Gene-Based Methods for Feline Induced Sterilization

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1		Rita Payan-Carreira	--	2938	2023-12-15 10:55:04	\|
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This entry is adapted from the peer-reviewed paper 10.3390/futurepharmacol3040057

Feline population control remains a concern as to whether it is intended for the short- or long-term. Gene-based sterilization refers to the use of genetic manipulation to control reproductive processes and induce infertility or sterility. Gene therapy sterilization is taking its first steps in product development and in vivo testing, although no established method has yet been approved for widespread use. Gene-based therapy represents the promise of durable clinical benefits to complex human diseases and brought significant progress in the medical field.

contraception hormonal-methods non-hormonal methods gene therapy

1. Introduction

Because of their naturally high fertility, the control of cat reproduction is fundamental for managing free-roaming, feral populations. According to Vansandt et al. ^[1], four-fifths of the estimated 600 million domestic cats worldwide are free-roaming. Stray and homeless cats are critical problems worldwide ^[2]^[3]^[4]. Those who survive adversity adopt a free-roaming lifestyle and establish a community population of cats (colonies). Some of them cluster in groups and survive, supported by offers of food and shelter ^[4]. Others survive in urban and suburban areas, in smaller groups, or individually, accessing multiple scattered food sources ^[5].

Even though the proportion of owned neutered cats may vary across the globe, the contribution of homeless cats to population replenishment is substantially higher than that of owned cats ^[5]. Different strategies have been implemented to control the population of feral and homeless cats, focusing on permanent sterilization in association with other measures ^[5]^[6], such as relocation to shelters financed by governments or pet rescuing associations, the adoption of trap-neuter-return programs, or animal adoption by particulars ^[5]. In these situations, most animals undergo surgical (ovariohysterectomy in females and orchiectomy in males) or chemical sterilization (intratesticular injection of sterilant to induce azoospermia), which requires financial investment, labor, and time, as it is followed by the intervention’ recovery period. In addition, some animals are unsuitable for adoption or suffer from stress when in captivity. In addition, it has been referred to as presenting important limitations, such as failing to reach the necessary scale to be effective ^[5]^[7], supporting the growing quest for more accessible and effective strategies to control cat reproductive function while guaranteeing the animals’ and environmental welfare.

2. Mechanistic of Gene-Based Therapy in Brief

Gene therapy aims to manipulate or modify genes to treat diverse congenital or acquired disorders ^[8]^[9]. More recently, it has been extended to control reproductive function in males and females ^[10].

Gene-based therapy involves a complex process. In brief, for gene-based therapy, it is crucial to understand the pathophysiology of the disease or the biological process and the role of the gene and protein that is targeted; then it is needed to produce the modified gene (or transgene), according to the species-genome, and inserting the gene into a carrier system and finally, to inject the product. Usually, the gene-delivering system contains three components: a plasmid gene expression system (which regulates the function of the gene of interest), the transgene (i.e., a gene encoding for a target protein), and the delivery system—or vectors—(that will deliver the transgene into the body) ^[9]. These delivery systems can be viral (a non-pathogenic vector ^[11]^[12], whose main characteristics are listed in Table 1), non-viral (relying upon chemical or physical methods to introduce the protein in the cells, including the use of inorganic nanoparticles with a functionalized surface, such as liposomes and nanotubes, among others ^[12]^[13]^[14]), or hybrid (e.g., genetic combination of viral vectors ^[15]; combination of viral and chemical vectors ^[16]; hybrid viral nanoparticles ^[16] or non-viral nanovectors engineered with pH-sensitive materials ^[17]^[18]. Figure 1 depicts the variety of gene carrier systems that are available for gene therapy.

Figure 1. Different types of vectors available in gene therapy.

