Canada Brain Power

Tag: Vision

  • Discovery of a new therapeutic avenue to protect vision in diabetic patients

    Discovery of a new therapeutic avenue to protect vision in diabetic patients

    This is a Brain Star Award feature of Dr. Sergio Crespo-Garcia, from the Maisonneuve-Rosemont Hospital Research Center. Dr. Crespo-Garcia he is first place winner of the 2024 competition and also the winner of the Marlene-Reimer Award for 2024. Congratulations!

    Diabetes is a silent epidemic with profound complications in the retina, including a profound visual impairment that robs individuals of their ability to connect with the world around them. Dr. Sergio Crespo-Garcia, working as a post-doctoral fellow in the laboratory of Dr. Przemyslaw (Mike) Sapieha at the Maisonneuve-Rosemont Hospital Research Center, has identified a novel therapeutic strategy aimed at reversing diabetic macular edema (DME), a pervasive blinding condition in diabetic patients. This new therapeutic approach has the potential to be applied to other neurodegenerative diseases.

    Specifically, Dr. Crespo-Garcia and his colleagues investigated the role of cell aging (senescence) in the development of diabetic macular edema (DME). They showed that senescent cells play a critical role in driving leakage from blood vessels and neuroinflammation of the retina leading to retinal damage in diabetes. Further, they identified a protein, called B-cell lymphoma extra-large (BCL-xL), as a potential target to selectively eliminate senescent cells. By employing foselutoclax (UBX1325), a small molecule drug, they demonstrated reduction in retinal neuroinflammation and improvement in vascular and neuronal function. Importantly, these preclinical data translated to human trials where patients enrolled in the Phase 1 trial showed a gain in visual acuity – these were patients for whom other treatments were no longer beneficial. Most excitingly, Phase 2 trials are currently underway, and could transform the way we protect vision in diabetic patients.

    Read the full story here: https://canadabrainpower.com/brain-star-award-winner-sergio-crespo-garcia/

    Read the full scientific publication here:

    Crespo-Garcia S, Fournier F, Diaz-Marin R, Klier S, Ragusa D, Masaki L, Cagnone G, Blot G, Hafiane I, Dejda A, Rizk R, Juneau R, Buscarlet M, Chorfi S, Patel P, Beltran PJ, Joyal JS, Rezende FA, Hata M, Nguyen A, Sullivan L, Damiano J, Wilson AM, Mallette FA, David NE, Ghosh A, Tsuruda PR, Dananberg J, Sapieha P. Therapeutic targeting of cellular senescence in diabetic macular edema: preclinical and phase 1 trial results. Nature Medicine 2024 Feb;30(2):443-454. doi: 10.1038/s41591-024-02802-4. Epub 2024 Feb 6. PMID: 38321220.

    https://www.nature.com/articles/s41591-024-02802-4

  • An optomapping approach to better understand connections in the visual cortex of the brain

    An optomapping approach to better understand connections in the visual cortex of the brain

    This is a Brain Star Award Feature: Christina You Chien Chou – McGill University, won this prize based on the excellence of the research and its potential benefits to the health of Canadians. Brain Star Awards are presented by the Canadian Association for Neuroscience (CAN) and the Canadian Institutes of Health’s Institute of Neurosciences, Mental Health and Addiction

    In the brain, information is passed from neuron to neuron via connections called synapses. Synaptic dysfunction unsurprisingly underlies many neurological diseases, such as autism, schizophrenia, and epilepsy. Understanding how synapses are wired up in a cell-type-specific way is fundamental to understanding brain function. In this publication, Christina Chou, working in Jesper Sjöström’s research group at McGill University, used a new technique called optomapping to reveal previously unknown circuit wiring principles for excitatory and inhibitory neurons in mouse visual cortex. She found that different cell types have distinct connectivity patterns and that excitatory synapses onto inhibitory neurons are stronger, denser, and farther reaching than onto excitatory neurons. In other words, inhibition may win over and temper excitation. She additionally found that short-term synaptic dynamics depend on both input neuron location and on target cell type. These findings are key to understanding how the diversity of synapses underlie cell-type-specific circuit functions.

