Research Funded 2011-2012
- Operating Grants Newly Awarded in 2011
- Research Funding Partnerships with the Canadian Institutes of Health Research
- Ongoing Operating Grants
New Operating Grants Approved 2011 - 2012
Dr. Bremner’s work focuses on proteins called cell cycle regulators that determine how long it take a cell to divide and mature. With previous FFB funds, he has shown that the activity of these proteins in the retina is increased in animal models of retinitis pigmentosa. With this renewed funding, Dr. Bremner will test the possibility that drugs that inhibit the action of these proteins will prolong photoreceptor survival.
Przemyslaw (Mike) Sapieha
Centre de recherche Hôpital Maisonneuve-Rosemont, Université de Montréal
Therapeutic Modulation of ω-3-Poly Unsaturated Fatty Acid Metabolism for Neovascular AMD
Granted: $35,000 Development Grant, 1 year, July 2011 - June 2012
For people living with AMD, some nutritional therapies have been shown to be a useful to prevent the development of wet AMD, a severe form of the disease associated with the growth of abnormal blood vessels under the retina. Wet AMD can cause rapid and severe vision loss.
Omega-3 fatty acids are one of the nutrients being studied for their preventative benefits, but Dr. Sapieha and his colleagues have also gathered preliminary data showing that certain metabolites (breakdown products) of omega-3 fatty acids might be useful as a therapy for wet AMD. This one year development grant will allow Dr. Sapieha to gather more preliminary data and to plot a strategy for a combined analysis of human patients, laboratory studies, and work with animal models that would provide useful evidence for this potential new, non-invasive and inexpensive treatment. If successful, it might be used in concert with current anti-VEGF treatments.
When the human retina is damaged, it cannot repair itself and blindness may result. This is not true for all animals. Dr. Vince Tropepe and his team study zebrafish. In these fish, retinal stem cells and progenitor cells (a type of partially differentiated stem cell) are present in the ciliary marginal zone (CMZ) of the retina, where they can constantly generate new retinal cells throughout life. The human retina also has a CMZ-like region containing retinal stem and progenitor cells, a fact that was discovered by an FFB-funded research team that included Dr. Tropepe and was led by Dr. van der Kooy (see below). However, the capacity to produce new retinal cells from this region in the adult human eye is uncertain. Dr. Tropepe and his team are working to understand the genes that regulate the life-long production of new retinal cells in the zebrafish CMZ, in the hopes of one day learning how to active these genes in humans. During the tenure of this grant, he and his team will focus on a gene called kiaa0947. During his previous grant, Dr. Tropepe showed that fish with a mutation in this gene are less able to make new retinal neurons from the CMZ. He and his team will study the changes that happen in the zebrafish eye when this gene is absent, and how the functions of this gene can be turned on.
Dr. Catherine Tsilfidis is leading a 1.4 million dollar team grant funded by the FFB and the Canadian Institutes of Health Research to develop a new gene therapy for patients, who are losing their vision due to retinal disease. This therapy aims to prevent the death of photoreceptors and preserve vision. This one-year operating grant complements her major team research project with funding towards additional forms of pre-clinical testing of the gene therapy. In addition, this grant will support ongoing work on the mechanism of action of the XIAP protein and how it delays cell death. The investigators hope to develop and evaluate a XIAP protein therapy as a potential alternative to XIAP gene therapy. Unlike gene therapy, a protein therapy would not make permanent changes to the eye and could be halted or changed as the technology develops.
Derek van der Kooy
University of Toronto
Specification and Transplantation of Adult Retinal Stem Cell Progeny
Granted: $300,000 over 3 years, July 2011 - June 2014
Funded with the support of the Krembil Foundation.
