Featuring two Future Venture’s portfolio companies, excerpt from BusinessWeek:
“As scientists finally begin to unravel what makes the reproductive system age so rapidly, they’re also uncovering a tantalizing possibility: There may be ways to slow that aging down. Not only could this extend a woman’s childbearing years, it could dramatically improve women’s health, staving off the ill effects associated with the onset of menopause. Research has shown that women who go through menopause later in life tend to live longer.
The ovary is an ideal model to study aging. Watching the ovaries age is a little like listening to a podcast at double speed, which is why the ovary could even become a proving ground for longevity drugs, a therapeutics market expected to reach more than $44 billion within the next decade. This could have benefits for everyone, since most of the developed world’s biggest killers for men and women—heart disease, stroke, cancer, dementia—are diseases for which age is the main risk factor.
Scientists and startups are racing to turn these revelations into therapies that could one day advance treatment for menopause and infertility and perhaps eventually intervene in the process of aging itself. A startup called Gameto has used stem cell science to create a less intensive version of IVF and plans to use the same technology to create better menopause therapies.
Two-and-a-half years ago, Pepin, along with Donahoe and Harvard University Ph.D. Daisy Robinton, founded Oviva Therapeutics Inc. with funding from aging-focused drug development company Cambrian BioPharma Inc. Their goal: to turn AMH into treatments that could improve ovarian function and extend life span. Eventually, Oviva hopes to pull off a feat that seems almost unimaginable: giving women a drug that will allow them to choose when—and whether—they go through menopause. At a time when politicians are eroding women’s hard-won reproductive choices, Oviva’s founders want to give them even more control. “I see it very much akin to how the contraceptive pill really changed the game for women in the ’70s,” Robinton says.
Human females are the odd ones out in terms of the reproductive life cycle. Most mammals are fertile right up to the end of their lives. The only other mammals that go through menopause are a few species of whales and, depending on whom you ask, some great apes. No one is even quite sure why menopause occurs at all.
At 31, Daisy Robinton suddenly found herself confronted by the incessant, inevitable ticking of her biological clock. It was 2019, and she’d recently finished her postdoc at Boston Children’s Hospital researching the cellular interaction at the root of neurodegenerative diseases. She’d also just ended a five-year relationship and moved to New York City. Her work had received attention, including a popular TedX London talk on the science of aging, but the lab, she realized, wasn’t for her. She didn’t quite know what she wanted to do professionally—she was making a living with a combination of scientific consulting and fashion modeling. She did know that she wanted a family. So she set up an appointment with a reproductive endocrinologist to explore freezing her eggs. She walked away reassured by the state of her own reproductive system but furious at the state of women’s health.
Around this time, she happened to reconnect with stem cell biologist James Peyer, whom she’d once met at an entrepreneurship event and who’d recently started Cambrian Bio. Over coffee, he told her about his company. “All I was thinking about was how our ovaries stop working halfway through our lives and that in any room I had been in that was focused on aging, no one had brought this up,” says Robinton. “It was shocking to me. I just thought it was stupid and rude and horrifying.”
Peyer hired Robinton as a staff scientist to hunt for a way to turn her outrage into a capitalist endeavor. In fall 2020 she organized a virtual summit on reproductive longevity where someone mentioned Pepin’s research. It seemed to mesh with an idea she was already exploring, that slowing the decline of the ovarian reserve could also extend the lifetime of the ovaries. Robinton cold-emailed Pepin, and by the next year Oviva was born. “I was looking to find a way to get this to the clinic, and she was looking for things that she could bring to the clinic,” Pepin says.
To solve the issue of the aging ovaries, three key problems will need to be addressed. The first is that the number of a woman’s eggs decreases, eventually to zero. The general wisdom is that a human female is born with 1 million to 2 million eggs, and more than half are gone by the time she even hits puberty. When she reaches her 30s, not only does she have just a fraction of those eggs left, but the quality of the remaining ones has declined steeply. That’s the second problem: Older eggs are more likely to contain genetic abnormalities, one reason miscarriages become more common with age. Then there’s the third problem, which has to do with the environment of the ovary itself: Over time it becomes fibrotic, stiffening and making it harder for healthy eggs to grow. “If you can solve all these problems, then maybe you can slow down ovarian aging,” Pepin says.
