Animal Models of Age-related Macular Degeneration (AMD)
Dr. Sandeep Kumar
Senior Scientist, Ophthalmology Department, Absorption Systems
Age-related macular degeneration (AMD), a leading cause of irreversible blindness in the elderly due to loss of photoreceptors in the macula, is a progressive, polygenic, and multi-factorial disease with poorly understood etiology. Approximately 8.7% of the worldwide population suffers from AMD, with the number of cases expected to rise from around 196 million in 2010 to around 288 million in 2040. There are two types of AMD, the ”dry” and ”wet” forms. The chronic form, “dry AMD,” is much more prevalent than the wet form and is characterized by the deposition of acellular, polymorphous debris called “drusen,” consisting of esterified cholesterol, phosphatidylcholine, and proteins, between the retinal pigment epithelium (RPE) and Bruch’s membrane (BM). Currently, there is no FDA-approved treatment or cure for dry AMD; however, a number of clinical trials are underway. Excessive drusen deposition may result in damage to the RPE, BM, retina, and choroid vasculature, which may lead to the wet form of AMD, which is characterized by the growth of abnormal blood vessels within the sub-RPE and in the sub-retinal space. Therefore, dry AMD is considered a precursor for wet AMD. One of the variants of wet AMD is choroidal neovascularization (CNV), which is responsible for severe vision loss in 80-90% of AMD patients. The standard treatment for neovascular AMD is monthly or bimonthly intravitreal injections of anti-vascular endothelial growth factor (VEGF) agents such as bevacizumab (Avastin®), ranibizumab (Lucentis®), or aflibercept (Eylea®). However, the exploration of new therapeutic targets is necessary to develop additional novel therapies for neovascular eye diseases such as wet AMD.
Transgenic and experimental animal models provide reproducible systems to explore the key molecules and pathways involved in the etiology of neovascular eye diseases as well as platforms to evaluate the efficacy and safety of novel treatments. Nonetheless, all of the available models have certain limitations and selection of an animal model is entirely dependent on the objectives of a given study. Animals immunized with carboxyethylpyrrole-adducted proteins, which are found in drusen and in the plasma of dry AMD patients, might be a good model to screen dry AMD drugs. Laser photocoagulation, a model of acute injury and inflammation, has contributed greatly towards our present understanding of the pathogenesis of CNV. Laser-induced CNV model may be chosen for drug screening because lesions show higher consistency (80%) and follow predictable stages of CNV development: early membrane formation, the establishment of a mature fibrovascular network, and involution. However, the major limitation for laser CNV models is that damage to the BM can only be performed in pigmented animals because the pigment in the RPE absorbs laser energy efficiently thereby enabling a more reliable response to the damage than non-pigmented animals.
On the other hand, for longitudinal studies, animal models involving the delivery of angiogenic agents (genes, proteins or cells) and insult to BM are more suitable. Angiogenic agents can be delivered alone or using recombinant viral vectors driven by tissue-specific or constitutive or inducible promotors via intravitreal or subretinal injections for long-term expression and a disease phenotype. For example, intravitreal delivery of streptozotocin results in features similar to diabetic retinopathy. Pharmacokinetic studies for anti-neovascular IVT drugs can be performed in a rabbit model developed by the IVT delivery of VEGF which compromises the integrity of the retinal vasculature, makes them leaky and creates a closely related pathological condition, retinal neovascularization. In addition, a number of genetically modified and transgenic mouse models have provided insights into the pathophysiology and etiology of AMD and also became standard platforms for drug screening for AMD and other vascular eye diseases.
In these animal models, disease phenotype progression and efficacy of a pharmacological agent can be analyzed over time by using available in vivo imaging tools such as direct& indirect ophthalmoscopy, fundus photography, sodium fluorescein, and indocyanine green angiography, spectral-domain optical coherence tomography, and electroretinography. With relevant models of ocular diseases, state-of-the-art equipment, and outstanding scientific expertise on hand, Absorption Systems is the CRO of choice for preclinical testing of drug pharmacokinetics, safety
About the Author:
Dr. Sandeep Kumar is working as a “Senior Scientist” at the Ophthalmology department, Absorption System Inc, San Diego. He serves as Principal Investigator or Study Director for preclinical ophthalmic studies and interface with different teams including in-vivo scientists, QC/QA, Account Managers/Sales. Dr. Kumar has 10 years of experience working in the ocular research field. He worked at Karolinska Institute, Sweden; Moran Eye Center, University of Utah; Cullen Eye Institute at Baylor College of Medicine, USA. Dr. Kumar has made significant contributions in creating animal models for eye disease research. He has transgenically generated and characterized a mouse model for Polypoidal Choroidal Vasculopathy (PCV), a variant of Age-Related Macular Degeneration (AMD), which mimics human PCV condition. Dr. Kumar also developed novel methods to characterize the pathology in the choroid/retina vasculature. In collaborative work, he answered a long-debated question in the field on the existence of Visual Pigment as a monomer or dimer? and showed for the first time that “inside a living organism” rhodopsin exists as a dimer. In addition, He has shown therapeutic implications of CRISPR/dCas9 technology by delivering Lentivirus vectors containing CRISPR dCas9 & VEGF sgRNAs in laser-induced CNV mouse model and showed that VEGF levels can be significantly down-regulated in long term. Dr. Kumar’s scientific papers and presentations have been published in prestigious journals such as Proceedings of the National Academy of Science USA, Circulation Research, Investigative Ophthalmology Vision Science, Clinical genetics, BBA and Molecular and Cellular Biochemistry, etc. His research interest is to develop animal models for ocular diseases and use them to develop new treatment strategies.