Study reveals effective gene therapy for long-term contraception in domestic cats

Surgical procedures require anesthesia, surgical skills, and post-operative care, making them resource-intensive and sometimes impractical for large-scale population control efforts.

Scientists have found a durable contraception method for domestic female cats by delivering a specific gene called the feline anti-Müllerian hormone (AMH). The research was a collaboration between researchers from the Cincinnati Zoo & Botanical Garden, Harvard Medical School, and the University of Massachusetts Chan Medical School.

Viral-vectored delivery of AMH

AMH is a protein that plays a crucial role in sex determination during fetal development and is found in the ovarian follicles of female cats.

Recent research has shown that high levels of AMH can prevent follicle development and lead to permanent contraception in female mice when achieved through gene therapy using an adeno-associated virus or AAV vector. 

Unlike traditional contraceptive methods, this method works by inhibiting the activation of primordial follicles, the initial structures that give rise to mature eggs. By preventing the activation of these early follicles, the contraceptive method effectively interrupts the reproductive process and prevents pregnancy.

The present study aimed to develop a genetic approach to induce contraception in cats using an optimized AMH transgene and an adeno-associated virus serotype 9 (AAV9) vector to deliver the transgene into feline cells efficiently. 

AAV9 is a virus commonly used as a delivery system, or vector, in gene therapy. It was chosen because it prefers muscle tissues and is not usually blocked by antibodies in cats, making it an effective gene delivery vehicle.

The researchers developed two versions of the AMH gene using genetic information of domestic cats, fcMISv1 and fcMISv2. The second version, fcMISv2, was modified to fix differences in amino acids from the first.

The modification increased the likelihood that the fcMISv2 gene will effectively induce the desired physiological changes and deliver the desired contraceptive effects when delivered to cats using the viral vector. 

Testing in mice and cats

For the initial test, the researchers used mice. By injecting the AAV9-fcMISv2 vector into mice lacking immune defenses, the researchers observed the production of AMH protein in various tissues. They also noticed a decrease in the size of the ovaries and the number of follicles in the treated mice compared to the control group.

This meant the genes functioned as intended and were ready to be tested in cats. The AAV9-fcMISv2 was administered to nine female cats with no significant adverse effects or immune responses. 

The cats were followed for two years, during which the researchers observed that the cats exhibited continuous secretion of supraphysiological (higher than normal) levels of AMH, and no anti-fcMISv2 antibodies were detected. 

The researchers thus concluded that the AAV9-fcMISv2 prevents breeding-induced ovulation, resulting in safe and durable contraception in the female domestic cat. However, further research is needed to understand the physiological impacts of high AMH levels on feline reproduction and optimize the vector for effective contraception.

The findings are published in Nature Communications.

Study abstract:

Eighty percent of the estimated 600 million domestic cats in the world are free-roaming. These cats typically experience suboptimal welfare and inflict high levels of predation on wildlife. Additionally, euthanasia of healthy animals in overpopulated shelters raises ethical considerations. While surgical sterilization is the mainstay of pet population control, there is a need for efficient, safe, and cost-effective permanent contraception alternatives. Herein, we report evidence that a single intramuscular treatment with an adeno-associated viral vector delivering an anti-Müllerian hormone transgene produces long-term contraception in the domestic cat. Treated females are followed for over two years, during which transgene expression, anti-transgene antibodies, and reproductive hormones are monitored. Mating behavior and reproductive success are measured during two mating studies. Here we show that ectopic expression of anti-Müllerian hormone does not impair sex steroids nor estrous cycling, but prevents breeding-induced ovulation, resulting in safe and durable contraception in the female domestic cat.