Like roughly a quarter of people in the U.S., Cincinnati Zoo & Botanical Garden Director of Animal Research Bill Swanson, DVM, Ph.D., owns cats—or, as he puts it, “co-exists” with them.
“You don’t really own cats,” Swanson told Fierce Biotech in an interview. “They live here with me.”
The cats co-existing with Swanson aren’t just any cats: They’re among the first to receive a gene therapy that prevents pregnancy in felines. Swanson adopted the furry research subjects six years ago after they were treated with an early version of the treatment, which was co-developed by him and Massachusetts General Hospital researcher David Pépin, Ph.D.
On June 6, Swanson and Pépin’s team published the initial results from a study on the cat contraceptive. They described in Nature how a single shot of an updated form of the therapy was able to prevent pregnancy in six adult female cats for at least two years, without any side effects. While they have much more work ahead of them before the therapy is ready for the clinic, the scientists believe it could eventually take the place of surgical sterilization.
From cancer to feline birth control
Preventing pregnancy in female cats currently requires surgically removing their uterus and ovaries when they’re around five months old, an operation known as an ovariohysterectomy, or spaying in cats and dogs. While some clinics offer low-cost spaying to pet owners, the surgery isn’t scalable enough to meaningfully cut down on the millions of cats that wind up on the streets or in shelters every year. This has led animal welfare groups to call for research into non-surgical long-term contraceptives that can be easily deployed.
Cat overpopulation wasn’t necessarily the problem Pépin was looking to solve more than a decade ago when he began studying the effects of anti-Müllerian hormone, or AMH (sometimes also called Müllerian inhibiting substance) on the ovary. In fact, he was looking for something else entirely: a gene therapy to treat ovarian cancer. Though that application hasn’t yet panned out, a different light bulb went off when Pépin’s team saw how the hormone affected mice.
“We discovered that if you had high levels of this hormone AMH that you were suppressing the ovaries,” he recalled to Fierce Biotech. “So that became the main research question I’ve been working on for more than ten years now—how does AMH suppress the ovary, and can we use it as a contraceptive?”
While a long-term sterilizing gene therapy may not be appealing to humans, it seemed like a good tool for controlling animal reproduction, Pépin recalled. That led him to apply for funding from the Michelson Found Animal Foundation, a nonprofit that invests in research on non-surgical animal contraceptives. Swanson, who sits on the organization’s board, was the one who reviewed Pépin’s application.
“It seemed like a good connection for us because he needed somebody that knew about domestic cat reproduction, and with his expertise on gene therapy and AMH, we thought we could really test this together,” Swanson recalled.
The researchers designed an adeno-associated virus vector (AAV9) using the genetic sequence that encodes feline AMH. They then injected it into the thigh muscles of three groups of three female adult cats, giving them either a low dose of the therapy, a high dose, or an empty AAV9 that served as a control. The transgene prompted the muscle cells to express AMH, which then made its way through the circulation and ultimately to the ovaries.
Why muscle cells? For one, AAV9 can easily infiltrate them, Pépin explained. And on top of that, they last a long time.
“They don’t really proliferate, divide, or die, and they get repaired over time, so the hormone is continuously being secreted into the blood,” he said. “Muscle cells don’t naturally make AMH—it’s an ovarian hormone—but they’re quite capable of doing so.”
Testing the cats’ blood over time showed that to be the case. For both the low and high-dose therapies, AMH levels remained above the researchers’ target threshold for the full two-year study period. But unlike oral contraceptives used in humans, AMH acts directly on the developing egg follicles in the ovaries rather than altering estrogen or progesterone levels. (A bit of lab trivia: The researchers measured sex steroid levels from freeze-dried poop samples—15,220 of them in total, Swanson told the New York Times.)
“With current oral contraceptives, you’re disrupting feedback between the ovary and the pituitary, so you’re preventing the signal to ovulate,” Pépin said. “Here, the hormones are a little bit different, but otherwise the outcome is the same: The follicles don’t mature normally, so the cats don’t ovulate.”
To see how the contraceptive affected mating behavior, the female subjects were housed with male breeder cats during two separate four-month-long mating trials. The researchers placed one of two males with all nine of the female cats in the study for eight hours a day, five days a week, continuously recording video to monitor them. They performed ultrasounds on the females once a week to check for pregnancy.
None of the treated cats conceived at any point in the study, while all the control animals did so after the first breeding session. Among the treated cats, two of them allowed mating activity; the rest did not. Hormone analysis showed that none of the cats that received the therapy had luteal phases, validation that AMH had indeed suppressed ovulation.