Viral vectors can rely on either RNA or DNA for carrying the transgene; the latter usually integrate their load into the genome and have long-lasting actions, while the former directly transcribe from the inoculated RNA transcripts, and therefore, their actions are not permanent ^[19]. RNA viral vectors are often used for vaccine development ^[20]. The most promising viral vectors used are retroviruses, particularly lentiviruses and spumaviruses, adenovirus, and adeno-associated adenoviruses (AAVs). These are usually selected because of their more efficient and non-toxic gene transfer ^[8]. In AVV vectors, viral coding sequences are replaced by transgenes. They usually carry smaller gene packages (up to 0.5 kb of DNA) ^[8], contrasting with lentiviruses and spumaviruses that can carry larger and more complex transgenes (Table 2); another difference between AVVs and the latter respect the ability to integrate the cell DNA ^[11]^[19]. When a lifelong effect is sought, particularly in gene therapies designed for the correction of congenital diseases, the vector must be able to integrate the carried information into the cell genome so that the gene will be transferred to the daughter cells during the mechanisms of cell replication, in the case of stem cells, or be stabilized in the cell, in the case of long-lived postmitotic cells ^[21], providing long-lasting expression.

Table 1. Summary of the main properties of the most frequently used virus-based gene delivery systems (compiled from ^[11]^[20]^[21]^[22]).

Features	Retroviruses	Lentiviruses	Spumaviruses	Adenovirus	Adeno-Associated Adenoviruses
Viral genome	Single-stranded RNA	Single-stranded RNA	Single-stranded RNA	DNA	DNA
Cell division requirements in target cells	Dividing cells	G1 phase	No preferences	No	No
Gene loading limitation	8 kb	8 kb	9.2 kb	8–37 kb	4–5 kb
Immune responses to the vector	Low	Low	Low	Extensive at the inoculation local	Low
Genome integration	Yes	Yes	No preferences	No	Some integration ability
Main disadvantages	Random integration Low titers	Random integration Potential for pathogenic vector mutation	Random integration	Transient expression Requests repeated administration	Later onset of expression
Main advantages	Persistent gene transfer in dividing cells Long term expression	Broad host range High transduction efficiency Persistent gene transfer in transduced tissues	Highly effective in dividing cells No expression of viral proteins	Highly effective in transducing various tissues Large gene loading capacity	Elicits few inflammatory responses Sustained gene expression Non-pathogenic

Implementing gene therapy involves three steps ^[23]: administration of the compound, the transgene delivery into the target cells, and its expression to achieve the proposed outcome. The last but not the least important aspect to consider, is to survey the results of clinical trials, check the results, compare them to conventional therapies, and evaluate for potential side effects. Furthermore, gene therapy strategies can be integrated into two categories according to the administration pathways: in vivo, directly in the patient vs. ex vivo, and in cell cultures originating from a patient to be posteriorly transferred back ^[21].

3. Gene-Based Sterilization

One of the first references to the potential use of gene-based therapy in the reproductive field was presented by Stribley and colleagues ^[22] in 2002, who discussed the potential application of gene therapy in the reproductive medicine field. The potential areas of interest identified by the authors were obstetrics (for treating fetal pathology) and gynecologic oncology (for treating benign and malignant diseases, particularly ovarian and cervical cancer). The latter has been embraced and developed along with many other gene therapies in the oncological field and has entered the clinical trial stage ^[24]^[25].

Over time, the Anti-Müllerian hormone (AMH) ‘s role in follicular development and sustaining ovarian activity in different species was researched. It has been shown that in females, but not males, AMH is a determinant player in follicle recruitment and growth ^[26]. Indirectly, AMH also determines the estrous cycle exhibition by controlling follicular development and maturation. Also, it has been shown that high concentrations of AMH in adult male rats inhibit adult Leydig cell steroidogenesis, thereby decreasing the testosterone secretion by Leydig cells ^[27]. Evidence collected from AMH research led to the hypothesis that a vectored-gene delivery approach might also successfully induce long-term infertility in males.

This hypothesis has been developed and tested in the Dr. Pépin laboratory, linked to gene therapy research in oncology. In 2015, Pépin et al. ^[28] reported the use of adeno-associated virus-delivered gene therapy to block primordial follicle activation by up-regulating human AMH synthesis. Later, another study from the same team showed that the arrest of primordial follicle development achieved with this gene therapy was reversible once the standard hormone levels were re-established, e.g., by transplanting the ovaries of treated mice. The authors defend that this technique would also protect the ovarian follicular pool from the deleterious effects of chemotherapy in young animals ^[29]. Moreover, they also analyzed the genital tract development in pups born from transplanted ovaries to demonstrate that no vertical transmission of the edited gene occurred in litters born from treated mothers with high levels of MIS.

