, Luis Rajman and Steve Horwath are equity owners of Iduna Therapeutics. George Church and Noah Davidshaw are co-founders of the Rejuvenation Bio.

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