Current Research Funding
The FFB is supporting leading-edge research to address vision loss. We have committed $3.4 million to the 20 ongoing multi-year research initiatives described below:- Operating Grants Newly Awarded in 2010
- Research Funding Partnerships with the Canadian Institutes of Health Research
- Ongoing Operating Grants
- Fellowships
New Operating Grants Approved 2010 - 2011
Robert KoenekoopMcGill University
Identifying novel retinal degeneration genes by novel strategies
[Renewal] Granted: $240,000 over 3 years, July 2010 - June 2013
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.
Jane McGladeHospital for Sick Children
The Crumbs protein network in cell polarity and retinal degeneration
[Renewal] Granted: $210,000 over 3 years, July 2010 - June 2013
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
Orson MoritzUniversity 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.
Andrew WaskiewiczUniversity of Alberta
Investigation of the role of TGF-beta signaling in the causation of Leber congenital amaurosis (LCA)
Granted: $210,000 over 3 years, July 2010 - June 2013
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.
Judith West-MaysMcMaster University
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.
Partnerships with the Canadian Institutes of Health Research
Novel Molecular Approaches to Combination Therapy
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.
Eye Stem Cells: Biology and Therapeutic Applications – Sun Life Financial
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, 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.
Novel Gene Therapy Approaches for the Treatment of Retinal Degenerative Diseases
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. 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 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.
XIAP Gene Therapy for the Treatment of Retinal Degeneration
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, Jean Boddy and Jim & Colleen Pallister, Scotiabank
Previously funded by FFB: $40,000 over 6 months, July 2009 - December 2009
The goal of this project is to begin testing a new gene therapy in patients, who are losing their vision due to retinal disease, by the end of five years. 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.
Ongoing Operating Grants
Gautam Awatramani
Dalhousie University
Probing and Repairing Circuits During Retinal Degeneration
Granted: $270,000 over 3 years, July 2009 - June 2012
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.
Gilbert Bernier
Maisonneuve Rosemont Hospital
Stem Cell Transplantation for the Treatment of Retinal Degenerative Disease
[Renewal] Granted: $187,750 over 3 years, July 2009 - June 2012
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.
Rod Bremner - Estate of Olga Variollo
University Health Network
Mechanism of protection of retinal cells by p107 and p27
[Renewal] Granted: $300,000 over 3 years, July 2008 – June 2011
This project is a renewal of Dr. Bremner’s project, Role of Rb Effector Genes in Retinal Development. He and his team have found previously that proteins in the Rb and p27 family are necessary for the survival of rod and cone photoreceptors. Understanding how they promote survival has potential benefits for the treatment of retinal diseases where these cell types die, such as in retinitis pigmentosa. The proposed studies will determine whether it is the Rb-like or p27-like activity of p107 that is most critical for photoreceptor survival, and thus provide a clearer picture of what is required to protect photoreceptors from death. This kind of knowledge may suggest new therapies to protect these vital cells from dying, in humans with a blinding disease.
Michel Cayouette
Institut de recherches cliniques de Montréal
Specification of temporal identity in retinal progenitor cells
[Renewal] Granted: $280,000 over 3 years, July 2009 - June 2012
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”.
David D. Eisenstat
University of Manitoba
Role of DLX homeobox genes in retinal development
Granted: $180,000 over 3 years, July 2008 – July 2011
Dr. Eisenstat and his team will study DLX homeobox genes (a type of transcription factor), which are genes involved in regulating the development of the mouse retina.
Dr. Eisenstat will explore whether these DLX transcription factors block the development of photoreceptors in retinal progenitors while at the same time promoting ganglion cell fate and survival. He will also examine mice missing only one DLX gene rather than two, to determine whether DLX1 or DLX2 is more important for normal retinal development. He will also identify all of the genes directly controlled by DLX transcription factors during retina development. It is important to understand the mechanisms of retinal development in a mouse model to uncover the causes of retinal disease.
David Picketts
Ottawa Hospital Research Institute
Epigenetic regulation of interneuron homeostasis in the mammalian retina
Granted: $270,000 over 3 years, July 2008 – June 2011
Dr. David Picketts and Dr. Valerie Wallace at the Ottawa Hospital Research Institute are studying how the Atrx gene promotes the health and survival of interneurons in the mouse retina.
Amacrine and horizontal cells are interneurons in the retina whose function is to process information from photoreceptors before it is sent to the brain and transmitted as an image. These interneurons must remain intact and receptive to continued photoreceptor signals during treatment to restore vision, however, very little is known about how the health of these cells is maintained.
