Time magazine’s list of Best Inventions of 2006 included an unusual creation. It wasn’t a gadget; it was a cat.

“Love cats but your nose doesn’t?” the magazine asked. “A San Diego company is breeding felines that are naturally hypoallergenic.” There was a 15-month waiting list for the “sniffle­-proof kitties,” which sold for $3,950 or more.

The company selling the cats, Allerca, had tapped into a tantalizing dream for allergy-prone cat lovers: the hypoallergenic cat. Given that just two genes are responsible for making cats a problem for many people, it seemed like a no-brainer to engineer cats that lacked those genes, or to simply breed cats with versions of the genes that made the animals less allergenic.

But so far, itchy-eyed cat lovers have been left disappointed.

By 2010, Allerca had stopped taking orders — and lawsuits were lining up. The sniffle-proof kitties never materialized. Some angry customers said they never received a kitten, others were sent a cat that triggered their allergies.

But for all those who haven’t given up hope, there may be new options around the corner. An allergic owner might pop open a can of allergy-fighting food — for the cat. Or maybe vaccinate the cat to produce fewer allergens. And allergy shots for owners might shift from burdensome weekly or monthly injections to a shot that offers immediate relief.

The new gene-editing technology called CRISPR/Cas9 might even come to the rescue, delivering the ultimate dream to those who can afford it: a cat that doesn’t produce allergens at all. One company has made some progress applying CRISPR/Cas9 to cats.

Success in taming cat allergies could bring good news for people whose allergies have nothing to do with cats. If any of the cat allergy–fighting measures prove safe and effective, they could be deployed against other allergens, especially airborne ones like pollen, dog dander or dust mites. With up to 30 percent of the world’s population suffering from airborne allergens, that’s plenty of runny noses to dry up.

When it comes to cat allergies, the main culprit is Fel d1, a small protein produced primarily in cats’ salivary and sebaceous glands. Fel d1 is found in flakes of dead skin, or dander, and is spread to hair when a cat licks itself. Thus it’s not cat hair that people are allergic to, just hair coated in cat spit.

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A singular target

As allergens go, Fel d1 gets around. It sticks to hair and clothing, so it’s readily transported from place to place. It lasts for weeks or months before breaking down. It’s light and easily goes airborne, making it even more insidious. In fact, even houses without a cat tend to have a little Fel d1 in their dust, says immunologist Martin Chapman, president and CEO of Indoor Biotechnologies, a company in Charlottesville, Va., that tests for allergens and allergies.

All cats produce some amount of Fel d1, but that doesn’t mean that all cats are equally allergenic. In tests of hundreds of cats, Indoor Biotechnologies found levels ranging from just 5 micrograms of Fel d1 per gram of fur to 2,000 micrograms. Variations in two key genes drive that variability, but no one knows exactly which versions of the genes result in low-allergen cats.

And it’s not clear what function Fel d1 serves in cats. Lions and other big cats have their own version of the protein, Chapman says. So it seems to have stuck around during cat evolution — which suggests the protein does something. Male cats that haven’t been neutered tend to have the highest Fel d1 levels, which have been linked to male hormones. Based on that association and the protein’s similarity to other molecules, Fel d1 might be a pheromone, a chemical used to communicate via scent. But whether cats need the protein to be healthy is unknown.

All this uncertainty has made allergies to cats difficult to tackle. For now, the options are limited. People can take antihistamines and other medications to reduce symptoms, but the drugs don’t stop the allergy.

Traditional allergy shots, also known as immuno­therapy or desensitization therapy, aim to retrain a person’s immune system to be less sensitive to the allergen. But those shots are a commitment; a patient may need up to 100 injections over three to five years. Some people can avoid needles by taking under-the-tongue daily drops of the same U.S. Food and Drug Administration­–approved allergens as in the injections. But this treatment is an off-label use, so is often not covered by insurance.

