AMD is an eye disease that affects central vision. It is the leading cause of irreversible vision loss in people over 50 years of age in developed countries. This accounts for half of all legal blindness.

One in seven people over 50 have some degree of AMD. By age 90, almost one in four experience vision loss from AMD.

This has a significant effect on quality of life, impacting the ability to read, drive and recognise faces. It also increases depression, falls and fractures, requiring an increased level of care.

Direct and indirect costs of visual impairment from AMD in Australia is expected to grow to $6.5 billion by 2025.

In the early and intermediate stages of AMD, most people do not notice overt changes to their vision. However, in the late stages of AMD, central vision is lost due to damage to the retinal cells in the macula.

New treatments have transformed the care for one devastating late complication of AMD,  neovascular AMD (commonly known as wet AMD).

However, there is currently no approved treatment for the other form of late AMD, geographic atrophy (dry AMD). There is also no proven intervention to slow the disease progressing from intermediate AMD to late AMD, where vision is threatened.

Until recently, everyone with the early stages of AMD was considered to have the same type of disease. The risk of progression to late-AMD was determined by the size of waste deposits in the retina.

With new imaging techniques it is now possible to distinguish different types of deposits. One of these – reticular pseudodrusen (RPD) – is associated with increased risk of progressing from the early stages of AMD to late AMD.

Everyone with the early and intermediate stages of AMD have drusen but around 25-33 per cent of those also have RPD. The latter represents a critical group that is at high-risk of progressing to the vision-threatening late stage of AMD.

Understanding the genetic associations and causes of RPD will help determine where new treatments could intervene to prevent people with the early stages of AMD from progressing to late AMD and losing vision.

1. That RPD will have a genetic association.
2. Identifying the genetic causes of RPD will provide key information for understanding the pathways leading to their development.
3. Understanding these pathways will help develop new interventions to prevent progression to late stage AMD.

The central purpose of this research is to reduce vision loss in people with AMD by uncovering the underlying causes of RPD and their role in increasing the risk of disease progression.

There are three research themes.

Theme 1 – Discovering novel genetic causes of RPD

The genetics of those with RPD and those without will be compared using large patient cohorts. Retinal images from these patients will be expertly phenotyped by senior graders or an artificial intelligence algorithm.

Then, well-established as well as novel genetic and bioinformatic methods will be used to determine the underlying genetic causes of RPD.

Theme 2 – Uncovering the mechanisms of disease

Researchers will explore the link between genetic variations associated with RPD and changes in underlying biology using in vitro induced pluripotent stem cell technology and in vivo preclinical models of disease.

Theme 3 – Moving from bench to bedside

A range of systemic markers (e.g. lipid profiles and innate immunity) and visual function markers (e.g. dark adaptation) will be used to establish causal links between specific genetic risk factors and functional/systemic changes in those with RPD.

This deeper knowledge is critical for identifying what biological pathways leading to RPD. Knowledge of these pathways will help develop new treatments to slow progression of AMD.

The scope of this study offers an unprecedented opportunity to understand what drives vision loss in AMD and what processes to target to potentially develop effectively interventions.

It is now possible to assess a high-risk AMD phenotype (RPD) at both an anatomical and functional level using new retinal imaging techniques and ways of assessing visual function. This is more robust than the simplistic grading of colour photographs.

RPD has been validated as a critical new severity biomarker. The presence of RPD greatly increases risk of vision loss.

By analysing data from extensive international collaborations, the study will refine clinical cohorts to adequately demonstrate and characterise RPD. This offers a new opportunity to understand the key early events leading to AMD progression and vision loss.

This information is critical for identifying new intervention pathways that could become viable new targets for novel treatments.

This study was awarded $5 million in the inaugural year of the National Medical Health and Research Council (NHMRC) Synergy Grants scheme. Synergy Grants support multidisciplinary research teams to investigate problems that are too big to be solved by an individual researcher or a single group.