Many studies examine how transplanted cells during cell transplantation or gene therapy will survive and replenish the photoreceptors, but less is known about how they establish new connections with the remaining retinal neurons.
Mice that lack the Atrx gene in the retina lose a significant proportion of their amacrine and horizontal cells after birth. By identifying the Atrx-dependent pathways and genes that promote survival of these cells, we will gain insight into how the retinal circuitry is maintained. Understanding the biology underlining the maintenance of these cells could improve the outcome of gene and cell therapy to the eye.
Vincent Tropepe
University of Toronto
Genetic & molecular studies of neurogenesis and regeneration in the zebrafish
Granted: $150,000 over 3 years, July 2008 – July 2011
Dr. Vince Tropepe of the University of Toronto will use the natural ability of zebrafish to regenerate retinal cells under normal and pathological conditions in order to investigate the genetic basis for tissue self-repair in the retina.
The zebrafish can regenerate all of the specialized cells in the retina, including photoreceptors (rods and cones), unlike adult human retina, which cannot naturally produce new specialized cells to replace those that are lost or damaged by diseases, such as RP, AMD, glaucoma. On almost all other levels of organization and function, the fish retina and the human retina are similar. Recent discovery of stem cells in the adult human retina suggests that there might be a hidden capacity for regeneration if researchers can find a way to properly stimulate and control them.
The goal of the research is to gain clear understanding of the molecular mechanisms controlling retinal cell regeneration. This research will provide an important foundation for investigating whether similar mechanisms can be stimulated in the human retina, which may lead to new cell-based therapies to treat retinal degenerative diseases.
Fellowships
W.K. Stell Award (A New Investigator Award)
Mechanisms of cell diversification in the retina
Granted: $50,000 for 5 years, July 2006 - June 2011
Dr. Michel Cayouette studies how retinal stem cells divide and how they produce the specialized cells of the retina such as photoreceptors. His work explores how to predict the reproductive actions of stem cells and how to safely use this process to regenerated healthy retinal cells.
Post-Doctoral Fellowship
Role of MMP2 in retinal regeneration
Granted: $105,000 over 3 years, July 2008 – June 2011
Dr. Tucker will utilize tissue-engineering techniques, specifically polymers that degrade following transplantation, to deliver active MMP2 (an enzyme known to degrade proteins that block regeneration) directly to injured retina in an attempt to restore vision following retinal transplantation.
Injury caused by retinal degeneration creates an inhibitory scar, at the outer areas of the retina. This scar contains molecules such as the chondroitin sulfate proteoglycans (CSPGs) that are known to stop cellular growth and movement, thus acting as a barrier to regeneration. If successful, the removal of this inhibitory barrier, by delivering MMP2, will stimulate cellular integration and vision restoration following retinal transplantation.
Graduate Student Scholarships
University of Calgary
Supervisor: Sarah McFarlane, Ph.D.
The Expression and Function of Class 3 Semaphorins in the Developing Retina
Awarded: $100,000 over 5 years, January 2010 - December 2015
Blindness can be caused by damage to retinal cells that link the eye to the brain, as in glaucoma. But there is hope that sight might be restored by replacing the damaged cells and by guiding them to make the right connections in the brain. Under the supervision of Prof. Sarah McFarlane, Ms. Elizabeth Kita is studying proteins called semaphorins, which act like signs to direct these connections during development. By learning to read these signs and understand how they work, we might use them to guide re-growth of eye-brain connections and thus restore vision in many blind people.
The role of Zac1 in rod photoreceptor development
Granted: $60,000 over 3 years, July 2008 – June 2011
Rob Cantrup of the University of Calgary is focused on understanding how Zac1, a gene found in the retina, interacts with other genes and effector molecules to negatively regulate the formation of rod photoreceptors.
Evidence exists that in the absence of Zac1, extra rod photoreceptors are generated, while on the other hand, the overexpression of Zac1 decreases the number of rods generated.
Through genetic, molecular and cellular studies, Rob Cantrup will explain how Zac1 acts as a negative regulator of a rod fate. More specifically, Rob Cantrup will identify the genetic partners of Zac1 and the downstream genes that Zac1 regulates. He will also test if the inhibition of Zac1, which should increase photoreceptor production, would be therapeutically useful in a mouse model of RP.
In the long-term, this research may allow the manipulation of Zac1 (either alone or in combination with other genes) to be used as a preventative therapy used prior to the onset of photoreceptor loss in RP patients. While cell based therapies offer some promise for the replacement of lost photoreceptors in RP or AMD patients, the ability to generate even more photoreceptors via genetic manipulation is likely to further enhance the design of novel treatment regimes.