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Retinal Genomics and Therapy

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Retinal Genomics and Therapy

Building on over 10 years of collaborative research that started when Dr Carvalho pursed her PhD studies in Professor Hunt’s lab at the UCL Institute of Ophthalmology in London, they are now working towards creating novel research platforms within the LEI to study inherited retinal degeneration, gene therapy and neuroprotective treatment approaches and photoreceptor cell death mechanisms.

During 2016, they have successfully established a working lab at the LEI and started working in new and ongoing projects. They were both involved in the application and award of a NHMRC equipment grant for an electroretinogram (ERG) equipment especially designed for use in laboratory rodent models.

This new equipment will assist LEI researchers in measuring visual function in animal models of visual disorders, important in the assessment and validation of novel treatment strategies and in the determination of disease progression. Dr Carvalho was directly responsible for the setup, installation and training of the new ERG which will be heavily used in her research projects.

The group currently holds six mouse lines that comprise four models of achromatopsia, an inherited retinal disorder that causes complete loss of colour vision, and two lines with targeted knock-out of voltage-gated potassium channel genes. For five of these lines, they are the sole holders in the world.

Also during 2016, Dr Carvalho was awarded a UWA Research Collaboration Award together with international collaborators from the University of Tubingen in Germany to study the effect of neuroprotective drug compounds for preserving cone photoreceptors. She is also a co-investigator on a four-year NHMRC project grant, funded in 2016, with Dr Alex Hewitt and Dr Rick Liu at the University of Melbourne.

In January 2016, Dr Carvalho was selected for the New Investigator of the Month Award from the American Society for Gene and Cell Therapy (ASGCT).

Publications for 2016 include a chapter in a book on Human Color Vision (Springer, USA) titled “The genetics of color vision and congenital color deficiencies”, co-authored by Professor Hunt and Dr Carvalho; a review about cone photoreceptor cell death mechanisms in achromatopsia in Advances in Experimental Medicine and Biology authored by Dr Carvalho; two papers on the visual opsins and the concept of transmutations of rods and cones in snakes published in Proceedings of the Royal Society and Molecular Biology and Evolution; a paper on the visual sensitivity of the emu, with an emphasis on the presence of vision into the ultraviolet published in in Proceedings of the Royal Society, and a paper on the evolution of phototransduction in vertebrates published in Molecular Biology and Evolution.

Current research projects

As part of Dr Carvalho’s DECRA fellowship, the aim of this project is to investigate the molecular mechanisms behind cone cell death and migration impairments during retinal development and how it is affected during diseases like achromatopsia. We are in the process of characterising cone migration using mouse models and will use state-of-the-art technologies like next generation sequencing and proteomics to establish the basic cellular and molecular pathways that are activated during cone photoreceptor cell death and migration in normal and degenerate retinas. Different mouse lines have now been established for this work which has opened up new international collaborations with researchers at the University of Tubingen, who are experts in the area of cone degeneration mechanisms.

At the clinical level it is not possible to diagnose the precise genetic lesion of inherited retinal disease without molecular analysis but a major exception to this is a disorder which presents as a cone dystrophy with supernormal rod electroretinogram (CDSRR) and it has now been established that the unusual electroretinogram (ERG) is diagnostic for the disorder. Professor Hunt has previously demonstrated that mutations in the gene KCNV2 which encodes the voltage-gated K+ channel protein Kv8.2 are responsible for this disorder. The ERG disease phenotype indicates that mutations in KCNV2 disrupt photoreceptor adaptation, the fundamental physiological process by which photoreceptor sensitivity is modulated. However, the precise mechanism has yet to be defined. Kv8.2 is the first and, as yet, only voltage-gated K+ channel protein where disease-causing mutations affecting vision have been identified. Also, CDSRR is a good candidate for treatment using viral-based gene therapy approaches. As part of a NHMRC project grant (2012-2014), Professor Hunt has been characterising novel mouse models of potassium channel deficiencies that affect vision. He has established that disease progression and phenotype in these models shows close similarities to the human condition and therefore provide good models for studying the role of Kv subunits in modulating the visual response and for validating gene therapy treatment approaches. Currently in preparation, a manuscript will soon be submitted with the initial findings of this study.

The process of phototransduction in the rod and cone photoreceptors whereby light is converted into an electrical signal within the retina is now understood in some detail. However, many of the steps in phototransduction, although identical in rod and cones, are nevertheless carried by rod and cone-specific isoforms that are encoded by different genes. The project seeks to address the question of when in vertebrate evolution did these isoforms appear. The approach undertaken by Professor Hunt (in collaboration with Professor Trevor Lamb FRS at ANU in Canberra, Associate Professor Nathan Hart at Macquarie University in Sydney and Professor Shaun Collin and Dr Wayne Davies at UWA) has been to sequence the transcripts of all the genes expressed in the retina/eye of a large number of “ancient” vertebrates that include hagfish, lampreys, chimaeras, sharks, rays, and bony fish. These sequences are then aligned with the sequences of similar genes found in other members of vertebrate kingdom, including humans to determine when the isoforms first appeared.

  • David M Hunt – UWA/LEI Emeritus Honorary Professor
  • Livia S Carvalho – ARC DECRA Fellow
  • Melanie Barth – Research Assistant (past)

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