Animal model of retinal vascular diseases
January 4, 2021
Methods for preparation and screening of therapeutic or prophylactic drugs for retinal vascular diseases
Key Word : animal model, blindness, diabetes mellitus, drug therapy, edema, endothelial cells, growth factors, hemorrhage, ischemic, nephropathy, retinal detachment, retinopathy, vascular disease
Background / Context / Abstract:
Chronic complications of diabetes mellitus are caused by microangiopathy and cause retinopathy, nephropathy, and neuropathy. In particular, diabetic retinopathy is a disease that can potentially cause blindness in late middle ages. In advanced cases of diabetic retinopathy, abnormal neovessels generated in the ischemic retina with microvascular occlusion cause vitreous hemorrhage and retinal detachment, and lead to blindness. The methods for treatment of retinal ischemia include photocoagulation, anti-vascular endothelial growth factor (VEGF) drugs, and vitreous surgery. All of them have certain therapeutic effects. On the other hand, retinal edema due to increased vascular permeability (a condition potentially occurring in both early and advanced stages of diabetic retinopathy) may not lead to blindness when it occurs alone, but may cause advanced visual impairment. Effective treatment for retinal edema is not readily available. One possible reason for this is the lack of an animal model manifesting conditions similar to diabetic retinopathy.
A meta-analysis based on 35 studies in the world reporting the prevalence of diabetic retinopathy showed that one of three patients with diabetes had retinopathy of any type, and that one of eight to nine patients with diabetes had vision-threatening retinopathy. Moreover, anti VEGF drugs recently used for the treatment of retinal edema are not only very expensive, but also a palliative care requiring frequent administration and thereby increase the medical costs. Therefore, development of a new drug therapy for retinopathy is an urgent issue.
The present invention is a method for inducing microaneurysm formation and retinal edema in the retina in a short period of time by administration of 4-hydroxytamoxifen (4-OHT) in mice expressing Act-Mer, a fusion protein of the active form of signal transduction factor (a serine/threonine kinase) Akt and a mutant estrogen receptor, to prepare an animal model of retinal edema due to increased vascular permeability and a condition similar to human diabetic retinopathy.
Furthermore, the inventors found that changing the dose or dosing period of 4-OHT enabled preparation of animal models at varying disease severity, and that Akt inhibitors exhibited therapeutic effects on retinal edema.
Use of the animal model provided by this invention enables screening of drugs for the treatment of retinal edema, which has been unfeasible so far.
While spontaneous, drug-induced, and genetically modified animal models of diabetes mellitus are available, retinopathy similar to human diabetic retinopathy has not yet been reported in animal models.
In the early stage of diabetic retinopathy in humans, retinal edema and hemorrhage develop due to increased vascular permeability caused by degeneration of vascular endothelial cells, shedding of pericytes, thickening of basement membrane, and formation of microaneurysm. However, animal models developing retinal edema due to increased vascular permeability have been scarcely reported.
Potential Applications / Potential Markets:
A mouse model exhibiting conditions similar to those of human diabetic retinopathy.
State of Development / Opportunity / Seeking:
・Available for exclusive and non-exclusive licensing
・Exclusive/non-exclusive evaluation for defined period (set up for options)
Applied in Japan (JP2019-033745A1) and US (US2019/0045759A1)