动物造模,疾病动物模型 z-bio 2021-09-19 531

　　Introduction: The pathology of the eye is usually divided into different categories according to the affected area: ocular surface diseases, anterior and posterior diseases. Cataracts, age-related macular degeneration (AMD), glaucoma, presbyopia, dry eye (DED), eye allergies and other diseases can cause visual impairment and blindness. Ocular pathology is also common in a variety of systemic diseases, including rheumatoid arthritis, Sjogren’s syndrome (SS), graft versus host disease, and chronic diseases such as diabetes and hypertension. The formulation of treatment strategies for eye diseases requires an in-depth understanding of the cause of the disease, its molecular and anatomical pathogenesis, and its natural history. Simulating human diseases in mouse, rat, guinea pig, rabbit, dog, and primate animal models is essential for us to understand several human eye diseases, develop new drugs, drug delivery strategies, and improve ophthalmic diagnostic techniques. This review focuses on key models for the development of new therapies for the most common eye diseases (eye allergy, DED, glaucoma, presbyopia, diabetic retinopathy (DR) and AMD). This article also discusses the application of these models in ophthalmological pharmacology and their transformational potential for human diseases. Our purpose is not to provide a complete list of all preclinical models of these eye diseases. Instead, we focus on the key in vivo models used to establish preclinical POC before entering the clinic, and focus on drugs that have proven clinical efficacy. By reviewing regulatory documents (such as new drug applications, confidentiality agreements), conference abstracts, patent publications, completeness experimental model knowledge fields and information provided in published literature, the drugs and their preclinical POC models have been sorted out. Although many of these animal models simulate various aspects of eye diseases, none of them can fully reflect the complexity of human diseases. Therefore, multiple models of the same disease are often needed to summarize different aspects of human pathology. Finally, we outline several gaps in current preclinical models and endpoints that should be considered in the development of new therapies in the future to meet unmet patient needs.

　　Ocular surface disease: The ocular surface is a complex tissue system that is coordinated to obtain a stable tear film and help vision. Lacrimal glands and lacrimal sac glands, mucus-secreting goblet cells, and nervous system are the key components of the lacrimal function unit and help maintain a stable tear film. In addition, epithelial cells and potentially lymphoid-related tissues provide mucosal barriers to prevent irritants and pathogens from entering the body. The ocular surface is susceptible to environmental damage, and when the tissue components are damaged, mild to severe diseases can follow. The most common ocular surface diseases include dry eye (DED), blepharitis, eyelid gland dysfunction (MGD) and eye allergies. Patients may experience dry eyes, itching, photosensitivity, and foreign body sensation. In many cases, these are common symptoms of several ocular surface diseases. The progression of the disease requires drug intervention, such as anti-inflammatory drugs for anti-DED and eye allergies, and antibiotics for the treatment of blepharitis. Although many patients respond to drug therapy, there are still a large number of patients who do not respond to drug therapy or cannot tolerate the side effects associated with drug therapy. For effective treatment, a variety of in vivo models that simulate multi-tissue heterogeneous pathologies have been developed. This part of the review focuses on animal models of ocular allergies, dry eye syndrome (water shortage and evaporation), and eye pain for drug development. We will not discuss preclinical models of ocular infections or ocular wound healing because they have been reviewed elsewhere.

　　ocular inflammation: ocular allergy and dry eye inflammation. Inflammation plays a key role in the pathology of a variety of ocular surface diseases including DED, SS, and ocular allergies, so ideal drug candidates include anti-inflammatory or immunomodulatory molecules. A variety of preclinical eye models have been used to verify the anti-inflammatory properties of drugs, because one model may not represent all aspects of pathology. Discussed below are pre-clinical models for ocular allergy and DED drug development. Several SS models have been reported in the literature.