At the same moment, revisiting the immunocontraception ideas, Li et al. ^[10] tested the use of a therapeutic antibody gene transfer approach to induce long-term sterilization in mice. In this approach, the gene controlling the production of a specific antibody is introduced in the body, driving the production of endogenous antibodies against that specific molecule. The authors report the results for two different antibody genes ^[10]. In one of the experiments, a vectored anti-GnRH antibody gene was delivered by a recombinant AAV, administered in a single intramuscular dose, to male and female mice, originating a long-term suppression of the reproductive function in a dose-dependent manner (seven unevenly dosed-groups of 3 to 11 mice each). Despite that females developing titers above 200 g/mL were mainly infertile, four animals (out of 42) reversed the situation after an initial period of 8 weeks. Fertility in females was tested by the production of pups after breeding with a fertile, untreated male at predefined moments of the experiment (at 8-, 28-, 36-, and 44-weeks post-administration). Females treated with higher titers evidenced a complete suspension of follicular development in the ovaries, whereas the counterpart-treated males showed a reduction of the testicular size, along with a decrease in testosterone production and the arrest of meiosis in seminiferous tubules, associated with a lack of spermatozoa in the epididymis ^[10]. In the second experiment, the authors claimed to achieve long-term sterilization in female mice treated with a vectored anti-zona pellucida_2 (ZP2) antibody gene ^[10]. Even though, in this experiment, around 42% (5 in 12) of the females were able to produce pups (although with reduced litter sizes) after a first breeding trial five weeks after the product administration, all but one of the treated females failed to produce progeny in subsequent allowed mating periods. The histological evaluation of the gonads of treated females evidenced developing follicles and corpora lutea, like those of control mice, although the zona pellucida around oocytes showed disturbed morphology. As a conclusion for this second experiment, the authors defend that the vectored expression of anti-ZP antibodies was able to induce long-term infertility ^[10]. Nonetheless, sterility was not obtained, and the evidence hints at the persistence of ovarian cyclic activity as the treatment failed to disrupt the normal follicular maturation.

Some disadvantages have been experienced or expected when cells are transfected with immunoglobulin genes, limiting the technique’s efficiency, namely: the rise in the antibody titers registered following the treatment response was variable with the individual, originating unpredictable “non-responders”; their persistence in plasma tended to decrease with time, driving a temporary effect requesting repeated administrations; reproductive behavior and fertility were not completely abolished, but only transitory infertility was obtained.

Despite the reported challenges, the experiments in mice ^[10]^[29] contributed to supporting the hypothesis that using vectored transgene delivery upon a single product administration was a feasible approach for lifetime, non-surgical induced contraception in small animals ^[30], which the authors deem particularly useful to control community or feral animals’ populations. According to the authors, administering molecules with contraceptive potential (such as an antibody against a specific molecule or hormone transgene) would allow the body to synthesize that molecule for long periods, bypassing the natural reactivity and time-limited response of the body’s immune system, and consequently leading to the annulment of crucial reproductive pathways, for which they named the technique vectored contraception. Nonetheless, the developed vectored gonadotropin-releasing hormone vaccine’s limited contraceptive effect, particularly when using homologous GnRH ^[31]^[32].

Embedding this line of thought, a very recent publication reported the development and experimental use of an adeno-associated viral vector carrying an AMH transgene that, used in a single dose, was able to suppress the ovarian function in intact young and mature female cats throughout a period of 42 months without evidence of deleterious side-effects ^[1]. The treatment led to a sharp increase in serum AMH concentrations at the end of the first week, the change depending on the product dose. This increase was followed by a gradual decrease, starting five months after the treatment, which was more pronounced at the end of the first year. AMH values stabilized at lower values at the beginning of the second year after the injection, even though they remained higher than the physiological threshold of 0.25 µg/mL ^[1]. One-third of the treated females demonstrated unwanted estrous behavior in the scheduled testing mounting periods. The breeding activity failed to induce ovulation and the formation of corpora lutea in only one female in the high-dose group ^[1]. The authors reported the absence of antibodies against the vector complexes when using the AMH transgene developed exclusively from the cat genome ^[1]. The authors recognize that their experiment shows that an ectopic expression of anti-Müllerian hormone failed to hinder sex steroid secretion or the expression of regular estrous cycles, even though it prevented breeding-induced ovulation ^[1]. The major inconvenience inferred from this study could be the inability to suppress feline estrous cycles and follicular development, a crucial aspect when the expected outcome will be to control feline populations.

