Key Points:
- Life Biosciences, a biotech company co-founded by Harvard’s David Sinclair, received the FDA’s permission to start a clinical trial of a gene therapy designed to rejuvenate dying cells.
- The gene therapy approach will use partial epigenetic reprogramming—a technique that modifies chemical tags on DNA to make old cells act younger.
- The primary focus of the trial is safety; however, an overarching goal of the gene therapy is to restore vision to some degree in patients with glaucoma and a rarer eye condition called non-arteritic anterior ischemic optic neuropathy (NAION).
One of the most renowned theories of aging attempting to explain some of the causes of aging and how to rejuvenate cells, the Information Theory of Aging from Harvard’s David Sinclair, will soon be put to the test. In that respect, Life Biosciences, a biotech company co-founded by Sinclair, received the FDA’s approval to begin a human trial testing its gene therapy based on the Information Theory of Aging. The gene therapy is designed to rewind the clock and restore the function of dying cells.
Background on the Gene Therapy Life Biosciences Will Test
Life Biosciences’ gene therapy has been under development for quite a while. In the 1990s, David Sinclair first contended that the deterioration and loss of epigenetic information—chemical tagging patterns on DNA that regulate which genes are turned on and off—plays an important role in driving aging. Sinclair subsequently dubbed this contention the Information Theory of Aging. Fast forward to the present day, and Life Biosciences has produced a gene therapy that delivers three proteins, which Sinclair’s laboratory helped establish, to reset epigenetic information to a more youthful state.
“It’s extremely exciting,” Sinclair told Endpoints News. “It’s been over 30 years to get to this point, and we’re about to learn if all of that work is going to come to fruition this year.”
The gene therapy technique that Sinclair and the team at Life Biosciences will use, called partial epigenetic reprogramming, is rooted in a Nobel Prize-winning approach that can turn adult cells into stem cells. The key difference between Life Biosciences’ partial epigenetic reprogramming technique and the Nobel Prize-winning one is that Life Biosciences’ technique stops short of converting adult cells into full-fledged stem cells. The reason for this is that scientists believe turning adult cells into stem cells in the body would be quite dangerous.
Preclinical research has shown that the partial epigenetic reprogramming gene therapy technique Life Biosciences will use rejuvenates cells rather than turning them into stem cells and extends mouse lifespan. Sinclair and his team’s recently approved human trial will be the first to test this technique in humans. Furthermore, partial epigenetic reprogramming falls under the umbrella of experimental therapeutics known as cellular rejuvenation, which several well-funded biotech startups, backed by high-profile executives, have focused on in recent years.
Life Biosciences Has Beaten Other Well-Funded Companies to Test Cell Rejuvenation
Altos Labs, a biotech startup launched four years ago with investors including Amazon’s Jeff Bezos, garnered a record $3 billion in investments and has been working on its own version of partial epigenetic reprogramming. Moreover, Retro Biosciences, a biotech company backed by OpenAI’s Sam Altman, along with New Limit, backed by CoinBase CEO Brian Armstrong, have also been working on cell reprogramming therapeutics.
Now, it appears that Boston-based Life Bioscience has beaten these other companies to the punch to administer the first human trial using their gene therapy based on partial epigenetic reprogramming. Also, since the FDA does not recognize aging as a disease, the company’s Phase I human trial will test its approach in two forms of vision loss. In that regard, although the trial will primarily assess safety, Life Biosciences will also conduct several measurements in an attempt to detect hints of efficacy.
“The goal is to restore vision to some level and prevent further vision loss,” Life Biosciences CEO Jerry McLaughlin said.
More Details on the Information Theory of Aging
David Sinclair and members of his laboratory have spent an extensive amount of time over the last decade trying to prove his Information Theory of Aging with experiments done in animals. This research has been geared toward searching for ways to restore lost epigenetic information.
For example, Yuancheng Lu, a graduate student who worked under David Sinclair’s supervision, had the task of testing dozens of genes to find if any could restore epigenetic information to potentially rewind the clock on aging. He first tried using embryonic genes, a specific subset of genes activated during early development, since sterilized embryos have been found to reset their epigenetic information. However, none of the embryonic genes tested worked.
Then, Sinclair and his laboratory members reflected on work done years earlier that won a Nobel Prize. Accordingly, the Japanese scientist, Shinya Yamanaka, had discovered that four proteins could turn adult cells into stem cells, for which he was awarded the Nobel Prize in 2012.