More than ten years ago, with funding from FFB donors, Dr. Derek van der Kooy and his colleagues made the remarkable discovery that retinal stem cells are present in the adult human eye. Since that time, Dr. van der Kooy has studied how to harvest these stem cells and use them to replace photoreceptors that have been lost to retinal degeneration. With new funding from the FFB, Dr. van der Kooy will test several specific ways of culturing (growing) these cells that maximizes the production of cone and rod photoreceptors. Dr. van der Kooy and his team will also evaluate the use of a new biodegradable gel, known as HAMC (hyaluronan and methylcellulose) to help spread implanted cells across the retina. The team will also look at the possibilities of integrating other drugs into HAMC that will facilitate the ability of the transplanted cells to make connections with the nerve cells of the eye and ultimately to restore vision.
Primary Investigator: Ian MacDonald, University of Alberta
Tania M Bubela, University of Alberta
Elena Posse de Chaves, University of Alberta
Yves Sauve, University of Alberta
Collaborators: Matt Tennant, University of Alberta; Robert MacLaren, Oxford, UK; Miguel Seabra, Imperial College, London, and Elise Heon, Sick Children’s Hospital, Toronto.
University of Alberta
Granted: $1.35 million over 5 years, Jan 2012 - Dec 2016
Funded by: CIHR – Institute of Genetics; Institute of Neurosciences, Mental Health and Addictions; FFB; The Choroideremia Research Foundation Canada
Choroideremia is an x-linked retinal degenerative disease that first affects young men in childhood or their early teens. Dr. MacDonald and his colleagues will undertake the first human clinical trial of a treatment for choroideremia in Canada, as well as continuing their basic science investigations of the disease’s underlying causes. The trial will test a gene therapy to replace the patient’s mutated REP-1 gene with a healthy gene capable of producing the protein missing in men with choroideremia. The gene will be transferred into the cells of the retinal pigment epithelium and photoreceptors through subretinal delivery of an adeno-associated viral (AAV) vector carrying a normal copy of the RPE65 gene. This trial uses the methods and techniques pioneered by Dr. Robert MacLaren and Dr. Miguel Seabra of the UK, who are collaborators on this study. The objective is to normalizing cellular function and stopping progressive retinal degeneration. The project team will also look at how information is communicated to potential patients about gene therapy research and clinical trials.
For more details see $1.3 million awarded to University of Alberta team will enable a clinical trial of a potential treatment for the rare eye disease choroideremia.
Primary Investigator: Kevin Gregory-Evans, University of British Columbia
Cheryl Gregory-Evans, University of British Columbia
Joanne Matsubara, University of British Columbia
Orson Moritz, University of British Columbia
University of British Columbia
Granted: $1.5 million over 5 years, July 2010 - June 2015
Funded by: CIHR - Neurosciences, Mental Health and Addiction, FFB
Age-related macular degeneration, retinitis pigmentosa, and other retinal disorders impair the vision of more than one million Canadians. Together this team of scientists will explore the molecular mechanisms behind these forms of vision loss aiming to identify therapies that will inhibit cell death, protein errors, and inflammation in the retina. The team will explore using these therapies in combination for more effective treatment. They will also investigate approaches that would allow the delivery of multiple therapies via a single injection into the eye.
For more details see Combination Therapy: Applying our Growing Expertise in Molecular Biology and New Partnership Aims to Develop Therapies to Treat Vision Loss
Primary Investigator: Valerie Wallace, Ottawa Hospital Research Institute
Per Fagerholm, Linköping University, Sweden
May Griffith, Ottawa Hospital Research Institute, University of Ottawa
Bernard Hurley, Ottawa Hospital
Derek van der Kooy, University of Toronto
Carol Schuurmans, University of Calgary
Vincent Tropepe, University of Toronto
Ottawa Hospital Research Institute
Granted: $2.4 million over 5 years, January 2009 - December 2013
Funded by: CIHR - Regenerative Medicine and Nanomedicine, FFB with the support of Sun Life Financial
Stem cell therapies have the potential to benefit more than one million Canadians affected by degenerative eye diseases, such as retinitis pigmentosa, age-related macular degeneration and corneal diseases; all of which cause blindness. By replacing cells that have been lost through disease or injury, stem cell therapies could potentially benefit anyone, at any stage of eye disease.