“Desensitization therapy has been the only therapy for decades,” says Gerald Nepom, director of the Immune Tolerance Network in Seattle, a research group funded by the National Institutes of Health. Exactly how desensitization works is still not fully understood. But the basic idea is that exposing the immune system to small amounts of allergens causes the body to make antibodies that block part of the allergic response. Unfortunately, Nepom says, desensitization generally doesn’t eliminate all symptoms, and the effects aren’t always permanent.

All the newer approaches being studied focus on Fel d1, either by directly neutralizing it or by blocking its interaction with the human immune system. The competition is fierce to devise an effective solution to cat allergies because of the large potential market — about 10 percent (some estimate 20 percent) of people are allergic to cats.

The opportunity to apply lessons learned to other allergies is a strong incentive as well.

Allergy treatments There is no permanent cure for cat allergies, though a number of available treatments can reduce many allergy sufferers’ symptoms. New treatments aim to do a better job against symptoms or stop the allergy process in its tracks. Treatment Available now? Action Pros and cons Antihistamines Yes Block histamine production Newer drugs like cetirizine (Zyrtec) and fexofenadine (Allegra) cause less drowsiness than previous drugs; may not eliminate symptoms Nasal steroids Yes Reduce inflammation in the nose Reduce sneezing, congestion and runny nose; only treat symptoms Traditional allergy shots or drops Yes Exact mechanism unknown; may increase helpful antibodies The only current therapy that reverses some allergies; requires many shots over several years Allergy shots of lab-made antibody No Block immune system’s recognition of allergen Fast-acting prevention of allergic response; boosters required Pet food with antibodies No Cuts amount of active Fel d1 allergen in cat saliva No shots needed; does not eliminate all Fel d1 Vaccine for cats No Prevents human immune system from recognizing cat allergen Does not eliminate all Fel d1; more testing needed to confirm safety for cats Genetic engineering of cats No Removes genes that direct Fel d1 production in cats With no Fel d1, nearly all cat allergies would be eliminated; effects on cats are unknown

Improving immunotherapy

One problem with traditional immunotherapy is that it attempts to stop one of the later steps in the allergic response, the histamine-producing part known as the immunoglobulin E, or IgE, response. But that’s only one part of the body’s response to an allergen.

“We now see allergy as an immune-activation symphony,” Nepom says. Rather than a strict chain of single events, it’s more like an orchestra with many molecular players performing on cue.

Today, Nepom says, allergy researchers are getting a better handle on the role of each player. “This is like figuring out which part of the orchestra is creating the problem. Is it the horn section or the strings, or do you have a single oboe player going rogue?” Knowing that could help researchers target players in the immune system more efficiently.

For example, one research group funded by the Immune Tolerance Network is wrapping up a clinical trial under the name CATNIP to test what’s called an “allergen-plus” approach. Scientists combine small amounts of Fel d1 with an antibody that blocks a substance important to triggering the allergic response. The substance is a protein called TSLP, or thymic stromal lymphopoietin, which may be one of those rogue oboists, because it helps spark and maintain allergic reactions. The idea, if it works, is that a patient would develop a long-lasting tolerance from a one-year course of allergy shots, instead of the three to five years of current therapies.

Other parts of the allergic response are prime targets, too, says immunologist Jamie Orengo of Regeneron Pharmaceuticals in Tarrytown, N.Y. (Regeneron is a major financial supporter of the Society for Science & the Public, which publishes Science News.)

Easier shots For people with cat allergies, one injection of an antibody that binds to the protein Fel d1 provided more relief from nasal symptoms than did a placebo shot. Total nasal symptom score T. Tibbitts T. Tibbitts Source: J.M. Orengo et al/Nature Communications 2018

The company has designed antibodies that are highly specific to Fel d1. The antibodies bind to and lock up the allergen before an allergic person’s immune system has a chance to react to it. It’s an amped-up version of traditional immunotherapy, one that could also be targeted to other allergens, Orengo notes.

“We don’t have to rely on the human body; we can make those antibodies in the laboratory instead of waiting for them to be generated by the person naturally,” Orengo says. Her team reported in 2018 in Nature Communications that tests in mice and in people allergic to cats showed a reduction of allergy symptoms after just one treatment that was equivalent to years of conventional immunotherapy, with the majority of people achieving as much as a 60 percent reduction in nasal symptoms.

