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AniLocus | Preclinical CRO | Eye Disease, Retinal Disease, Cataracts, Glaucoma, Ophthalmic Drug Development

Animal Models for Glycomimetic Drugs in AMD

Age-related macular degeneration (AMD) is a progressive eye disease that affects millions of people worldwide, leading to vision loss and blindness in the elderly population. As there is currently no cure for AMD, ongoing research aims to develop effective treatments to slow down or prevent its progression. One promising avenue for AMD treatment involves the use of glycomimetic nanoparticle drugs. To evaluate the potential efficacy of these novel drugs, researchers rely on animal models of AMD. In this article, we will explore the importance of animal models in AMD research and how they are employed to assess the effectiveness of glycomimetic nanoparticle drugs.

Understanding Age-Related Macular Degeneration (AMD)

AMD is a multifactorial disease characterized by the degeneration of the macula, a central part of the retina responsible for sharp and central vision. The disease is typically categorized into two forms: dry AMD (atrophic) and wet AMD (neovascular or exudative). Dry AMD is characterized by the buildup of drusen, small deposits under the retina, while wet AMD involves abnormal blood vessel growth leading to leakage and scarring. Both forms can lead to vision impairment, making AMD a significant public health concern.

Animal Models in AMD Research

To develop and test potential treatments for AMD, researchers rely on animal models that closely mimic the disease’s progression in humans. These models serve several critical purposes:

Several animal models have been employed in AMD research, each with its own advantages and limitations. Some of the most commonly used animal models include:

Complement Factor H (CFH) Knockout Mouse Model

  • Targeted Gene: CFH
  • Model Induction: CFH knockout mice are genetically modified to lack the complement factor H gene, leading to complement dysregulation and drusen-like deposits in the retina.
  • Translational Capacity: This model replicates some aspects of dry AMD, specifically the formation of drusen, which is a hallmark of early AMD in humans.

Apolipoprotein E (ApoE) Knockout Mouse Model

  • Targeted Gene: ApoE
  • Model Induction: ApoE knockout mice lack the ApoE gene, which results in lipid metabolism dysfunction and the development of subretinal drusenoid deposits resembling drusen in human AMD.
  • Translational Capacity: This model is valuable for studying lipid-related aspects of AMD and provides insights into drusen formation.

Laser-Induced Choroidal Neovascularization (CNV) Mouse Model

  • Targeted Gene: Not gene-specific
  • Model Induction: Laser photocoagulation is used to induce damage to the Bruch’s membrane and the underlying choroid, leading to the formation of CNV lesions.
  • Translational Capacity: This model is primarily used to study the wet form of AMD and the development of CNV, making it relevant to human wet AMD pathogenesis.

LDLR Knockout Mouse Model

  • Targeted Gene: VLDLR (Very Low-Density Lipoprotein Receptor)
  • Model Induction: These mice lack the VLDLR gene, leading to lipoprotein accumulation in the retina and the formation of retinal lesions similar to those seen in dry AMD.
  • Translational Capacity: This model helps in understanding lipid metabolism-related aspects of AMD and drusen formation.

Aging Mice Models (Senescence-Accelerated Mice, SAMP8)

  • Targeted Gene: Not gene-specific
  • Model Induction: These mice naturally age and develop features resembling AMD, such as retinal pigment epithelial changes, photoreceptor degeneration, and visual dysfunction.
  • Translational Capacity: While not gene-specific, these models mimic age-related changes seen in human AMD, making them relevant for studying the aging aspect of the disease.

Rat Laser-Induced CNV Model

  • Targeted Gene: Not gene-specific
  • Model Induction: Similar to the mouse laser-induced CNV model, laser photocoagulation is used to induce choroidal neovascularization in rats.
  • Translational Capacity: This model is valuable for studying wet AMD and testing anti-angiogenic therapies.