Together the team hopes to develop better methods for controlling stem cells, so that they can coax these cells into producing different kinds of eye cells, such as retinal and corneal cells. This is currently the greatest obstacle to successful stem cell therapies. They will also develop more efficient transplantation methods that help new eye cells integrate with existing tissue to restore lost vision. And they will work towards combining cells, genes, biomaterials and pharmaceuticals to create an improved artificial cornea.
Primary Investigator: Robert Molday, University of British Columbia
Jim Hu, University of Toronto
Bill Hauswirth, University of Florida
Robert Koenekoop, McGill University
Marinko Sarunic, Simon Fraser University
University of British Columbia
Granted: $3 million over 6 years, January 2009 - December 2014
Funded by: CIHR - Regenerative Medicine and Nanomedicine, FFB with the support of Maxwell Munday, Carolyn Bacon & their families
The application of gene therapy for retinal degenerative diseases will be investigated in Stargardt macular dystrophy, cone-rod dystrophy, Leber congenital amaurosis (LCA), and x-linked retinitis pigmentosa (RP). The strategy is to replace the defective gene with a “new healthy gene” in specific animal models for retinal degenerative diseases with the aim of slowing photoreceptor loss and partially restoring vision. Success in these animal models would lead to future human clinical trials. The recent success in gene therapy for RPE65 has been highly conclusive for LCA; we believe that we can learn from this and advance even more quickly this time.
Primary Investigator: Catherine Tsilfidis, Ottawa Hospital Research Institute
Robert Korneluk, University of Ottawa
William Hauswirth, University of Florida
David Zacks, Kellogg Eye Center and the University of Michigan
Stuart Coupland, University of Ottawa Eye Institute
Brian Leonard, University of Ottawa Eye Institute
Ottawa Hospital Research Institute
Granted: $1.4 million over 5 years, January 2010 - December 2015
Funded by: CIHR - Institute of Aging, FFB, with the support of Scotiabank as well as donations from Jean Boddy and Jim & Colleen Pallister
Previously funded by FFB: $40,000 over 6 months, July 2009 - December 2009
The goal of this project is to develop a new gene therapy for patients, who are losing their vision due to retinal disease. Dr. Tsilfidis and her team have shown that a gene called XIAP can block this process and prevent retinal cell death. The gene can be delivered to the eye using a virus called Adeno-Associated Virus (AAV). This therapy has proven particularly promising in an experimental model of retinitis pigmentosa, a genetic condition and important cause of blindness in which a large portion of the outer layer of the retina is lost. XIAP gene therapy was able to protect the cells of this critical part of the eye from dying, resulting in significant preservation of vision. The objective of this team is to complete the pre-clinical work to move this therapy into clinical trials at the conclusion of this five-year grant.
For more details see Ottawa Researcher will Lead an International Team on a New Gene Therapy.
Ongoing Operating Grants
Dr. Awatramani is leading a team to test and design strategies to restore vision in people already blind from retinal degeneration. The focus is on probing and repairing circuits during retinal degeneration. Dr. Awatramani is part of a team that partially restored vision in animals that were otherwise completely blind from inherited retinal degeneration (Lagali et al., 2008). This breakthrough revealed the importance of reprogramming surviving, non-photoreceptive retinal neurons to be light-responsive.
Outcomes of the research include a better understanding of the bipolar cells (neurons that normally relay signals from rods and cones) and what is most effective way to make them respond beneficially. Light sensitivity, kinetics and responses in animals with restored vision will be measured for development of new treatment theories and pre-clinical tests.
Hear Stuart Trenholm, a student in the Awatramani lab talk about this research.
In RP and AMD, replacement of lost photoreceptors is one potential way to stop disease progression and restore visual function. Human embryonic stem cells can be expanded and manipulated in culture to produce specific cell types, and recent work revealed that post-mitotic photoreceptor precursors from newborn mice could functionally integrate the retina of adult mice. The goal here to differentiate pluripotent hES cells into photoreceptors in the test tube and test their therapeutic potential in animal models of retinal degeneration.
Bernier and his team will grow hES cells in novel cell culture conditions and inducing them to become rods and cones, by applying chemical factors known to do this; also enhancing survival by engineering them to make their own survival factors; testing integration of transplants with microscopy and electrophysiology.