One shortcoming: While this approach is very fast-acting, it doesn’t retrain the person’s immune system. A patient receiving the treatment would need periodic boosters, perhaps every few months.

Special cat food

Since saliva is the biggest source of Fel d1, researchers at Nestlé Purina are testing cat food containing an antibody that binds to the protein in saliva as the cat eats. The antibody blocks binding sites on the allergen, essentially rendering it unrecognizable to the human immune system. The antibody doesn’t prevent the cat from producing the allergen.

“In fact, this was an important strategy behind our research,” says immunologist Ebenezer Satyaraj, who’s leading the research at the Purina Institute in St. Louis. “We didn’t want to stop the production of Fel d1 because currently it is not clear what role it has in the cat.”

Edible antibody When 105 cats ate an experimental Purina pet food containing a Fel d1 antibody, levels of the allergen dropped below baseline levels over a 10-week period. Cat food’s effects on allergen levels T. Tibbitts T. Tibbitts Source: E. Satyaraj et al/Immun., Inflamm. and Disease 2019

Tests so far suggest that the food can knock down the amount of active allergen on cat hair by about half (SN: 8/31/19, p. 5). That may be enough to offer relief to some people with mild to moderate allergies; the company expects to market the cat food to consumers sometime this year. But people with severe allergies or asthma may be unable to tolerate any amount of Fel d1 without symptoms, says Michael Blaiss, executive medical director of the American College of Allergy, Asthma and Immunology.

Vaccinate the cat

There are cat lovers out there who’d probably be happier letting the cat get the shots. So another new approach aims to vaccinate cats against their own Fel d1. The vaccine stimulates the cat’s immune system to produce antibodies that bind to Fel d1. That binding cloaks the protein so that human immune cells no longer recognize it and react.

Researchers at HypoPet AG in Zurich studded an inactive fragment of a virus with dozens of Fel d1 molecules. “If you make the allergen look like a virus, the immune system thinks it is a virus,” says Martin Bachmann, chief scientific officer of HypoPet and an immunologist at the University of Bern in Switzerland. This Trojan horse then triggers the cat’s immune system to start seeing Fel d1, which it normally ignores, as an invader.

In an initial test in more than 50 cats, three injections of the vaccine given three weeks apart stimulated the production of antibodies specific to the allergen, reducing cats’ Fel d1 secretion by more than half without harming the cats, the researchers reported in July 2019 in the Journal of Allergy and Clinical Immunology. The company is planning further safety testing, Bachmann says. HypoPet is working with U.S. and European Union regulators to bring the vaccine to market.

The hypoallergenic cat

Producing a cat that makes no allergens at all is still the goal for some researchers. The fact that some cats are naturally low in Fel d1 suggests that they could be bred, as Allerca tried and failed to do a decade ago. But frustratingly, you can’t just breed two cats with low Fel d1 levels and get a litterful of hypoallergenic kittens.

Cat breeder Tom Lundberg has bred Siberian cats for more than a decade in Oregon, with the explicit goal of breeding low-allergen cats. Lundberg himself is allergic to cats. He became fascinated by Siberians after owning one that he wasn’t allergic to. A second one gave him a “snotty nose and itchy eyes,” he says.

Because he has long measured his cats’ allergen levels and tracks the results of breeding, Lundberg can confirm that there’s no way to guarantee that all the kittens in a litter will hit the genetic jackpot. He and his wife, Meredith, now sell the cats they breed based on their Fel d1 levels. Those tested with the lowest levels command the highest prices, up to $5,200 for a kitten in the “extremely low” range of less than 1 microgram of Fel d1 per gram of fur. Only about 1 in 15 of the kittens he breeds from low-allergen cats are in that category, Lundberg says. He has received hundreds of calls from people giving up Siberian cats that breeders had claimed were hypoallergenic.