　　Eye allergy: Eye allergy (allergic conjunctivitis) is an allergic disease that affects the conjunctiva, eyelids and/or cornea, with a prevalence of up to 20% in the United States. There are strong clinical symptoms and signs between subtypes, such as tearing, chemotherapy, mucus secretion, and itching, and severe allergies may involve keratitis and corneal ulcers. Ocular allergic reactions are caused by IgE-mediated reactions, and factors that cause mast cell degranulation drive signs and symptoms. This early reaction peaks within 1 hour, and 4-6 hours later may lead to late reactions, including an influx of eosinophils and neutrophils. Although mild ocular allergies are usually self-healing and do not affect vision, the increase in immunopathology mediated by T cells and eosinophils in VKC and AKC is related to chronic diseases and can lead to impaired vision. Treatment includes identifying and avoiding allergens, while drug treatment options mainly include local/systemic antihistamines and mast cell stabilizers, and topical steroids can be used for severe disease states. The choice of next-generation anti-inflammatory drugs is aimed at prolonging the efficacy of antihistamines and limiting the side effects of standard anti-inflammatory drugs (such as steroids), which are known to induce glaucoma.

　　Allergy therapy: Some preclinical models of rodents, rabbits and dogs have been described. These models describe the stages of allergic reactions and the severity of eye allergic diseases. The main pharmacodynamic activity of rapid anti-inflammatory drugs against histamine H1 receptor and/or mast cell stabilization or other immune regulatory mechanisms has been supported by histamine therapy, compound 48/80 therapy, and antigen challenge induction models. Passive anti-ovalbumin therapy-mediated allergic reactions can increase vascular permeability. Similarly, topical ophthalmic treatment with histamine induces conjunctival vascular permeability. These methods of ocular allergic reactions are quick and short-lived, but are helpful for early drug development, such as AL-4943A administration studies in rats and guinea pigs. Compound 48/80 (a non-immunogenic mast cell degranulation agent) can also be used to rapidly induce ocular allergies, which can produce chemotherapy, tearing, mucus secretion and itching reactions in animals and humans. Local treatment with compound 48/80 can lead to strong granulocyte infiltration. The rapid histamine response peaks within 1 hour after treatment. In humans and animals, T cell-mediated inflammation can last up to 3 days. New Zealand white rabbits were used to successfully prove the antihistamine activity of lastacaft. In addition, the 48/80-induced allergic reaction has been transferred to the clinic and used to evaluate the efficacy of the second-generation histamine H1 receptor antagonist levocetine in the treatment of patients. Compared with models that mainly capture the degranulation response of mast cells, the antigen challenge model provides a better opportunity to evaluate factors related to chronic diseases. The induction of antigen challenge begins in the sensitization phase of peripheral immunity, usually protein, ovalbumin or environmental antigens. This is followed by local antigen stimulation, which induces chemotherapy, tearing, mucus discharge, redness and itching. Similar to the cytokines observed under the induction of compound 48/80, the antigen-stimulated stimulation pattern resulted in more obvious infiltration of conjunctival eosinophils and maintained T helper type 2 (Th2) cell-mediated immunopathology. In addition, the interaction of other types of cells, including polymorphonuclear cells and T helper 17 cells (Th17), is also described. Recently, a severe model called allergic eye disease (AED) was developed in mice. Compared with the traditional model of allergic conjunctivitis, it can produce conjunctival fibrosis, corneal lymphangiogenesis and higher Persistent clinical symptoms of IgE levels. The AED model has been applied in the development of the interleukin 1R antagonist Isunakinra (EBI-005, 11 biological therapies). Interleukin-1 is the main regulator of ocular inflammation and plays an important role in the pathogenesis of acute and chronic diseases. In AED and another DED ocular surface disease model, isunakinra showed efficacy when administered locally. This will show whether a new non-traditional anti-inflammatory treatment can be clinically successful, and support the translatability of these antigen challenge models. Other methods may include local sensitization and stimulation to better mimic clinical conjunctival antigen challenge models, and more importantly, models including keratitis or corneal ulcers to replicate the observations in more severe chronic human eye allergies Symptoms.

