Investigating genetic variants leading to AMD

Brief lay background

The complement cascade is a process that is triggered when there is a threat to the immune system. In response, activation pathways converge to recognise and destroy unwanted pathogens by promoting an inflammatory response. Complement activation can occur on both host and foreign surfaces and is tightly regulated by the alternative pathway to prevent unwanted self-directed damage.

Variants in alternative pathway genes and have consistently been associated with age-related macular degeneration (AMD)- a global leading cause of visual loss- these are estimated to collectively account for around 60% AMD genetic risk.

It is now widely accepted that excessive inflammation caused by over activation of the complement cascade of innate immunity is a major driver of AMD.

However, the mechanisms via which AMD-associated genes and variants increase disease risk are poorly understood.

What problem/knowledge gap does it help address

Genetic variation in complement genes plays an important role in AMD. Although advanced sequencing technologies have facilitated the identification of variants underlying disease, data interpretation represents a significant bottleneck and is limiting the clinical utility of genetic testing for AMD.

Animal and cellular models fail to accurately represent the genetic and metabolic complexities in AMD. Patient-derived induced pluripotent stem cell (iPSC) models can help determine variant effect in disease relevant cell types. However, iPSC derivation is a long and expensive process that is heavily dependent on patient reliability and consent to invasive sampling. Genetic manipulation of established iPSCs could be a solution. However, a lack of available targeting sequence and low experimental efficiency can severely hamper the creation of specific mutations.

Aim of the project

To determine whether this system can be used to successfully identify variant pathogenicity in AMD.

Key procedures/objectives

1. Verifiy the use of an iPSC model to accurately annotate variant pathogenicity and model human disease.
2. Establish a platform that could increase the clinical use of genetic testing for AMD.
3. Provide greater insight into the mechanisms of AMD.
4. Identify specific variants that result in complement dysregulation as well as those that moderate responsiveness to current therapies.

Potential impact on people with sight loss

This work could lead to an increased understanding of the role of variants in complement dysregulation and AMD pathology, and will explore whether certain genes respond better to therapy. Research in this area is particularly important since complement therapies have shown great potential for prevention and treatment of AMD and are currently subject to clinical trial. This work could help to identify patients that are most likely to respond to such treatments.

Additionally, the work could lead to a model system that could be used to calculate the impact of additional disease contributors (i.e.- environment and diet), which would identify novel therapeutic molecules, and improve personalised medicine approaches in the care of AMD patients.