Swanson and Pépin are now working on investigational new drug-enabling studies with the hope of launching clinical trials to test the therapy in more felines. They’re also watching closely to make sure the therapy is both safe and effective for the long term, Swanson said.
“We want to make sure the protein is being produced at a high enough level, so we have to follow these cats out for several more years to make sure something doesn't crop up,” he explained. “We also want to make sure the ovaries and the uterus aren’t developing any issues.”
To do that, the team has adopted out the study animals to private homes. Each cat returns to the researchers every year for a check-up, during which the scientists do blood work to measure its AMH levels and examine its reproductive tract.
The researchers don’t anticipate problems, however. Unlike androgens, estrogens or progestins, AMH receptor expression is restricted to the reproductive organs, so the hormone isn’t likely to have off-target effects, Pépin noted. Even with relatively high concentrations of AMH in their systems, the researchers didn’t see any adverse effects over the course of the study. And high levels of AMH occur naturally in male kittens and young boys without issue, he explained.
Swanson’s own study cats received a slightly different version of the therapy that they plan to take to the clinic, but its long-term effects are likely the same. The results so far are promising.
“They’re now 11 or 12 years of age and they’re doing fine,” Swanson said. “No problems.”
That said, veterinarians have questions they hope to see addressed. Luqman Javed, in-house veterinarian at pet product company Hepper, noted in an email that he would like to see whether the treatment has consequences for fetal development.
“When tackling the issue of strays and feral cats, this contraceptive has to be tested for safety with regards to animals that are already pregnant at the time it is administered,” he wrote. “Would there be significant damage to the kittens in-utero?”
Covering the cost
If and when the gene therapy does make it to the clinic, the researchers anticipate that it won’t cost nearly as much as human gene therapies do. That’s due in part to the fact that the treatment population is in the hundreds of millions, unlike therapies to treat rare diseases. That lowers the threshold for recouping the investment in development and manufacturing.
“There are 600 million cats in the world and 80% are free-roaming—that’s our addressable patient population, essentially,” Pépin said. As companies rise to the challenge of scaling viral vector manufacturing, he expects that production will get more efficient over time.
“Looking at the figures even now, we think this will be cost-effective,” he said. “And really, that’s what we’re trying to achieve: Something that’s comparable, or even cheaper, than surgery.”
Surgical spaying costs about $300 to $500 per cat by a private veterinarian. Low-cost clinics offer it for as little as $50 to qualified low-income households, the cost of which is offset by funds from the regularly-priced procedure. Even as gene therapy production costs come down, getting to the point that the shots can get to cats in need might require a similar business model, Pépin added.
“There may be a case where there’s a price for the private, owned cats for the procedure,” he explained. “This would subsidize the cost of controlling the feral or free-roaming cat population in the field.”
Notably, while it’s likely that most pet owners would prefer not to put their cats through the stress of surgery, some may still choose to do so on account of its other benefits. For one, cats that are spayed before six months to a year old have a 91% to 86% reduction, respectively, in the risk of mammary gland cancer, Javed pointed out. And the fact that some of the cats still allowed mating activity suggests that other behaviors that come with estrus, like yowling and attempting to escape, might not be suppressed, he added.
“This coupled with other health benefits of an early ovariohysterectomy might still render the surgical option more desirable,” Javed wrote.
Cats aren’t the only pet that could eventually get the gene therapy. Research on a version for dogs is ongoing too, Swanson said.
“It’s a little too early to tell, but we think the general idea of using gene therapy with AMH is likely to work in many different mammalian species,” he explained.
As Pépin pointed out, gene therapy probably wouldn’t make an ideal human contraceptive. But that doesn’t mean the hormone couldn’t be leveraged in other ways, like protecting ovarian reserve in women and girls who are undergoing chemotherapy—an application his team has looked into already.
“Here we had something that could act very early, even on the first step of activation [of follicle development], and then we showed at least in a preclinical model that we could reduce damage to the ovaries,” Pépin explained.
There’s also the possibility of using AMH in the context of in vitro fertilization, or IVF. In a study on mice with diminished ovarian reserve, Pépin and his team found that it was possible to improve the yield of superovulation—a method used in IVF to double or triple the number of eggs released in a single ovulation cycle—by reversibly suppressing ovulation with AMH. This synchronized the wave of growing follicles, so more of them were available for harvesting after ovarian stimulation.
The findings about AMH’s therapeutic potential ultimately led Pépin to co-found Oviva Therapeutics alongside fellow researchers Patricia Donahoe, M.D. and Daisy Robinton, Ph.D. His work on the feline contraceptive helps validate some of their ideas, as cats’ estrus cycles are more similar to humans than rodents.
“Cats look a lot more like us,” Pépin said. “So, we can potentially learn a lot about human applications from them.”