　　Dry eye syndrome: Dry eye syndrome is a multi-factorial ocular surface disease that can cause a series of symptoms and/or signs that affect 5-30% of the population. Dry eye usually causes symptoms of discomfort and visual impairment, which are described as dry eyes, foreign body sensation, hoarseness, light sensitivity, and pain. Common signs of DED include decreased tear volume, increased ocular surface staining, shortened tear breakup time, and abnormal syphilis glands. The core of DED is the high osmotic pressure of tears, which can cause inflammation and cause damage to the surface of the eye, thus forming a vicious circle. Traditionally, dry eye is divided into insufficient tear type and evaporation type, which are related to insufficient tear production, tear stability, and evaporation loss, respectively. The DEWS report defines DED as including inflammation and neurosensory abnormalities as the etiology. Another factor that causes loss of homeostasis in the tear film is MGD, which is the most common cause of DED. Treatment strategies for dry eye include artificial tear substitutes, gels/ointments, moisture chamber glasses, topical anti-inflammatory agents, tetracyclines, punctual plugs, tear and mucus secretion agents, serum, systemic immunosuppressants, and surgical substitutes. Eye pain and discomfort are also the main components of DED, and treatment strategies are currently being developed to address these diseases. Some preclinical models have contributed to the early development of drug treatments. The following is a review of preclinical models related to the development of topical anti-inflammatory drugs, secretory drugs, and ocular pain therapies.

　　Anti-inflammatory therapy: In human and animal models, inflammation causes a series of similar ocular surface changes: loss of corneal epithelial integrity, decrease in goblet cell density, tear gland damage, changes in tear production and composition, and abnormal cornea nerve. Although many animal models of dry eye have been produced, only a few models have a transformative effect in the development of anti-inflammatory drugs, which will be reviewed below. Currently, there are two anti-inflammatory drugs approved for DED: restasis and xiidra. xiidra inhibits inflammation by inhibiting the integrin interaction between ICAM-1:LFA-1. This interaction plays a role in cell migration and the formation of immune synapses that promote T cell activation. The rat streptozotocin (STZ) DR model was used to evaluate the preclinical efficacy of lixiidra in non-dry eyes, and to evaluate retinal white blood stasis and blood retinal barrier rupture. After approval, the efficacy of .iidra was observed in a mouse desiccation stress model, in which scopolamine was administered to induce tear insufficiency and exposure to low humidity and airflow conditions to induce tears to evaporate. The model was characterized, and changes in tear production, corneal barrier function, conjunctival morphology, and goblet cell density were observed, all of which are characteristics of human DED. Compared with the vehicle treatment group, the xiidra treatment group had significantly lower expression of T helper type 1 cytokine family genes, less damage to the corneal barrier, and greater density/area of conjunctival goblet cells. In addition, the dry stress model is used in preclinical efficacy studies of other anti-inflammatory drugs. In mice exposed to dry stress, local treatment with CP-690550 or EBI-005 resulted in corneal staining and/or the expression of inflammatory mediators in cornea and conjunctival tissues was significantly reduced relative to excipients. The changes in the dry stress model were studied, revealing the unique immunopathology and the ability to simulate chronic diseases. The research results of Chen et al. showed that when comparing drugs and environmental stress induction methods, different effector T cell populations contribute to the disease. Chen discussed the chronic phase of the dry stress model, and the results showed that the corneal fluorescein staining score remained elevated 16 weeks after the dry stress. In addition, immunopathological evaluations showed that memory Th17 cells are key inducers of chronic and recurrent DED processes, which was confirmed by adaptive transfer to the recipient before exposure to environmental stress. Although the dry model of DED continues to provide valuable insights into the immunopathology of DED, and progress has been made in chronic models that better mimic the role of DED in humans, but in higher species, Using larger eyes to evaluate drug efficacy can provide a better model to evaluate the relationship between pharmacokinetics and pharmacodynamics (pk-pd). The key model is the canine model of dry eye: canine keratotic conjunctivitis SICCA (KCS). Canine KCS is a spontaneous disease with a prevalence of about 1%. It has similar clinical symptoms to human DED, such as decreased tear secretion, eye irritation, epithelial disease, and similar immunopathological mechanisms. The topical cyclosporin treatment of canine KCS can improve keratitis and conjunctivitis, regulate the expression of cytokines, and reduce the infiltration of cells into the lacrimal gland. These studies highlight the main features of canine KCS immunopathology, which are also described in human DED: increased T cell infiltration in the lacrimal gland and conjunctiva, increased apoptosis of lacrimal gland and conjunctival epithelial cells, and inhibition of T cell apoptosis in these tissues. In a 12-week treatment study, we performed a Lifitegrast evaluation on KCS dogs. Treatment resulted in a significant increase in tear production from baseline, which corresponds to a decrease in conjunctival inflammatory cell infiltration relative to baseline. Although these findings indicate that the canine KCS model is an effective method for detecting wide-ranging anti-inflammatory drugs, the immune pathogenesis of canine KCS has not been fully established, and the disease symptoms in dogs are often more severe than those observed in DED patients. Canine KCS can have obvious conjunctival hyperemia, thick mucus-like secretions, recurrent ulcers, and systemic effects similar to those observed in human SS patients.