Tom Lundberg breeds Siberian cats in Oregon. He cautions that breeding two cats that are naturally low in the allergen Fel d1 doesn’t guarantee their kittens will also have low levels of the protein. His advice: If you need a low-allergen cat, get it tested and meet the cat before bringing it home. Sarah Starr

“They’ll say the kittens were ‘bred from hypo­allergenic lines,’ ” he says. “That’s like saying corn was bred from corn — it’s meaningless.” He suggests that anyone interested in buying a low-­allergen cat insist on seeing test results. He also notes that buyers with severe allergies may not be able to tolerate any amount of Fel d1.

Indoor Biotechnologies is trying to genetically engineer a cat that makes no Fel d1. “We’re working on it,” says Chapman, who founded the company. Indoor Biotechnologies has used the gene-editing tool CRISPR/Cas9 to delete the genes that encode the production of Fel d1, called Ch1 and Ch2, in feline cell cultures, and has filed for a patent on the technique.

Next, the company will try knocking out the genes in cat salivary tissues in a lab dish and make sure Fel d1 is no longer being made, says Nicole Brackett, a postdoctoral scientist at the company. She has analyzed the DNA sequence of the Ch1 and Ch2 genes of 50 cats and plans to do the same for 200 additional cats, narrowing down the best gene region to target using CRISPR/Cas9.

If the genetic trick works, engineered cats would lack part or all of the genes needed to make Fel d1. Since some cats naturally produce very little Fel d1 with no ill health effects, the thinking is that preventing cats from making the protein is unlikely to harm them. But scientists won’t know for sure until someone tries it. “That’s precisely the reason to do the experiment,” Chapman says.

Typically, producing such a cat would require deleting the gene from an embryo, which would then be implanted in a female cat and carried to term. But Chapman doesn’t want to get into the breeding business. Instead, he hopes to ultimately edit the genes of adult cats, much like gene therapies being developed now for humans, which use a harmless virus to deliver gene-editing tools. Recent experiments have successfully edited the genes of adult mice and even people with sickle cell disease, for instance (SN: 12/21/19 & 1/4/20, p. 28).

If such a virus could deliver a genetic tool that edits the genes for Fel d1 — maybe by having a veterinarian inject it into the cat’s salivary glands, or as a topical application to reach the sebaceous glands in the skin — “that would be exciting,” Chapman says.

One of the researchers working to wipe out cat allergies won’t be standing in line for any injections, however. Bachmann, of HypoPet, says that he and his son are allergic to cats. When asked if he would try any of the new allergy treatments, he replied no. “I don’t love cats that much,” he says. “I’m more a dog person.”

A personal quest I’ve always been a cat person. So when I married Jay, who’s allergic to cats, I had a problem. Whenever Jay spent time around a cat, his eyes would start to itch, and his nose would run. But Jay loves cats too. Like many allergy sufferers, he tried all the allergy treatments. For a couple of years, he got monthly allergy shots. He now uses daily nasal steroids and the antihistamine cetirizine. Eventually, his allergies didn’t seem so bad, and we wondered if he could tolerate a cat. I’d been seeing a lot of claims about hypoallergenic cat breeds, and was skeptical but curious. Siberian cats, like the author’s cat, Stoli (shown), are considered hypoallergenic by some people. But there’s no evidence that any cat breed is universally low in Fel d1. E. Engelhaupt We’re both biologists by training, so we dove into the scientific literature. We didn’t find much. One small study in Veterinary Sciences from 2017 reported on mutations in Siberian cats that could potentially lower their Fel d1 levels or render the protein less allergenic. It was the barest of hints, but we decided to visit a Siberian cat breeder in Georgia and see if we might luck out. That day we brought home Stoli, a nearly 17-pound sweetheart, on a trial basis. Jay’s allergic reaction to him was occasional and mild, and over a few months the sniffling seemed to diminish even more. Jackpot, we thought, we found our low Fel d1 cat! Then in the course of reporting this story, I decided to test Stoli, sending off a fur sample to Indoor Biotechnologies. The result: Stoli’s fur tested at 790 micrograms per gram of fur—pretty darn high. Maybe the immunotherapy that Jay has endured gets more credit than Stoli’s genes. It’s OK. Despite those test results, we are definitely keeping the cat.