4. Risks and Limitations in Gene Therapy

It is important to note that gene therapy is generally still largely experimental and faces numerous scientific, ethical, and regulatory challenges. Besides, these methods may not be readily accepted without reservations by the community, as they are yet to be proven effective, long-lasting, and safe. Consequently, an existing reluctance to accept gene therapy techniques may compromise the willingness to participate in study trials, delaying the gathering of the necessary volume of data to determine the efficiency and efficacy of these techniques.

Screening the available information in gene-based therapy, mainly when applied to induced contraception or sterilization raises two main concerns: the safety of the therapy and its efficacy. An additional issue can be the cost, which will limit the broad use of this technique in different veterinary medicine contexts.

In general, there are some safety concerns about viral usage, i.e., the ability of the viral genome to be incorporated into the receiver species ^[33] and the possibility that viral shedding occurs in bodily fluids ^[34] and poses a public health risk. Using non-pathogenic viral vectors with stable genomes or the engineering of nonviral carriers allows for circumventing this issue and mitigating potential safety risks. Nonetheless, further studies are needed to ensure safety during clinical trials and therapy applications ^[34]^[35]. Another safety concern relates to the interaction with the receiver organism, both by the accidental activation or inhibition of endogenous gene expression (e.g., driving oncogene expression ^[12]), the non-specific uptake by non-targeted organs, which could originate unwanted side effects or loss of efficacy ^[35], or the ability to induce unwanted inflammatory and immune reactions ^[12]. Besides any discomfort and temporary disease-like conditions, the reactions against the delivered complex may foster the development of antibodies against the vectored transgene, thus reducing its therapeutic action and originating unpredictable “non-responders”. To avoid this risk, researchers have explored the manipulation of immune tolerance, the choice of delivery vector and dosage, the design of new vectors, and the study of alternative routes of inoculation, among others ^[12]^[35].

The main efficacy-related concerns expand from the previously mentioned to include the gene carrier systems, the length of the successful therapy (or the intervals between administrations), and the specificity of the response ^[36]^[37]. Most advances in this respect result from the increasing number of multiple-stage clinical trials (cells, animal models, and humans) and the progress in genetic engineering. The success of some clinical trials opened space to offer innovative treatments to selected patients and the route to the production of new laws and regimentations. However, this field is still expanding, and much work is still foreseen.

When extending the abovementioned concerns to the use of gene therapy to induce long-term sterilization and control feline feral and free-roaming populations, according to data reported in some studies ^[1]^[10]^[29], the proposed approaches still fail to achieve the promised long-lasting sterilization that enables the control of community or feral populations of cats. Contrasting to the conceptualization of the term contraception used in human medicine, where the main goal is to prevent pregnancy while retaining the sexual drive, the paradigm of contraception in veterinary medicine includes annulling all the reproductive activity from the animal, including the expression of the estrous cycle and breeding behavior that might reflect in the group dynamics (by enhancing animals roaming and fighting). Until this moment, the reported methods have failed to suppress gonadal activity completely. To achieve such desired control, a logical approach would be to target the GnRH hormone, as the central master controlling gonadal activity. So far, virus-vectored immunocontraceptive vaccines tested in other species have failed to ensure contraception. Despite the vector effect on the production of anti-GnRH antibodies, the contraceptive effect is limited and highly variable between individuals. This raises a different question: are these results related to the species’ particularities, and should the rhythm of administration be tailored to the species? Or is the brain-blood barrier, preventing the passive diffusion of antibodies ^[38], contributing to impairing an immune-modulated suppression of gonadotrophin secretion from the pituitary? Anyway, considering that for the control of feral and colony populations, a long-term suspension of reproductive activity is desired, it may be possible that a completely different approach must be faced, such as the gene silencing of a main pathway controlling reproduction.

The costs of gene therapy are possibly the most expensive treatment in human medicine because of the costs (including the R&D costs for cell and gene therapies ^[39], the intellectual property costs, and the production and delivery costs ^[40]), limiting the access of many to the new gene therapies. The cost brings a new concern regarding the translation of gene therapy technologies to the veterinary medicine field, particularly for much-needed population control.

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