　　Secretagogue: It is well known that in addition to the above-mentioned inflammatory mechanism, DED also involves a complex mechanism, including hypertonic pressure, tear fluid instability and insufficiency, and loss of mucin. Tear fluid plays a vital role in the etiology, progression and pathogenesis of DED. The stable tear film is composed of mucus layer, water layer and lipid layer, among which the lacrimal gland and meibomian gland play a vital role. Treatments for tear deficiency include artificial tears or lubricants, biological tear substitutes, "secreting agents" or in some cases the use of perforated plugs to delay tear clearance. In addition to the lacrimal glands, it has recently been discovered that the ocular surface epithelium may be a key regulator of basal tear volume and composition through cAMP and calcium-dependent cl-transporters, as well as the absorption of sodium (NA+) through the epithelial sodium channel (ENaC). Based on these observations, a new method for improving ocular surface hydration by inhibiting the sodium absorption of the epithelial sodium channel (ENAC) inhibitor has recently been developed, which has been proven effective in early clinical studies and is currently underway 2 Phase 3 clinical research. The molecular progress of this mechanism is based on key preclinical studies, which have shown that ENAC blockers can permanently increase ocular surface hydration and provide a new mechanism for the treatment of dry eye. The lead compounds were locally tested in normal mice to evaluate the effect on tear output, and the results showed that the tear duration of lead compounds was longer than that observed with purinergic agonists. Using the acute model of dry eye dehydration, the pro-inflammatory cytokine interleukin-1 was injected into the extraorbital lacrimal glands, resulting in lacrimal gland dysfunction. The results showed that this model can induce severe inflammation, stimulate the proliferation of acinar and ductal cells, and increase the cornea Fluorescein staining inhibits protein secretion and tearing. The results showed that in this model, the ENAC inhibitor's tear output increased and the corneal fluorescein staining score decreased.

