Why did we fund this fellowship?
This award aims to replace the use of rodents and monkeys in studies of Age-related Macular Degeneration (AMD) by developing a microfluidic in vitro model of the human macula.
The underlying cause of AMD is not fully understood, and researchers have developed a number of in vivo models to provide insights into the disease. Models can either be spontaneous, where animals develop aspects of AMD naturally, or induced, for example by damaging the eye with a laser in a controlled manner. Rodents are most commonly used, however, they do not have an anatomical macular, the specialised part of the eye that is affected in AMD. Monkeys have an eye anatomy most similar to humans and have been used in some ageing studies to investigate macular pathology. In vitro models are available, but these often do not recapitulate the complexity of macular vasculature. In humans, the central macular encompasses a zone free of vasculature to ensure light can reach the retina. The presence of this zone is thought to be a key component in the risk of developing AMD and is not present in current in vitro models of AMD.
During her NC3Rs-funded PhD, Dr Savannah Lynn developed an in vitro method using cultured human retinal pigment epithelium (RPE) cells and demonstrated the model recapitulated characteristics of early AMD such as drusen formation and inflammation. During her Fellowship, Savannah will now combine these methods with microfluidics and 3D printing to incorporate both vascularisation and the vasculature free zone and establish an in vitro model of AMD – termed MacuSIM. She will develop skills in immunofluorescence, electron microscopy and computer-aided design.
Age-related Macular Degeneration (AMD) is a common blinding condition that results in the gradual loss of central vision. This is often associated with difficulties in performing simple daily activities such as reading, driving and recognising faces and is a particular concern for the elderly who are at a greater risk of developing the disease. In fact, one in three people will exhibit some form of AMD by the age of 70. AMD currently affects around 600,000 people in the UK alone and costs the economy £1.6 billion annually. This is predicted to increase as our population ages, where outpatient appointments have risen by 30% over the past 4 years and approximately 200 new AMD cases are reported daily. Although treatments exist for some forms of AMD, these are only applicable to 50% of cases and remain ineffective long-term. Thus, there is no cure for AMD at present, which is largely due to our limited understanding of how the disease develops. This constantly remains under investigation by scientists in order to develop new treatments.
A number of animals are used by AMD researchers to investigate the underlying causes of disease and in the development of new drugs. Of these, rodents are the most commonly used species which have provided important insights into detrimental changes associated with AMD. However, the structure of the rodent eye is markedly different to that of humans and therefore they have been questioned as a relevant model for the study of AMD. In fact, rodents do not have a macula, the specialised part of the eye affected in AMD. Monkeys (non-human primates) offer the closest similarity to the human eye but come with considerable ethical concerns and must be aged for long periods in order to exhibit disease symptoms. There has therefore been a longstanding requirement for a system that is capable of modelling the full disease spectrum of AMD, but that also exhibits fast turnaround times as well as economic viability.
One method of avoiding this difficulty is using cells cultured in a dish, which scientists have used effectively to make discoveries. However, whilst current cell culture models have allowed researchers to investigate individual components of the outer retina and how these are affected in AMD, none have succeeded in modelling the complex relationships and how they may collectively lead to disease.
In this proposal, we aim to validate and demonstrate the applicability of MacuSIM to AMD research, a novel cell culture model of the outer retina developed by the applicants that is capable of recapitulating the key cell types affected in AMD as well as their reliance on the retinal blood supply. This allows the region of the eye most susceptible to AMD to be investigated outside of animal models for the first time, thus reducing their requirement in AMD research. We will employ cutting edge techniques at the forefront of engineering and physics to manufacture this transformative model and will validate the system for use with various biological applications. Our experiments will then involve demonstrating its relevance to AMD research and benefits over existing methods, to promote its uptake within both the academic and pharmaceutical sectors. Here, we will model increased environmental stresses to the macula and test the ability of compounds to alleviate disease symptoms.
Through this research we hope to provide a more economic and high throughput model that will lead to the faster development of treatments for AMD patients and reduce associated costs to the NHS. In fact, this work will also benefit research into other eye diseases including Best disease, Stargardt disease and retinitis pigmentosa, highlighting the far reaching impacts and benefits of MacuSIM to society.