Can a ‘magic’ protein slow the aging process?

This article is part of Upstarta series about young companies taking advantage of new science and technology.

Several years ago, scientists studying aging at the Harvard Stem Cell Institute used a somewhat Frankensteinian technique known as parabiosis: surgically joining a young mouse and an old mouse to share blood, to see what would happen to the heart and brain. skeletal muscle tissue. They knew from previous research that putting young blood into old mice made them biologically younger, and that young mice exposed to old blood aged faster.

Harvard researchers Amy Wagers and Dr. Richard Lee found that the old mouse’s heart tissue had been repaired and rejuvenated, making it young again. In fact, the size of the old mouse’s heart had shrunk to that of a young heart.

“We all wonder, what is the magical matter in the blood?” said Lee Rubin, a professor of stem cell and regenerative medicine at Harvard and co-director of the neuroscience program at the Stem Cell Institute. The “magic” they identified was a protein, GDF11, one of tens of thousands produced in the human body. Dr. Rubin’s lab also found that GDF11 in mice stimulated the growth of new blood vessels in the brain and neurons in the hippocampus, a part of the brain associated with learning and memory. Dr. Wagers’ lab found that GDF11 also rejuvenated skeletal muscle tissue. The scientists’ findings were published in the journals Cell and Science in 2013 and 2014.

The obvious next question: Could GDF11 be harnessed to promote regeneration and repair in humans? In 2017, Drs. Rubin, Wagers and Lee, along with five others, founded the pharmaceutical startup Elevian with the goal of commercializing GDF11-based therapies to stop, delay or reverse diseases associated with aging. It’s a big step from mice to humans, but one that could have profound consequences.

“We are interested in proteins like GDF11 that are excreted into the bloodstream because they can cause changes throughout the body,” said Dr. Mark Allen, CEO of Elevian. “And those are the kind of changes we want.”

Dr. Allen started his first healthcare business while in medical school at the University of California, Los Angeles, leaving his residency position in 2000 to start a second. In early 2017, he and his investment partner, economist Sebastian Giwa, were looking to start a new one that would develop therapies targeting the degenerative processes involved in ageing. They looked at two dozen potential research projects before settling on GDF11.

“I had the idea that aging itself could be a target for therapeutic intervention,” said Dr. Allen, “because if we focus on one aspect of the aging process, then we have the potential to treat many different diseases.”

Initial research on the rejuvenating properties of GDF11 has received some rejection from the scientific community. In 2015, after Dr. Wagers and Dr. Lee published their results, a group of researchers led by David Glass, the executive director of the Novartis Biomedical Research Institutes in Cambridge, Massachusetts, at the time, questioned the accuracy of their findings in an article in the journal Cell Metabolism. The Harvard researchers later countered the Novartis team’s findings in another paper published that same year in the journal Circulation Research, in which the Harvard researchers cited a problem with the Novartis team’s findings.

Dr. Glass, who now works at the biotech company Regeneron, said in a recent email supporting his original work, which showed that GDF11 inhibits, rather than helps, muscle regeneration. But, he added, “our work still leaves open the possibility that GDF11 may have positive effects in particular settings.”

Dr. Allen said that since the original controversy, the Elevian research team has replicated and expanded on their original findings in multiple studies, but none have yet been published in peer-reviewed journals. However, institutions not related to Elevian have conducted and published many preclinical studies demonstrating the therapeutic efficacy of rGDF11 (the laboratory-developed form of GDF11) in the treatment of age-related diseases.

The company is on track to begin human clinical trials in the first quarter of 2023 and has raised $58 million in two rounds of funding, with another round scheduled for mid-2023.

Elevian is one of many companies striving to find ways to increase the length of human life by increasing the “span of health,” the period of life in which a person is in generally good health. This emerging sector of the pharmaceutical industry is often referred to as “longevity therapies” and includes companies such as Altos Labs, which started in January with $3 billion in funding; Calico Life Sciences at Google; Biotechnology Unit; Alkahest; and Juvenilescence. About $2 billion in venture capital was invested in pharmaceutical companies focused on anti-aging in 2021, according to Longevity Technology, a market research company and investment platform focused on the longevity sector.

For years, researchers have been searching for drugs that can extend lifespan and health. The National Institutes of Health’s Testing of Interventions Program began testing drugs, some approved by the Food and Drug Administration, some not, on mice 17 years ago to see if these interventions would extend their lives. Dr. Richard A. Miller, a professor of pathology at the University of Michigan and director of the Paul F. Glenn Center for the Biology of Aging Research, said anti-aging therapies are often tested in mice because aging in mice It is very similar to aging in humans. “Mice and people share organs, cell biology, and most varieties of neurons and neurotransmitters, and they often respond to drugs in similar ways,” he said.

All of these companies face a significant challenge: marketing a drug for aging is almost impossible because the FDA does not recognize aging as a disease that should be treated. And even if it were considered a disease, the clinical studies needed to prove that a treatment works would take many years.

“Clinical trials to see if any drug slows aging, and thus delays the many consequences of aging, are likely to take a long time,” Dr. Miller said.

So the founders of Elevian determined that the fastest way to market GDF11 was to target a specific medical condition.

“We thought, what is the worst disease that does not have a good treatment and that we could treat for the shortest possible time and show clinical effects?” Dr. Allen said. “We decided that stroke was the right target, because it is the No. 1 cause of long-term disability with very limited treatment options.”

Dr. Elisabeth Breese Marsh, medical director of the comprehensive stroke program at Johns Hopkins Bayview Medical Center in Baltimore, said the best treatments for strokes caused by clots (about 87 percent of them) are a type of medication known as tissue plasminogen activators, or tPA, which must be given within 4.5 hours after the stroke, and surgical removal of large clots.

But according to experts, only about 20 percent of stroke victims receive tPA, either because the stroke isn’t recognized early enough or because the patient doesn’t qualify because of pre-existing conditions. The Elevian researchers said that their preclinical (and as yet unpublished) studies have shown that just a few days of treatment with GDF11 can improve recovery after a stroke. They have found that GDF11 reduces inflammation, improves metabolism and stimulates the brain to regenerate blood vessels and neurons.

The next big hurdle for Elevian is scaling its manufacturing, which requires specialized equipment and conditions. So much research is being done in biotechnology that contract manufacturers are “full,” said Dr. Allen. “They are busy with Covid-related work and in general there has been a lot of funding in biotech,” he added. “So it’s a challenge to find the space that meets our specifications.”

And, like almost every other sector of the economy, biotech research faces supply chain problems, making it difficult for Elevian to obtain some of the basic materials it needs to conduct research. But the company is moving forward as fast as it can, and Dr. Allen said he believed the results of his work would have a profound impact on how we age and how long we live.

“By targeting the fundamental mechanisms of aging, we have the opportunity to treat or prevent multiple diseases related to aging and extend the duration of health,” he said. “We want to make 100 the new 50.”

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