　　An important class of drugs that have been developed to improve the balance of tears is a class called secretory drugs. Of the tear mucin secretion drugs, two have been evaluated in a number of preclinical models of dry eye with hypohydration and have been launched in Japan. These include the new quinolone derivative Mucosta (rebamipide, otsuka pharmaceuticals) and the purinergic agonist Diquas? (diquafasol, santen). The mechanism of action of rebamipide is not yet fully understood. It has a protective effect on the mucosa, promotes the re-epithelialization of damaged tissues, and plays a role in the resolution of inflammation. According to pre-clinical studies, a 2% ophthalmic suspension of the drug was approved in 2012. The drug has effects on mucus proteins, goblet cells, and ocular surface inflammation. Diquafosol is a uridine dinucleotide analog, as a purinergic P2Y2 receptor agonist, 3% ophthalmic solution is approved in Japan as a drug for the treatment of dry eye. The activation of P2Y2 receptors on the ocular surface increases the production of tear fluid and mucin. These two secretins were evaluated in superoxide dismutase-1 (SOD-1) knockout mice. Due to oxidative and inflammatory stress, tear secretion decreases, leading to shrinkage and fibrosis with age. Rebamipide and diquafosol were evaluated in 40-week-old male SOD-/- mice, and the results showed that they can improve tear stability, corneal epithelial damage, conjunctival goblet cell density and MUC5 messenger RNA expression. Therefore, this model represents an interesting way to test therapeutic strategies that promote the antioxidant defense system and reduce oxidative stress-induced damage. According to reports, several different changes in the function of the lacrimal gland in the mouse model are disrupted. In rodents, the lacrimal gland has two different anatomical divisions: the extraorbital gland on the temporal side of the eye and the smaller intraorbital gland under the bulbar conjunctiva of the outer corner of the eye. Stevenson W et al. In 2014, the lacrimal gland outside the orbit of mice was surgically removed to have a reproducible and lasting effect on tear secretion, severe corneal epithelial lesions, and ocular surface inflammation and immunity. In this model, it was also demonstrated that adding ovalbumin (a well-known inert antigen) to the ocular surface can disrupt mucosal tolerance. In order to simulate a more severe dehydration phenotype, another lacrimal insufficiency model was recently reported in mice. This model involves the removal of the outer lip and intraorbital lacrimal glands, resulting in severe and long-lasting (more than 10-12 weeks after surgery) Phenotype. Rats also underwent lacrimal gland excision to form a dry eye model with insufficient tear fluid. In this rat lacrimal excision-induced dry eye disease model, we have evaluated the above-mentioned Diquafosol and ENaC inhibitors and demonstrated that they can improve tear secretion and restore corneal epithelial barrier function. It has also been reported that dexamethasone treatment did not significantly improve the decrease in tear volume observed in this model. On the contrary, after treatment with these anti-inflammatory drugs, the observed corneal surface damage and inflammatory mediators were weakened. Therefore, this lacrimal gland resection may help distinguish the therapeutic mechanism of anti-inflammatory drugs and secretory drugs. Rebamipide and diquafosol were also tested in rabbits with normal and eye diseases. In normal rabbits, topical medication can increase the number of periodic Schiff stain (pas) positive cells and mucin secretion. They also tested in a rabbit model of desiccation stress, which involves removing the nictitating membrane and inducing a desiccation stress for 10 minutes by using a constant airflow at a speed of 10 m/s on the cornea. This leads to acute corneal injury. This model is a very acute model and is not suitable for evaluating the effects of drugs on existing diseases. Another rabbit model used to evaluate rebamipide is a model created by injecting 10% N-acetylcystine (NAC) solution (a well-known mucosal dissolving and anti-collagen dissolving agent) into rabbit eyes. Treatment with NAC can reduce the level of conjunctival mucin, so this model can be used to evaluate the effect of drugs on mucin secretion. BAC-induced dry eyes have been replicated in rodents, rabbits, and dogs, and have been shown to mimic many signs of human DED. BAC has been shown to destroy the tear film, promote the overexpression of inflammatory mediators, and cause goblet cell hyperemia and death. This model has been used to evaluate the efficacy of anti-inflammatory steroids and serum eye drops, which is a new method for the treatment of dry eye.

