FFB Funded Research Grants Approved 2005 - 2006
Operating Grants
Rod Bremner
Department of Cell Molecular Division
University Health Network
Role of RB effector Genes in Retinal Development
Granted: $100,000 for 3 years, July 2005 - June 2008
Background: During the normal development of the retina, new cells are created (by cell division) and excess cells are eliminated (by programmed cell death). These processes are controlled and balanced by particular genes, through the proteins that they encode. One protein that is crucial for normal retinal development is the retinoblastoma protein (Rb). If the gene for Rb is absent or non-functioning, cells divide abnormally, and some cell types – for example, rod photoreceptors – die, while other cell types survive. Rb is a member of a large family of closely related proteins, each one of which (like children of the same parents) is like the other members in some ways but different from them in other ways; for example, one family member called “p107” protects retinal cells from dying, but Rb does not. Dr. Bremner has been trying to understand how p107 protects retinal cells, because knowing this might lead to new ways to block unwanted cell death and vision loss death in retinal degenerative diseases.
Discoveries: Studies published by Dr. Bremner’s research team in the past three years have revealed that p107 shares the ability of the related proteins, p21 and p27, to block photoreceptor cell death and tumor-formation. They have also begun to explain the roles of proteins called transcription factors, specifically those of the “E2f” family, in determining what Rb and p107 do. Their data has advanced understanding of how Rb and other factors control retinal development, how they might be manipulated to optimize the therapeutic use of stem cells in humans, and how they work to protect against errors in retinal development.
Elise Héon - Patient Registry
The Hospital for Sick Children
Registry design, construction, testing for phenotype-genotype correlation and molecular characterization, management & therapy
Granted: $250,000 over 5 years, July 2005 - June 2010
Patient Registry (2005-10) was awarded to initiate a registry of patients affected by retinitis pigmentosa (RP). It will record clinical diagnostic and genetic data, while protecting the confidentiality of patients’ personal information. Thus it will provide a database for relating the clinical characteristics of RP to specific genetic mutations, thus identifying patientsfor testing new therapies as they emerge. The overall goal is for the registry to facilitate the capture and flow of information and ultimately, the safe delivery of vision-saving interventions to the appropriate candidates.
Jim Hu, Ph.D.
Departments of Paediatrics, and Laboratory Medicine and Pathology
The Hospital for Sick Children Research Institute, Toronto, Ontario
Development of animal models and novel methods for retinitis pigmentosa research using retina gene transfer
Renewal Awarded: $82,000 for 3 years, July 2005 – June 2008
Dr. Hu, from the Hospital for Sick Children, has developed new research tools for investigating and understanding how specific gene mutations cause specific losses of function and degeneration. He has created and tested new viral vectors (vehicles or carriers) for delivering gene therapies. The new vectors are expected to be safer than the ones that are currently in use, and to be able to deliver a wider variety of therapeutic genes. This approach has been applied successfully to understanding how mutations in the gene for one form of RP (RP18) cause photoreceptor degeneration. Vectors have also been made for delivery of gene therapy in another type of RP (RP1) and Stargardt disease, to be tested preclinically in collaboration with Drs. Pierce (Univ. Pennsylvania) and Molday (UBC), respectively. These achievements will contribute substantially to the development and refinement of gene therapies for all recessive forms of RP and should have major impact in moving these treatments into clinical trials.
Ian MacDonald (Michael Walter, Yves Sauve) and Robert K. Koenekoop - FFB/TD Financial Group Translational Eye Research Program, Electro-physiological testing and Genetic Counseling
University of Alberta and McGill University
Electro-physiological testing and Genetic Counselling
Granted: $150,000 for 2 years, July 2006 - June 2008
FFB/TD Financial Group Translational Eye Research Program (2006-08) was awarded to be shared between two of Canada’s top ‘gene hunters’ at the University of Alberta and McGill University. The grant was used at these research centres to provide electrophysiological testing and genetic counselling, at no cost to the study patients. This testing has produced valuable DNA samples and patient data from both Canadian and non-Canadian sources. This information will be entered into the core database, where it will be available for further clinical genetic studies and identification of patients suitable for gene- and mutation-specific treatments.
Robert K. Koenekoop, M.D., Ph.D.
Department of Ophthalmology
McGill University/Montreal Children's Hospital, Montreal, Quebec
Molecular Studies of Leber Congenital Amaurosis: A Childhood Blindness and a Model for Retinal Development
Renewal Awarded: $85,000 for 3 years, July 2005 – June 2008
Dr. Koenekoop and his associates have pioneered the identification of genetic causes of RP, in particular Leber congenital amaurosis (LCA). During this 3 year study, they have discovered 4 new genes for retinal dystrophies, including 3 (CEP290, LCA3 and LCA5) that encode proteins associated with the “connecting cilium” (an extremely fine hairlike projection that joins the main part of the rod or cone photoreceptor to its “outer segment”, the part of the cell where light reception takes place). Changes to this structure can be expected to disrupt the supply of molecules that are necessary for the first steps of vision, or to impair visual signaling from the outer segment to the rest of the retina. Dr. Koenekoop’s team also has identified 4 new loci (specific regions of chromosomes) that contain RP-causing mutations, and as many as 30 other loci that may harbor genes involved in LCA. Powerful new methods have been devised and implemented, which will make possible the next steps: identifying the previously unknown genes and mutations that are responsible for some cases of LCA and other types of RP, and ultimately developing therapies for them. These next steps will be the focus on Dr. Koenekoop’s FFB funded grant in 2008-09.
