Associate Professor Riccardo Natoli
I am interested in developing novel innovative diagnostic and treatment strategies for neurodegenerative diseases using microRNA and extracellular vesicles. My main disease focus is retinal degenerations, specifically the number one cause of blindness in the western world Age-Related Macular Degeneration (AMD). AMD prevalence is accelerating in our ageing population. With treatment and early detection options severely lacking, it is estimated that by 2030 1.7 million Australians, and 300 million people worldwide will lose their vision because of this debilitating disease. My ground-breaking work using microRNA and extracellular vesicles to understand and treat this disease is funded by competitive funding agencies (including multiple NHMRC Ideas and Project Grants), industry partnerships, philanthropic funding and a prestigious ANU Translational Fellowship (2019-2021); all contributing to achieving my focus to address this major global health issue.
I am passionate about community engagement, education, and leadership, which inspired me to take a unique approach to nurturing the next generation of vision researchers and science communicators. My philosophy for research leadership and engagement is a bottom-up approach where supporting an individual’s educational aspirations drives research success. In 2017, I established my research group Clear Vision Research (www.clearvisionresearch.com) at JCSMR and ANUMS to provide a framework for supporting this philosophy and to provide pathways for the community to engage in our research. This initiative ensures that students and staff in my research lab participate in driving our research goals, gain direct exposure to the people impacted by AMD, and understand the critical need for science outreach. I consider research-led education to be integral to a researcher’s career. As such, I am a dedicated lecturer in genetics and cell biology in the ANUMS. I have chaired or co-chaired 8 graduated PhD students who have either gone to positions or been offered roles at the National Eye Institute (NIH), Berkley, Harvard, University of Melbourne, University of Sydney and University of Queensland. I currently have 4 postdocs, 2 PhD students (one finishing in 2021) and one honours students in the lab and have supervised numerous Honours, Masters and ANUMS Research Projects students. I am also currently the co-chair of the ANUMS research committee, helping frame the future of medical research at the ANU.
I am active in the international retinal research community. In 2018, I received a University of Wisconsin (USA), Madison McPherson Eye Research Institute Scholarship, allowing me to present at America Association of Vision Sciences (ARVO) and at the University of Wisconsin, Madison. In 2019 I received a Tall Poppy Award in recognition of my scientific excellence and achievements in the fields of vision sciences. I am currently a section chair of the International Society for Eye Research (ISER) 2022 conference, bringing together a symposia of over 60 international and national researchers presenting across 12 symposia sessions. Through Clear Vision Research I developed a school outreach program called the ‘Young Visionaries’ to promote the importance of science to school children and educate parents and teachers on the importance of eye health. I have had repeated invitations to present to Retina Australia and The Blind Society and am actively involved in science public events such as National Science Week, Science in ACTion and National Science Youth Forum. I have featured in national and local media both for my research on AMD and for my promotion of the importance of donating one’s body to medical research. My research has been featured on National Nine News, Win Local News, and SBSs The Feed, as well as ABC Radio, Radio National and various print and online media.
1. MicroRNA as diagnostics and therapeutics for retinal degenerations
MicroRNA (miRNA) are small, endogenous, non-coding molecules that are powerful regulators of genetic information. Despite only being discovered as recently as the turn of this century, miRNAs are already used in clinical trials as therapeutic candidates for complex diseases such as cancer. This rapid bench-to-bedside transition demonstrates the therapeutic potential of miRNAs, particularly for multi-faceted diseases. In fact, miRNAs have already been implicated in the pathogenesis of complex neurodegenerative disorders such as Parkinson’s, Alzheimer’s, and Age-related Macular Degeneration (AMD). At the Clear Vision Research Lab, we believe that we can use miRNAs for two key areas currently lacking in the clinical landscape for AMD:
The Clear Vision Research Lab is currently undertaking a project in which we are investigating the use of miRNA as biomarkers for retinal degenerations. MiRNA demonstrate relatively high stability and abundance in biofluids such as tears, saliva, urine and blood, making them a promising target for prognostic research. Current investigations exploiting biofluid miRNAs for AMD diagnosis has yielded inconsistent results due to the multifaceted nature of disease progression and existing co-morbidities. Our research aims to identify specific miRNAs indicative for different stages in retinal disease and develop a method of disease grading based on their expression in biofluids. We further aim to determine if this panel of miRNAs can also be used as an indicator of therapeutic efficacy.
We currently have a number of ongoing projects where we are attempting to harness the regulatory capabilities of miRNAs to use as therapeutics for AMD. A single miRNA has the ability to control multiple different mRNA, often within the same molecular pathway (e.g. inflammation). This ability makes miRNAs promising therapeutic molecules to target multiple players in a single pathway. Due to the complex nature of AMD, we believe that this approach may prove fruitful in ameliorating key pathways known to lead to retinal degeneration, such as inflammation and oxidative stress. Ourresearch aims to characterise key miRNAs in the retina and, by understanding their dynamic activity under retinal stress, exploit those as therapeutic molecules in the retina.