　　Considerations for preclinical models of ocular surface diseases: This section summarizes several preclinical models of ocular surface diseases used for drug development. In the context of eye allergy, preclinical models have good predictive value, because similar allergy induction methods are used in human studies. However, these models do not fully describe the mechanism of chronic allergies, nor do they have the clinical symptoms observed in severe allergic diseases such as VKC and AKC (corneal injury). Similarly, the preclinical model of DED cannot fully represent the complexity of the disease. DED is a multifactorial disease of tear fluid and ocular surface, leading to clinical symptoms of tear defect, inflammatory mechanism and ocular surface damage. The etiology of the clinical signs observed in DED can be caused by a variety of pathogenic mechanisms, including hypertonic pressure, chronic inflammation, insufficient tears, and damage to ocular surface tissues including epithelium, nerves, and secretory glands. No preclinical model is sufficient to capture all these pathogenic mechanisms. For example, the lacrimal gland resection model may be more suitable for evaluating drugs used to correct tear defects. Although the rodent dry stress model seems to capture the inflammatory mechanism of human dry eye, it is limited by the size of the eye, which leads to significant differences in the pharmacokinetics and required doses of the drug from humans. Another challenge of the pre-clinical model is that it cannot directly convert the symptoms observed in the clinical environment, including eye pain, discomfort, and visual impairment. This issue is at the core of the unmet need to treat ED. The use of animal behavior as a transformative manifestation of human eye discomfort and pain is still under development and is awaiting verification. Significant progress is needed to develop additional preclinical models of eye pain to capture the pathogenesis of pain in DED. Therefore, it may be necessary to use a variety of animal models to describe and evaluate the treatment of ocular surface diseases.

　　Anterior segment disease: The back of the cornea is the remaining part of the anterior segment, including all structures between the iris and the lens. The iris is a thin and round structure that adjusts the size of the pupil diameter and then the amount of light reaching the retina. There are important structures and fluids in the space between the iris and the lens, such as ciliated bodies, aqueous humor (AQH), and trabecular meshwork (TM). AQH is a thin, clear liquid that fills the anterior chamber. It is mainly composed of water (99.9%) and trace amounts of sugar, vitamins, proteins and other nutrients, as well as growth factors and cytokines. AQH, together with other structures in the anterior segment, supports eye health through intraocular pressure management, nutritional support of the cornea and lens, and physical support to maintain the shape of the eye. The ciliary body and its muscles change the curvature of the lens and its ability to focus the image on the retina. The extracellular matrix deposition at the TM leads to increased resistance to water outflow, which may lead to increased intraocular pressure (OHT). OHT is a risk factor for the progression of glaucoma and one of the main causes of irreversible blindness. Glaucoma refers to a group of eye diseases with elevated or non-elevated intraocular pressure (IOP). It is characterized by optic neuropathy, including loss of retinal ganglion cells (RGC) and their axons at the level of the lamina layer. This in turn can cause cupping of the optic disc and gradual loss of vision. Glaucoma can be further divided into multiple subtypes, including primary open angle (POAG), primary angle closure (PACG), normal tension (NTG), congenital, exfoliation (or pseudo exfoliation), and secondary glaucoma. The most common types are POAG and PACG, which are characterized by a pathological increase in intraocular pressure. Hardening of the lens, loss of accommodation, and clouding can lead to presbyopia and cataracts. Multiple animal models have been established to mimic the pathology observed under these conditions, and in some cases have been approved for therapeutics. The normal blood pressure rabbit and monkey models are the most widely used preclinical animal models to demonstrate the intraocular pressure reduction effect of the drug before regulatory approval. These normotensive models support brimonidine tartrate monotherapy and combination therapy with other compounds such as carbonic anhydride inhibitors. In addition to evaluation in normal animals, experimentally induced high intraocular pressure animal models (such as laser photocoagulation) are used to disrupt the water outflow channel and simulate the pathology observed in POAG and PACG. With the increase in intraocular pressure, scarring of TM and adjacent ocular tissues, loss of pigment, RGC death, optic nerve head cup process and RNFL thinning, these models have all been observed. In rodents, rabbits, and primates, TM or laser photocoagulation through the superior vein was performed. Similar to the effect on humans, in New Zealand male and female white rabbits, compared with the other two anti-glaucoma drugs, latanoprost showed the highest in normal blood pressure, steroid-induced ocular hypertension and water load models Peak intraocular pressure reduction and longest duration of action. Other preclinical OHT or glaucoma models, such as genetic models and microprobe injection, have been used for proof of concept and mechanism research. Injecting microbeads or microspheres into the anterior chamber is a challenging multi-species adaptability model. However, multiple injections may be required to maintain the necessary increase in intraocular pressure. According to the type and type of injury, some animal models can represent POAG or PACG subtypes. Timolol and brinzolamide have been evaluated in a minimally invasive ocular hypertension model of adult C57BL6 mice, and it has been demonstrated that compared with the control group, their intraocular pressure is reduced and RGC and axon survival rates are improved. Implementing these models in higher species may increase human translatability, but they also have their disadvantages.