    In the past, classic electrophysiology-based techniques have allowed researchers to precisely study synapses, but the low data yield of this technique has been a major obstacle towards comprehensive mapping of cell-type-specific connections in healthy and diseased states. As a result, there is a long-standing throughput problem in neuroscience research. In the lab of Prof. Jesper Sjöström, Christina Chou built a pipeline that combined electrophysiology and optogenetics for rapidly finding and studying synapses between different types of neurons without sacrificing precision and reliability. This method, which they called optomapping, is 100-fold faster than current electrophysiology-based techniques.

    Read the full story here: https://can-acn.org/brain-star-award-winner-christina-you-chien-chou/

    Read the original research article: Chou, C. Y. C., Wong, H. H. W., Guo, C., Boukoulou, K. E., Huang, C., Jannat, J., Klimenko, T., Li, V. Y., Liang, T. A., Wu, V. C., & Sjöström, P. J. (2024). Principles of visual cortex excitatory microcircuit organization. The Innovation, 6(1), 100735. DOI: 10.1016/j.xinn.2024.100735

    https://doi.org/10.1016/j.xinn.2024.100735

  • New mechanism underlying how we see the world in 3D discovered

    New mechanism underlying how we see the world in 3D discovered

    The Cellular Neurobiology Research Unit led by Dr. Michel Cayouette at the Montreal Clinical Research Institute (IRCM), and also Full Research Professor, Department of Medicine at Université de Montréal, has identified a key mechanism involved in the growth of nerve cells that are critical to mediate binocular vision, which allows us to see the world in 3D. 

    The marvel of human 3D vision

    To see the world in 3D, our eyes look at an object from two different parts of the retina, a thin layer tissue at the back of the eyes that transforms light into electrical signals used by nerve cells to communicate. The overlap between these two fields of vision allows us to determine the depth, distance and speed of an object and make fast, sometimes life saving decisions. Crucial for this process is the proper growth of nerves from the eye to the brain. When these nerve cells called retinal ganglion cells send projections to the brain via the optic nerve, they either remain on the same side or cross over to the other half of the brain. It is the balance of these projections that allows us to see the world in 3D, but how exactly this is controlled remains poorly understood. 

    In the study, the team of scientists identified a gene called Pou3f1 that acts as a major regulator controlling the expression of dozens of other genes, which together generate the full instructions to ensure retinal ganglion cells send projections that cross to the opposite hemisphere of the brain. Furthermore, the team showed that expression of Pou3f1 in retinal stem cells is sufficient to force them to become retinal ganglion cells sending projections to the optic nerve. 

    The work from the IRCM group published in the journal Cell Reports provides an important advance towards solving this mystery. The research was funded by the Canadian Institutes of Health Research.

    Read the full story on the Montreal Clinical Research Institute website: How we see the world in 3D.

  • Identifying a gene critical for vision

    Identifying a gene critical for vision

    A gene spanning cilia function is critical for vision

    Cilia are organelles present in most eukaryotic cells and are categorized into discrete groups: motile cilia (such as those found on spermatozoa) are required for locomotion and fluid dynamics whereas non-motile cilia (like those found in photoreceptors of the eye) are required for cell signalling. Paul William Chrystal, post-doctoral fellow at the University of Alberta, led a study that demonstrated that CFAP20 breaks this dichotomy by functioning in BOTH motile and non-motile cilia. They also identified CFAP20 as a novel cause of childhood blindness in humans, increasing the list of therapeutic targets for patients with the disease.

    Paul William Chrystal won a CAN-CIHR-INMHA Brain Star award for these discoveries.

    CFAP20 protein functions at the cilium inner junction (IJ), and is critical for connecting the component A- and B-microtubules together. The IJ is important in both motile and non-motile cilia function. When disrupted in zebrafish, cfap20 mutants displayed defective heart patterning and spine development (linked to motile cilia), and progressive retinal dystrophy and vision loss (linked to non-motile cilia). Mutations in the worm (C. elegans) Cfap-20 gene caused learning deficits resulting from dysfunction of non-motile cilia on sensory neurons. The researchers then showed that Cfap-20 loss caused an “open-seam” phenotype where the IJ was not connected, and the tubules were splayed apart. In the photoreceptor cells this led to shedding of parts of the cell and eventual cell death. These results show that CFAP20 bridges the two disparate cilia categories, and plays many important roles in cells of various organisms.

