Goodbye allergies? Genetic scissors must be fixed in cats

According to the European Foundation for Allergy Research, every ten Germans suffer from a cat allergy. In most cases, the ‘Fel d1’ protein is responsible for very unpleasant symptoms such as watery eyes, itchy skin and fits of sneezing – or in particularly severe cases neurodermatitis and asthma attacks. Cats secrete it in their salivary glands, tears, fat, and anus, and distribute it throughout the body with their tongue when brushing their fur. So you often come into contact with it, whether by stroking or touching cat hair or dander, which is spread all over the clothing.

Until now, people with allergies have only been able to combat symptoms with antihistamines or attempt desensitization therapy to gradually accustom the body to the antigen. However, immunotherapy does not work in every case, is not recommended for asthma and is also expensive because it requires monthly or even weekly injections of small amounts of the allergen.

That’s why there have been efforts for some time to turn off the “Fel d1” gene in cats. US company InBio recently announced another step in this direction with collaboration partners from Texas A&M University and Northwestern University. Before removing the gene with the CRISPR gene scissors, the company wants to know if this would be without health consequences for cats. So the research partners compared the CH1 and CH2 subunits of the “Fel d1” protein in domestic cats and big cats such as lions, tigers and pumas. They found many changes in their DNA sequence as well as in the protein units themselves, they wrote in the journal CRISPR.

Genes with important functions usually differ slightly across species so that they do not lose their function. Therefore, the InBio researchers are cautiously confident that ‘Fel d1’ also has no essential biological function. However, the biological function of the protein, which occurs only in the cat family, is still unknown. Researchers suspect a role in protecting the skin and in the transmission of steroid hormones and pheromones.

According to Nicole Brackett, who leads the cat CRISPR program at InBio, comparisons with proteins from other animals that partially match “Fel d1” in structure or DNA sequences could also provide clues to function. For example, a mouse protein with similar binding sites is used, among other things, for chemical communication when selecting a mate. In the case of lorises, sloth monkeys, on the other hand, have a structurally similar protein that acts as a defensive poison. Attempts to eliminate this gene, called ABP, in mice showed no measurable defects, according to Brackett and co-authors.

This does not yet mean that “Fel d1” is unnecessary in cats. Whether it still has a function, and if so, which one, must be clarified empirically in cat fetuses. The genes for the ‘Fel d1’ CH1 and CH2 subunits must be removed using CRISPR gene scissors. If these tests are successful and Fel d1 proves not necessary, the company will not want to turn off Fel d1 later in the embryo stage. Instead, gene therapy should only be done in the glands of adult animals that produce the protein.

Scientists have tried unsuccessfully to eradicate the feline gene for more than 20 years. Hopes are now pinned on a new, more accurate CRISPR technology. In the first lab experiments on cat fat cells, researchers working with Brackett actually removed the CH1 and CH2 genes individually using CRISPR. It will be years before attempts to remove both genes in cat embryos provide any evidence of how important or important they are. The question also arises whether these attempts are still morally justified.

This also applies to the strategy of inactivating Fel d1 in other ways. The American company Nestlé Purina offers cat food called “Pro Plan LiveClear” enriched with antibodies against “Fel d1”. In studies, it took about three weeks for the focus on fur to drop by about half on average, which is said to reduce allergic reactions. Another study did not identify any behavioral changes in house tigers. For those with severe allergies, this reduction probably isn’t enough, allergists say. However, it can help those who are less affected.

Using a related approach, Swiss company HypoPet has been trying to vaccinate cats directly against its “Fel d1” protein for nearly ten years. This should allow them to produce antibodies against it and thus remove it from the circulation. To do this, the company uses a genetically modified (recombinant) variant of the protein, along with a harmless portion of tetanus toxin, to activate the immune system against the antigen. In a pilot study in 18 cats, the amount of “Fel d1” was reduced by half after about 40 days.

Next, HypoPet wants to know if the effect will last or if regular booster vaccinations are necessary. In any case, it is certain that her body produced so-called IgG antibodies in response to the vaccination – one of a total of five types of immunoglobulin (Ig). This strain is not involved in allergic reactions and is the same as that produced in desensitization treatments. On the other hand, there is an overproduction of IgE antibodies in those with allergies.

In further tests, owners reported that they were able to pet their animals for an average of ten minutes longer than before: 27 instead of 17 minutes. This shows that there is still a long way to go before a lasting effect is achieved – and perhaps even longer before allergy sufferers have no symptoms at all. Hypo Pets are planning clinical trials with the owners themselves and will also attempt to use the same technology to combat potentially life-threatening allergies as those to peanuts.

“Current treatments only reduce allergy symptoms or are only partially effective,” Brackett sums up. “Our approach to targeting the Fel d1 protein with CRISPR would be the first treatment option that can remove a major allergen directly at the source. That would be a major advance.”

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