Translational capacity varies among these models, with some closely replicating specific aspects of AMD while others serve as more general tools for studying disease mechanisms. Researchers often combine multiple models to gain a comprehensive understanding of AMD pathogenesis and to evaluate potential therapeutic interventions. Additionally, the use of humanized mouse models and induced pluripotent stem cell-derived retinal models continues to advance translational research in the field of AMD.

Evaluating Glycomimetic Nanoparticle Drugs

Glycomimetic nanoparticle drugs are a promising class of compounds in AMD research. These drugs mimic the glycoproteins involved in regulating cell adhesion and angiogenesis, key processes implicated in AMD pathogenesis. Animal models play a crucial role in assessing the efficacy of glycomimetic nanoparticles by:

  • Testing Therapeutic Candidates: Researchers use animal models to administer glycomimetic nanoparticle drugs to simulate the effects of treatment in AMD. They assess changes in retinal structure and function, as well as the reduction of drusen or neovascularization.
  • Safety and Tolerability: Animal models help determine the safety and tolerability of glycomimetic nanoparticle drugs by monitoring adverse effects and potential toxicity.
  • Long-term Efficacy: These models allow researchers to investigate the long-term effects of treatment, providing insights into whether glycomimetic nanoparticles can slow AMD progression over time.

In recent news, the clinical safety of AVD-104, a novel glycomimetic nanoparticle therapeutic was assessed in clinical trials for the treatment of geographic atrophy (GA), a severe form of dry age-related macular degeneration (AMD). AVD-104, developed by Aviceda Therapeutics, demonstrates continued clinical safety in the treatment of GA. The treatment aims to address the unmet medical need for patients with GA, for which there are currently no approved therapies. AVD-104 is undergoing clinical trials to evaluate its efficacy and safety profile as a potential treatment option for GA, providing hope for individuals affected by this condition.

Key Takeaways for Novel Therapeutics for AMD

Animal models are indispensable tools in the evaluation of novel therapies for AMD, including glycomimetic nanoparticle drugs. These models enable researchers to gain critical insights into the disease’s mechanisms, test potential treatments, and assess their safety and efficacy. As research continues to advance, the hope is that these animal models will lead to the development of effective treatments that can improve the quality of life for those affected by age-related macular degeneration.

References

  1. Pennesi ME, Neuringer M, Courtney RJ. Animal models of age related macular degeneration. Mol Aspects Med. 2012;33(4):487-509. doi:10.1016/j.mam.2012.06.003.
  2. Aviceda Announces AVD-104, a Novel Glycomimetic Nanoparticle, Demonstrates Continued Clinical Safety in the Treatment of Geographic Atrophy Secondary to Macular Degeneration. Aviceda Therapeutics. October 11, 2023. Accessed October 17, 2023. https://www.businesswire.com/news/home/20231012725572/en/Aviceda-Announces-AVD-104-a-Novel-Glycomimetic-Nanoparticle-Demonstrates-Continued-Clinical-Safety-in-the-Treatment-of-Geographic-Atrophy-Secondary-to-Macular-Degeneration.
  3. Schnabolk G, Obert E, Banda NK, Rohrer B. Systemic Inflammation by Collagen-Induced Arthritis Affects the Progression of Age-Related Macular Degeneration Differently in Two Mouse Models of the Disease. Invest Ophthalmol Vis Sci. 2020;61(14):11. doi:10.1167/iovs.61.14.11.
  4. Kim SY, Kambhampati SP, Bhutto IA, McLeod DS, Lutty GA, Kannan RM. Evolution of oxidative stress, inflammation and neovascularization in the choroid and retina in a subretinal lipid induced age-related macular degeneration model. Exp Eye Res. 2021;203:108391. doi:10.1016/j.exer.2020.108391.
  5. Pennesi ME, Neuringer M, Courtney RJ. Animal models of age related macular degeneration. Mol Aspects Med. 2012;33(4):487-509. doi:10.1016/j.mam.2012.06.003.