　　Retinopathy: The retina constitutes the nerve sensory tissue of the eye, which is composed of multiple nerve layers and a tightly regulated blood vessel network. The light entering the eye is detected by rod and cone photoreceptors combined with bipolar cells, horizontal cells, and nonsecretory cells. These secondary neurons are connected to the ganglion cells, and the axons of the ganglion cells form a layer of nerve fibers that transmit visual signals to the brain through the optic nerve. The abnormally high metabolic needs of the retina are provided by two vascular beds; choroidal capillaries are a dense network of capillaries that oxidize the outer layer of the retina, and the vascular system in the retina is a terminal artery, and a multilayer capillary network permeates the interior of the retina. The most common retinal diseases, age-related macular degeneration and diabetic retinopathy, are related to pathological changes in retinal nerve cells and their vascular network. Optic nerve injury models can include transection (partially or completely) or squeezing of the optic nerve itself to cause initial damage to axons and RGC bodies. In a complete optic nerve transection model, all axons are transected, and the death of RGC is inevitable, so it is difficult to distinguish primary and secondary degeneration. Partial optic nerve transection causes damage to a group of axons in the optic nerve, and according to its projection, it leads to region-specific degeneration. The model also allows for secondary degeneration of neighboring cells, which can be distinguished from the initial damage based on location. The damage observed in the optic nerve crush model is similar to that observed in human diseases and is widely used in the literature to support brimonidine in the treatment of glaucoma. One disadvantage of this model is that the magnitude of the force and the duration of the applied force are not standard and can vary from laboratory to laboratory. Damaged axons are intertwined with surviving axons, and it is difficult to distinguish primary and secondary degeneration. Among these models, part of the optic nerve transection model is considered to be the best secondary degeneration model for evaluating the efficacy of neuroprotective test drugs. The aforementioned genetic models such as GLAST and EAAC1-deficient mice are also valuable for evaluating neuroprotective strategies for glaucoma. They may provide a unique opportunity to simulate the pathological effects of naturally progressive glaucoma on RGCs and axons. Two preclinical studies support its clinical development: one in a rabbit chronic vascular leakage model, and the other in a matrigel-induced CNV model in SD rats. Subcutaneous injection of nesivazumab significantly inhibited CNV damage. form. The chronic vascular leakage model in rabbits is caused by intravitreal injection of a colloidal toxin, DL-α-aminoadipate, which destroys the blood-retinal barrier caused by the toxicity of glial cells and retinal degeneration in the retina.

　　Conclusion: We have provided a summary of a major POC preclinical model used to develop treatments for common eye diseases that are approved or under evaluation. Multiple preclinical models are needed to capture different aspects of multifactorial diseases of the eye. Although one model may be suitable for defining the pathogenic mechanism of a disease and identifying new drug targets, another model may be needed to evaluate the time of action, pharmacokinetics/pharmacodynamics of new drugs and their impact on clinically relevant endpoints. Influence. Another common challenge in the laboratory environment is the ability to simulate chronic disease states in an adaptable test method. Existing preclinical models are essential for the development of treatments without visual symptoms; however, their utility in the development of disease-modifying drugs may be limited. Preclinically proved that the efficacy of a new drug under the preventive treatment mode may not be transformed into the clinical population that has already experienced disease progression. In this case, the new drug must intervene to slow or prevent its progression. The successful development of the next generation of ocular disease treatments will require improved models to capture key clinical features that can be evaluated through translational endpoints. Applying clinical biomarkers and endpoints to preclinical models will help bridge the gap between these two areas.