Robert K. Koenekoop and Rando Allikmets - FFB/Retina International/TELUS Retinal Diagnostic Chip Project
Department of Ophthalmology
Montreal Children's Hospital Research Institute
To design and validate a rapid, affordable tool to identify RP gene mutations
Granted: $25,000 for 2 years, 2005 and 2006
FFB/Retina International/TELUS International Retinal Diagnostic Chip Project (2005-2006) was awarded to fund Phase I development of the world’s first diagnostic screening chip for autosomal recessive retinitis pigmentosa, as part of an international collaboration. The screening chip aimed to provide five immediate benefits for the parents and children with RP: confirming the clinical diagnosis; providing a correct prognosis; pre-natal screening; carrier screening; and identifying patients who may benefit from specific clinical trials. As of 2008, thirty “chips” have been developed, which are capable of identifying 2000 mutations that cause hereditary blindness. The chips do this both quickly (in about 4 hours) and inexpensively ($200); by way of comparison, genetic testing by standard technology (which requires sequencing all the known RP genes) would take months to years and cost thousands of dollars.
C. Jane McGlade - Arthur and Sonia Labatt Endowment
Department of Cell Biology
The Hospital for Sick Children
Role of mammalian CRB1 (Crumb homologue 1) in retinal morphogenesis and degeneration
Awarded: $52,000 for 2 years, July 2005 - June 2007
Arthur and Sonia Labatt Endowment was established in 2006 to support long-term stability of research in the area of childhood blindness. It continues to be awarded to prominent Canadian senior investigators through FFB’s operating grant funding stream.
Partnership with the Stem Cell Network
Primary Investigator: Valerie Wallace, Departments of Biology, Microbiology and Immunology, University of Ottawa
Derek Van der Kooy, University of Toronto
C. May Griffith, University of Ottawa
Roderick R. McInnes, University of Toronto
Michael Rudnicki, University of Ottawa
David Carlsson, NRC
Chris Lohman, University of Ottawa
Eye Stem Cells Biology and Therapeutic Applications
[renewal] Awarded: $456,000 for 2.5 years, July 2005 – Dec. 2007
FFB/Stem Cell Network Partnership was established in 2003 to support fellowships and operating grants over several years in biomedical research and therapeutic applications relevant to retinal degenerative diseases. The FFB matches funds provided by the Stem Cell Network (SCN). The applications are reviewed and funded through the SCN’s Scientific Advisory Board. For more information, please visit:. The identification of adult retinal stem cells holds great promise for the development of new therapies to treat or prevent blindness.
To use these cells safely and effectively, we need to understand more about how these cells grow and how they can be coaxed to produce the types of cells needed for transplantation, for example cone and rod photoreceptors. Dr. Wallace and her collaborators have made significant progress towards understanding how RSC and photoreceptors develop. They have identified one signaling pathway that is required for the development of the part of the eye that gives rise to RSC in the adult and another pathway that helps the retina balance the number of photoreceptors that it generates. In the long term these findings will aid in the development of methods to induce RSC and photoreceptors from patient tissues for the benefit of patients with retinal degeneration.
An analysis of regulatory gene expression in the developing retina and adult ciliary margin, where RSCs are located, helped her team to identify the genetic cascades that determine pluripotency (the potential for forming many kinds of cells – essential for reconstituting functional retina) and possibly the ability of human RSCs to form functional photoreceptors.
The data were published: 39. Liu, H., Xu, S., Wang Y., Mazerolle, C., Thurig, S., Coles, B. L. K., Ren, J.-C., van der Kooy, D., and Wallace, V. A. 2007. Ciliary margin transdifferentiation from neural retina is controlled by canonical Wnt signaling. Dev Biol 308:54-67.
Postdoctoral Fellowships
Nancy F. Silva-Gagliardi
Supervisor:
C. Jane McGlade
Department of Cell Biology
The Hospital for Sick Children
The Role of the Mammalian CRB Complex in Retinal Morphogenesis and Disease
Awarded: $35,000 for 2 years, July 2005 - June 2007
Graduate Student Scholarships
Noelle Orton
Supervisor: Torben Bech-Hansen
Department of Medical Genetics
University of Calgary
Molecular and Genetic Studies of Incomplete Congenital Stationary Nigh Blindness
Awarded: $21,000 for 2 years, July 2005 - June 2007
Jean Peloquin
Supervisors: John McRory , Gerald Zamponi
Physiology and Biophysics
University of Calgary
Exploring the effects of multiple mutations found in Cav1.4 calcium channels
associated with X-linked congenital stationary night blindnessAwarded: $21,000 for 2 years, July 2005 - June 2007
Jason Robert Spence
Supervisor: Katia Del-Rio-Tsonis Yvan Arsenijevic
Department of Zoology
Miami University
Characterizing Human Retinal Stem Cell Homing and Differentiation in the Embryonic Chick Awarded: $21,000 for 1 year, July 2005 - June 2006