The work that could most immediately benefit women primarily focuses on the first problem. When Pepin made his initial discovery, he thought AMH could be the basis of a better birth control therapy. There are receptors for estrogen all over the body, a reason so many women experience a litany of side effects from taking the pill. But AMH receptors are limited to the reproductive system, the nearby adrenal glands and a small part of the brain that modulates reproduction. AMH, Pepin says, also seems to be the only known hormone that can inhibit the growth of primordial follicles, the pool of those waiting to develop.
That’s what made him think a decade ago that it also could help protect the fertility of those undergoing cancer treatment, which he initially demonstrated in mice. But, more recently, Pepin has shown that AMH can be used to create what’s basically a permanent birth control in cats. Working with the Cincinnati Zoo, he tested an AMH gene therapy on cats that halts ovulation. (He envisions it as an alternative to spaying, an invasive surgery in which female cats usually lose not just the ovaries but their uterus, too.) If you could dial that therapy down and turn it into, say, a pill—a difficult feat—then perhaps it could be used to slow the attrition of eggs from women’s resting pool.
Prolonging the depletion of a woman’s eggs could delay the march toward menopause, keeping up the body’s production of critical ovarian hormones for a longer period. In older experiments, when researchers transplanted the ovaries of younger mice into older ones, they lived about 40% longer and also appeared to have healthier hearts.
But bringing any drug from benchtop to market is a slog requiring time, uncertainty and millions of dollars. “There is more risk, simply because it just hasn’t been done,” says Cambrian’s Peyer. For Oviva’s AMH-based therapy to make it to market, there’s also the problem of the protein itself to solve.
One reason it took so long to figure out that AMH plays such a huge role in reproduction is that it’s difficult to produce in any sort of quantity. Estrogen, the first reproductive hormone isolated, in 1929, is among the least complicated to make. It’s physically small and structurally simple, making it easy to synthesize in a lab. You can plop its synthetic form into a pill, like birth control, and it will work.
AMH, in comparison, is massive in size, its structure made up of intricate folds. For it to be activated, AMH has to be cleaved precisely so that its two halves are separated but still in contact. The body does that naturally, but the process is too complex to synthesize. To produce it, you have to program mammalian cells to make AMH for you, creating what’s known as a recombinant protein, a protein produced by a host organism—in Pepin’s case, Chinese hamster ovarian cells. Figuring out how to do this was one of his first big breakthroughs as a postdoc.
Pepin’s cat contraceptive relies on this engineered AMH, a form of the protein close to the original. So will Oviva’s first human therapy, but this drug will amp up reproductive ability, not shut it down. The purpose is to help women going through IVF and egg freezing who are poor responders to traditional ovarian stimulation. The hope is to get them to produce larger quantities of eggs, which could improve the success rates of egg retrieval procedures that are intensive and expensive.
Such a drug, Robinton says, would show that AMH’s ability to influence the reproductive system can translate from mice and cats into humans in an already proven market. From there, Robinton says, Oviva can eventually tackle the bigger goal: delaying menopause. To achieve that, the complicated AMH protein will need to be altered further, turned into a new drug that is less painful than a jab, and virtually side-effect free, which throws novel challenges into the mix. “When I use the gene therapy, I’m using the natural hormone,” Pepin says. “I’ve modified it, but only a little bit. It’s very safe.”
Robinton envisions a not-too-distant future—maybe before she reaches menopause herself—in which women will have therapeutic interventions that allow their ovaries to keep working for longer, helping maintain the skin and hair and mood and health and maybe even the sex life of their younger years. “For me, the pie in the sky is really choosing when to have the sun set on your ovaries,” she says.”
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