Not only did Yamanaka demonstrate that the four proteins, called Yamanaka factors, could turn adult cells into stem cells, but importantly, his work demonstrated that a reset of epigenetic information is possible. However, scientists had long considered directly putting those four Yamanaka factors into animals or humans a bad idea, in part, because one of them, c-Myc, promotes cancer.
“Other labs had put in all four and found that it kills mice and causes tumors,” Sinclair said.
Then, Lu and Sinclair had the idea of performing a simple, yet overlooked, experiment. They decided to exclude c-Myc and commence experimentation using only the three other Yamanaka factors: OCT4, SOX2, and KLF4. Remarkably, using only these three Yamanaka factors, they restored more youthful epigenetic information and reversed vision loss in a mouse model of glaucoma.
Their published study subsequently landed on the cover of the renowned journal Nature in 2020. The study also kindled interest in partial epigenetic reprogramming, and Life Biosciences team members decided to use this technique as the basis for developing gene therapies.
“The dogma was that you need all four [Yamanaka factors] for there to be an effect. And when someone wins a Nobel Prize for that, you tend to believe it,” Sinclair said. “Nobody in the world believed that it would work until we tried it.”
According to David Sinclair, the potency of the gene therapy is much greater than anything that has come out to date. While prior pro-longevity therapeutics have perhaps just reversed aspects of aging, Sinclair says Life Biosciences’ gene therapy will be a “near-total reset” for cells.
The longevity field has long been filled with perhaps foolhardy claims and drugs with fuzzy mechanisms of action. Sinclair’s own work on supplements like resveratrol and NAD+ precursors like NMN has also been the subject of controversy, and his predictions on the potential efficacy of Life Biosciences’ gene therapy are sure to trigger skepticism, too. All the same, Sinclair has kept his confident fervor about the gene therapy technology and believes that the vision loss study will provide compelling evidence on whether partial epigenetic reprogramming is effective.
“It’s not like we’re going to have to look at the error bars on the graph. We’re going to know if it works or not,” Sinclair said. “Shortly, maybe it’s in the next few months, we’ll have our first indication of whether age reversal can work in humans.”
Resetting Epigenetic Information to Restore Vision
Life Biosciences’ human trial will focus on two forms of vision loss caused by damage to the optic nerve, a bundle of over one million nerve fibers that acts as the essential communication cable between the eye and the brain. These forms of vision loss come from the eye-related conditions of glaucoma and non-arteritic anterior ischemic optic neuropathy (NAION).
Interestingly, in a monkey model of NAION, the gene therapy, called ER-100, restored epigenetic information and improved electrical signaling in the optic nerve. According to Life Biosciences Chief Scientific Officer, Sharon Rosenzweig-Lipson, the results show that the gene therapy can improve the function of damaged cells. However, she added that it does not replace cells that have already died.
“We’re tapping back into that code that still exists, but has been degraded over time,” Rosenzweig-Lipson said.
As for how the gene therapy is designed, it uses viral vectors—a virus modified to be non-pathogenic used to deliver genetic material, such as therapeutic genes, directly into patients’ cells. Using one viral vector, the gene therapy will deliver the three proteins to the retinal ganglion cells, which help transmit light signals from the eye to the brain. A second delivered viral vector, which is activated by the antibiotic drug doxycycline, will code for a protein that activates the first vector, making doxycycline akin to a safety switch.
Hence, when patients take a doxycycline pill, the gene therapy will be turned on. When patients stop taking the pill, the gene therapy will be turned off.
In Life Biosciences’ upcoming human trial, patients who have received the gene therapy will take doxycycline for eight weeks, along with a steroid to reduce inflammation observed with some gene therapies. The company will test two different doses in up to six glaucoma patients before establishing a dose to test in up to six NAION patients.
Future Hopes for Partial Epigenetic Reprogramming Therapies
David Sinclair has also said that Life Biosciences is interested in tackling other diseases with their partial epigenetic reprogramming-based gene therapies. In that regard, the Life Bioscience team believes their technology could have potential applications for hearing loss, liver disease, lung disease, muscle atrophy, neurodegenerative conditions, and more.
“It’s a staged approach,” McLaughlin said. “We start with specific diseases, build evidence for the field and our technology organ by organ, indication by indication, but eventually there is a longer-term vision of potentially transcending into multi-organ cellular rejuvenation.”
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