Stem cells are promising source of replacements for photoreceptors lost through degeneration. But to design safe and efficient cell replacement therapies, researchers need to understand the mechanisms that guide formation of the various retinal cell types during normal development. Recently discovered Ikaros, a gene expressed in early retinal progenitor cells; test whether or how it is critical for generating early-born neurons (e.g., photoreceptors).
This will be done through genetically engineered mice (Ikaros-reporter, and mutant (gene-trap) of related gene Pegasus, both already created and in use in his lab); and through gene expression-profiling with gene “chips”.
Identifying novel retinal degeneration genes by novel strategies
[Renewal] Granted: $240,000 over 3 years, July 2010 - June 2013
Drive For Sight supports the ongoing work of Dr. Robert Koenekoop.
The purpose of this grant is to discovery new genes and treatments for Leber congenital amaurosis (LCA) & retinitis pigmentosa (RP) by using a successful gene-hunting program. This program was developed with FFB support and has allowed Dr. Koenekoop to identify six new LCA and RP genes in the past three years. Gene identification leads to new understanding of how photoreceptors live and die, and to gene-specific therapies, which have recently led to the successful rescue of photoreceptors and vision in LCA patients.
Hospital for Sick Children
The Crumbs protein network in cell polarity and retinal degeneration
[Renewal] Granted: $210,000 over 3 years, July 2010 - June 2013
Funded with the support of the Arthur and Sonia Labatt Endowment
Mutations in the CRB1 gene, which encodes Crumbs homolog 1 protein, are responsible for RP type 12 and up to 13% of LCA cases. Crumbs proteins maintain the organization of polarized cells, including photoreceptors. This project aims to understand how the CRB1-associated proteins normally function in healthy photoreceptors, how mutations in CRB1 lead to photoreceptor cell death and retinal degeneration, and whether disruption of CRB1-associated proteins is involved in retinal degeneration
University of British Columbia
Mechanisms of secondary retinal degeneration and regeneration in retinitis pigmentosa: Responses to acute and chronic rod photoreceptor cell death
[Renewal] Granted: $240,000 over 3 years, July 2010 - June 2013
Using a frog model developed by Dr. Moritz and funded by the FFB, Dr. Moritz and his team will study the mechanisms of retinal degeneration to understand how rod cell death causes cone cell death and other dysfunctional changes in the retina. This research will provide valuable information about the progression of retinal degeneration that may suggest potential rescue mechanisms and therapies for the treatment of RP.
Dr. Waskiewicz and his team are researching genes that cause Leber congenital amaurosis (LCA). LCA is a disease characterized by early onset loss of photoreceptor, leading to blindness before the age of one. Specifically, they will use modern molecular genetics techniques to identify mutations in human patients and will study gene function in zebrafish. This research will examine cell to cell signaling in the early embryo, to test the theory that this signaling is irregular in LCA patients.
Identification of Autonomous and Non-Autonomous Roles for the AP-2 Genes in Optic Cup Development
Granted: $210,000 over 3 years, July 2010 - June 2013
Dr. West-Mays and her team are studying the genes that guide development of the optical cup – an embryonic structure that ultimately forms the eye and retina. Defects in a family of genes which control this process are linked to Branchio-Oculo-Facial Syndrome (BOFS) and other forms of congenital vision loss. Dr. West-Mays is using a mouse model to understand how the genes in this family interact and how changes in these genes disrupt the early development of the eye.
Dr. Ebert studies retinal ganglion cells, cells that form the connection between the developing eye and the parts of the brain that control vision. Using zebrafish as a model, she works to understand how these cells form and maintain the right connections in the retina and the brain, connections that are necessary for normal vision. In particular, she is evaluating the role of a family of molecules called fibroblast growth factors (FGF) and their role in this process.
When today's developing therapies are able to restore the retina through gene therapy or stem cell transplant, an understanding of these connecting cells will also be essential. Studies like this may ultimately help rebuild the vital connections between the retina and the brain.