    In conjunction, this group identified CFAP20 variants as a novel cause of blindness in humans. Retinitis pigmentosa (RP) is the most common form of inherited retinal dystrophy, with visual deficit often starting in childhood. Sufferers experience tunnel vision and early-onset blindness. Human sequencing identified 8 patients, from 4 families, with RP and CFAP20 variants predicted to be disease-causing. By introducing the human CFAP20 variants into their mutant zebrafish, Chrystal et al. showed that patient variants retained different levels of functionality, and this correlated with patient disease severity. The researchers also propose CFAP20 as a putative cause of other disorders involving cilia (infertility, mental disability, epilepsy which were all found in this patient cohort) arising from more damaging CFAP20 mutations. Functional testing demonstrated that some mutations were more damaging to function than others and could explain the variable levels of symptoms observed between patients. Additionally, functional testing has provided evidence that reintroducing the wildtype CFAP20 sequence can reverse symptoms, the strategy used in human gene therapy.

    This work discovered a novel disease mechanism for retinitis pigmentosa originating at the inner junction, and could implicate other proteins that function at the IJ. While RP is the most common form of inherited retinal dystrophy, only one therapeutic currently exists, Luxturna, a gene-specific therapy to mutations in a gene called RPE65. This paper shows that CFAP20 is a novel cause of RP, adding to the molecular genetic underpinnings of the condition. Furthermore, these studies have provided 4 families with a genetic diagnosis that will allow for subsequent genetic counselling and intervention.

    This project was a hugely collaborative effort, with thirty listed authors. A major strength of this project was the establishment of both national (University of Alberta, Simon Fraser University, University of Calgary) and international (University College London, Moorfields Hospital) collaboration. These collaborations allowed for the researchers to combine human genetics and clinical reporting, C. elegans and zebrafish disease modelling, and a mammalian cell culture model that strengthened the conclusions. While these groups had no previous history of collaboration, they have now developed strong working relationships and hope to collaborate again in the future.

    About Paul William Chrystal

    Paul William Chrystal completed his PhD in developmental genetics at Newcastle University, UK before moving to Edmonton, Canada for postdoctoral studies. He led this study in the laboratory of Dr. W. Ted Allison at the University of Alberta, completing the zebrafish disease modelling, and contributing to analysis, and manuscript preparation. Dr. Chrystal is passionate about understanding the genetics of inherited retinal diseases and translating this knowledge into patient therapeutics. He currently works at the University of Toronto, Canada as a postdoctoral fellow testing gene therapy approaches for preservation of sight in Usher’s syndrome.

    Sources of funding

    This project was funded by the Canadian Institutes of Health Research (CIHR; grants PJT-156042 and MOP-142243), CIHR Rare Disease Models & Mechanisms award (M-UBC-27R00211), and the Natural Sciences and Engineering Research Council of Canada (NSERC; grant RGPIN-2019-04825). Student grants provided by NSERC, Alberta Innovates and CIHR. The UK team were supported by Fight For Sight UK (5045/46), National Institute of Health Research Biomedical Research Centre (NIHRBRC), NIHR-BRC Moorfields Eye Charity (Stephen and Elizabeth Archer in memory of Marion Woods), Wellcome Trust (206619/Z/17/Z), Science Foundation Ireland in partnership with BBSRC (16/BBSRC/3394), and Imperial Health Charity. Additional support provided by Olive Young Fund, University Hospital Foundation, Women and Children’s Health Research Institute Innovation Grant (WCHRI 2846), and the Michael Smith Foundation for Health Research.

    Scientific publication

    Paul W. Chrystal, Nils J. Lambacher, Lance P. Doucette, James Bellingham, Elena R. Schiff, Nicole C.L. Noel, Chunmei Li,  Sofia Tsiropoulou, Geoffrey A. Casey, Yi Zhai, Nathan J. Nadolski, Mohammed H. Majumder, Julia Tagoe, Fabiana D’Esposito, Maria Francesca Cordeiro, Susan Downes, Jill Clayton-Smith, Jamie Ellingford, Genomics England Research Consortium, Omar A. Mahroo, Jennifer C. Hocking, Michael E. Cheetham, Andrew Webster, Gert Jansen, Oliver E. Blacque, W. Ted Allison, Ping Yee Billie Au, Ian M. MacDonald, Gavin Arno, Michel R. Leroux.
    “The inner junction protein CFAP20 functions in motile and non-motile cilia and is critical for vision“. Nat Commun (2022), 13,

    https://www.nature.com/articles/s41467-022-33820-w