2. Exosomes in retinal degenerations
Exosomes are small membrane-enclosed delivery vehicles (40-150nm in diameter), which selectively package and transport molecules from host to target cells. Exosome-packaged molecules can be proteins, RNAs and non-coding RNAs such as microRNAs (miRNAs). MiRNAs are endogenous ‘master-regulators’ of gene expression and a single miRNA can control multiple different mRNAs, often found within similar biological pathways. The exosomal transfer of these molecules, particularly miRNAs, can therefore functionally alter the environment of target cells. Exosomes are paramount to the pathogenesis of a plethora of neurodegenerative diseases but their role in retinal degenerations remains largely unknown. At the Clear Vision Research Lab we study exosomes using several miRNA-centered approaches:
- We are characterising the molecular cargo of retinal exosomes, in particular their miRNA signature, to understand the relevance of these in the establishment and development of retinal degenerations.
- Exosomes are known to be efficient at delivering their molecular contents, including miRNA, to recipient cells. To utilize this high delivery efficiency, we are developing ways to enrich retinal exosomes with specific miRNAs of therapeutic potential in an effort to deliver these directly into the degenerating retina.
- Exosome-packaged molecules have high diagnostic potential. Exosomes also have the capacity to travel from their organ of origin, such as the retina, via biofluids such as blood. We are working towards uncovering the signature imprinted on blood-derived exosomes with the goal of establishing a panel of exosome-based biomarkers of retinal degenerations. This will aid the development of an objective and precise diagnostic kit for retinal degenerations.
3. The benefits of exercise for retinal health and reducing retinal degenerations
The benefits of exercise to the human body have long been known. Particularly in the central nervous system (CNS), regular exercise has been shown to improve memory, reduce inflammation and stimulate growth factors in the brain, and even prevent neuronal death. Exercise has also been shown to be an effective non-invasive therapy against neurodegenerative diseases such as Alzheimer’s and Parkinson’s. However, little is known if such benefits extend to another part of the CNS – the retina. At the Clear Vision Research Lab, we investigate the neuro-protective benefits of different forms of exercise to retinal health and aim to understand what molecular processes mediate this. Our ongoing projects aim to determine whether or not these benefits can be translated into therapeutic approaches for retinal diseases such as AMD.
4. Development of new animal models for retinal degenerations
The Clear Vision Research Lab has developed and incorporated a range of rodent models of retinal degenerations. While there is no perfect model to simulate all the pathologies associated with human AMD, we use a growing number of approaches to better understand the progression of AMD and retinal degenerations in general. These models also serve to test the efficacy of novel AMD therapeutic and diagnostic pipelines, with a view towards commercialisation and R&D avenues.
The Clear Vision Research Lab light-damage model, otherwise known as photo-oxidative damage (PD), was developed in-house (Natoli et al. 2016) as a means to induce AMD-like disease in pigmented rodents. In this model rodents are exposed to a high intensity of light with the key benefits that both the oxidative stress and inflammation arms of AMD progression are targeted. The light-damage model has been recognised for its uniqueness and has fostered industry collaborations that have led to the model’s commercialisation and distribution around the world.
Transgenic Mouse Models
The Clear Vision Research Lab has access to the Australian Phenomics Facility (APF), which is a nationally funded facility dedicated to the development, characterisation and archiving of mouse models of human disease. This facility has experts in place to identify genetic traits that lead to a particular disease. Through the APF, we have the capacity to import and generate transgenic mouse lines to mimic various retinal degenerations in vivo. We currently have transgenic mouse lines that mimic retinal pigment epithelium (RPE) dystrophy, which leads to photoreceptor loss in the retina. The benefit of transgenic mouse models is that retinal degeneration often progresses slowly, which parallels the progression of human AMD. The protracted nature of retinal degeneration provides a unique view toward early diagnostic markers of AMD and long-term efficacy of novel treatment strategies.
The sodium iodate model of retinal degeneration is widely used in the research space and one that we have recently begun to use. In this model, mice receive a single dose of sodium iodate which selectively induces RPE cell death, in turn leading to AMD-like pathologies. The simplicity of this model makes it a useful tool for initial screens of novel therapeutics agents that may promote photoreceptor survival.
The Phoenix MICRON IV™ system (Phoenix Technology Group) is a specialized rodent optical coherence tomography (OCT) and fundus imager that can deliver laser-mediated photocoagulation. This process results in a localized choroidal neovascularisation (CNV) response in rodent retinas that mimics pathologies associated with wet AMD. The MICRON IV™ allows the us to monitor the development of a CNV response in vivo and in real time and directly observe the efficacy of potential therapeutic agents.
