With a litter of tactics, scientists work to tame cat allergies

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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.

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.

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.)

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.”

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
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.”

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