The oxygen-induced retinopathy (ROP) model is a useful model to study the effects of neovascular diseases of the eye, such as retinopathy of prematurity (ROP) and wet AMD. Neonatal animals present with normal retinal vascularisation ex utero, rather than the abnormal retinal vascular development observed in premature infants. The ROP model takes advantage of the fact that by simply manipulating the environmental oxygen concentration, neovascularisation resembling that of premature infants can be induced and tightly controlled. This model provides us with a crucial tool to better understand ROP and test potential therapeutics together with the development of new medical devices.
5. Novel therapeutics to reduce the progression of retinal degenerations
In recent years, ophthalmic drugs have enjoyed a relatively high probability of success in progressing from Phase I clinical trials to market, estimated in 2015 at ~30%. This clinical success is driven by good preclinical models, especially for wet AMD. In 2016 we developed a mouse model for mimicking the oxidative stress, inflammation and cell death characteristics of the more prevalent form of AMD – dry AMD. This model has opened up both fundamental science and commercial opportunities to better understand and develop new strategies for combating dry AMD. In the Clear Vision Research Lab we are exploring a number of therapeutic options, developed at ANU and by commercial partners, which include gene-based therapies, non-invasive therapeutics (including the use of low-level laser therapy using red light) and novel compounds. We are actively engaging with commercial partners to help develop strategies to slow the progression of retinal degenerations, by targeting inflammation and oxidative stress processes.
- Principal investigator, MicroRNA as diagnostics and therapeutics for retinal degenerations
- Principal investigator, The benefits of exercise for retinal health and reducing retinal degenerations
- Principal investigator, Development of new animal models for retinal degenerations
- Principal investigator, Exosomes in retinal degenerations
- Principal investigator, Novel therapeutics to reduce the progression of retinal degenerations
- Researcher, Integration of single-cell and spatial transcriptomics underlies the molecular disparity in age-related macular degeneration mice eye
- Supervisor, 670nm Red Light as a treatment for Retinopathy of Prematurity (Phase 1 Clinical Trial)
- Supervisor, Optimising the dose of 670nm light therapy for treatment of retinal degenerations
- Supervisor, Role of miRNA in retinal degeneration
- Supervisor, The role of oxidative stress in the progression of retinal degenerations
- Supervisor, The use of miRNA as potential therapeutic targets in diseases causing retinal degenerations
- Jiao, H., Rutar, M., Fernando, N., Yednock, T., Sankaranarayanan, Aggio-Bruce, R., Provis, J., Natoli, R. Subretinal macrophages produce classical complement activator C1q leading to the progression of focal retinal degeneration. Mol. Neurodegener., 2018. 13, 45.
- Chu-Tan, J.A., Rutar, M., Saxena, K., Aggio-Bruce, R., Essex, R.W., Valter, K., Jiao, H., Fernando, N., Wooff, Y., Madigan, M.C., Provis, J., Natoli, R. MicroRNA-124 dysregulation is associated with retinal inflammation and photoreceptor death in the degenerating retina. Invest. Ophthalmol. Vis. Sci., 2018. 59(10) p. 4094-4105.
- Natoli, R., E. Mason, H. Jiao, A. Chuah, H. Patel, N. Fernando, K. Valter, C.A. Wells, J. Provis, and M. Rutar, Dynamic Interplay of Innate and Adaptive Immunity During Sterile Retinal Inflammation: Insights From the Transcriptome. Front Immunol, 2018. 9: p. 1666.
- Natoli, R.*, N. Fernando*, T. Dahlenburg*, H. Jiao, R. Aggio-Bruce, N.L. Barnett, J.M. Chao de la Barca, G. Tcherkez, P. Reynier, J. Fang, J.A. Chu-Tan, K. Valter, J. Provis, and M. Rutar, Obesity-induced metabolic disturbance drives oxidative stress and complement activation in the retinal environment. Mol Vis, 2018. 24: p. 201-217.
- Natoli, R. and N. Fernando, MicroRNA as Therapeutics for Age-Related Macular Degeneration. Adv Exp Med Biol, 2018. 1074: p. 37-43
- Lu, Y.Z., N. Fernando, R. Natoli, M. Madigan, and K. Valter, 670nm light treatment following retinal injury modulates Muller cell gliosis: Evidence from in vivo and in vitro stress models. Exp Eye Res, 2018. 169: p. 1-12.
- Fernando, N., R. Natoli, T. Racic, Y. Wooff, J. Provis, and K. Valter, The use of the vaccinia virus complement control protein (VCP) in the rat retina. PLoS One, 2018. 13(3): p. e0193740.
- Natoli, R, Fernando, N, Madigan, M et al 2017, 'Microglia-derived IL-1Î² promotes chemokine expression by Muller cells and RPE in focal retinal degeneration', Molecular Neurodegeneration, vol. 12, pp. 1-11pp.