2016 RESEARCH HIGHLIGHTS

Molday_NewBy Robert S. Molday, PhD
Director, Center for Macular Research
University of British Columbia, Vancouver, BC
Chairman, MVRF International Scientific Advisory Board

Significant advancements have been made in understanding the underlying causes of age-related macular degeneration (AMD) and early onset inherited retinal degenerative diseases. AMD is a leading cause of vision loss in people over the age of 50 affecting over 50 million people worldwide. It is caused by the interplay of genetic, environmental and lifestyle risk factors. An international effort has led to the identification of the most common genetic variants that contribute to one’s risk of developing AMD. These variants have been broadly associated with ocular inflammation and oxidative stress that can cause the destruction of retinal pigment epithelial (RPE) cells in the central (macula) region of the retina and as a consequence the death of  photoreceptor cells and the loss in vision. A number of studies, some of which are supported by MVRF, have focused on developing RPE cells and photoreceptor cells from stem cells for retinal transplantation. Although still early in its development, several clinical trials have been initiated to determine if transplantation of stem cell derived RPE cells is safe and can restore vision or at least slow or prevent further vision loss in individuals with AMD and Stargardt disease, an early onset inherited macular degeneration. Transplantation of photoreceptors is a more challenging problem, but steady progress is being made in developing appropriate cells for transplantation into animal models for retinal diseases.

In another area of study supported by MVRF, scientists are using gene therapy to restore vision in individuals with inherited retinal degenerative diseases. Earlier studies have shown that viral-mediated delivery of the RPE65 gene to individuals with a severe retinal degenerative disease known as Lebers Congenital Amaurosis (LCA) is safe and partially restores vision. Gene therapy has also been successfully used to restore vision and sustain photoreceptor cell survival in animal models for a number of inherited retinal degenerative diseases. These pioneering studies have now led to the initiation of new gene therapy clinical trials for a number of genetic eye diseases.

In another important area of study, researchers have developed a technology known as Crispr/Cas9 that has the power of editing existing genes. This method is now widely used to edit genes in cells grown in culture. As the technology matures, it has the potential of correcting defective genes in RPE and photoreceptors of animal models and eventually human with known retinal diseases.

The application of drug-based therapy is also under intense investigation as treatment for retinal diseases. Ranibizumab (trade name Lucentis) and bevacizumab (trade name Avastin), two related compounds that blocks the growth of abnormal blood vessels in the macula, have been shown to slow vision loss and in some cases improve visual acuity in individuals with the wet form of AMD. A number of new drugs are now being developed to further improve the outcome of individuals with the wet and dry form of AMD. Pharmaceutical agents are also being developed that target specific biochemical pathways associated with retinal degenerative diseases. Drug therapy may be particular useful in combination with other types of therapy including stem cell and gene therapy.

Finally in another area of MVRF supported investigation, research teams are developing new and improved instruments to image the retina. In one example adaptive optics which has been widely used in astronomy to correct for optical distortions is now being improved to image individual rod and cone photoreceptors at high resolution. Such instruments are important for monitoring disease progression and evaluating the effect of therapeutic interventions on photoreceptor cells.

These and other studies have greatly contributed to our understanding of retinal diseases. Translation of this knowledge into promising therapeutic interventions is proceeding at an ever increasing rate. With continued funding, there is optimism that treatments and cures for AMD and other diseases will be developed in the not too distant future that will benefit affected individuals.

2015 RESEARCH HIGHLIGHTS

dreamstime_s_27570369By Robert S. Molday, PhD
Director, Center for Macular Research
University of British Columbia, Vancouver, BC
Chairman, MVRF International Scientific Advisory Board

MVRF supports pioneering research on age-related macular degeneration (AMD) and early onset retinal degenerative diseases that are a major cause of blindness in the world.  Specific areas of research include 1) the identification and characterization of genetic, molecular, and cellular mechanisms underlying retinal degenerative diseases; 2) the development and application of drug, gene, and stem cell based approaches as treatments to prevent or slow vision loss in AMD and early onset inherited retinal degenerative diseases; and 3) the design and implementation of ‘state of the art’ diagnostic optical imaging techniques.

MVRF grant awardees have made significant progress over the past year as indicated in several examples highlighted below.

In one study, next generation sequencing is being used to identify novel disease-causing mutations in the ABCA4 gene associated with Stargardt disease, a common early onset macular degeneration associated with severe loss. The identification of novel disease-causing mutations is important for proper genetic counseling and the development of variant-specific therapies for Stargardt disease as we move towards personalized medicine. 

In another project funded by MVRF, a biochemical pathway that leads to photoreceptor cell death is being analyzed at a molecular and cellular level. Myriocin, a pharmacological agent known to inhibit a specific step in this pathway, has been shown to significantly slow photoreceptor cell death in animal models for retinal degenerative diseases. This drug also acts as an anti-inflammatory agent thereby reducing secondary immune-associated responses which can contribute to the severity of retinal degenerative diseases. These studies provide a basis for further evaluating Myriocin in various retinal degenerative diseases including age-related macular degeneration.  Success in these preclinical studies will lead to future Phase I clinical trials. 

Genetic studies have shown that variants in the complement factor H gene and other complement genes increase one’s risk of getting AMD. Suppression of complement activation should prevent or at least slow photoreceptor degeneration and loss in vision.  In one approach, gene therapy is being used to deliver factors which inhibit complement activation in retinal pigment epithelial (RPE) cells. RPE cells are crucial for photoreceptor survival and play a central role in the ocular immune response. Ongoing studies supported by MVRF point to the potential importance of limiting complement activation as a means to reduce photoreceptor cell loss.

A potential powerful approach to recover vision in individuals with vision loss from retinal degenerative diseases is to regenerate photoreceptors and/or retinal pigment epithelial (RPE) cells. MVRF is funding a number of studies exploring the application of stem cells as a means to regenerate photoreceptor and RPE cells that are lost as a result of retinal degenerative diseases. In one study in progress, efforts are underway to reprogram human RPE stem cells into photoreceptor cells for transplantation.

2014 RESEARCH HIGHLIGHTS

A Chinese Asian female medical or scientific researcher or doctor using a microscope in a laboratory with her colleague out of focus behind her.

By Robert S. Molday, PhD
Director, Center for Macular Research
University of British Columbia, Vancouver, BC
Chairman, MVRF International Scientific Advisory Board

  • Design and development of novel drugs that inhibit or slow photoreceptor cell death associated with inherited and age-related forms of macular degeneration
  • Evaluation of gene therapy to protect the retina against complement activation and inflammation known to cause many forms of AMD
  • Explore the reprogramming of retinal pigment epithelial stem cells to produce new photoreceptor cells which can ultimately be used for retinal transplantation studies.
  • Extend the genetic and clinical analysis of Stargardt macular degeneration to identify novel disease-causing genetic mutations.
  • Identify genetic factors underlying Central Serous Retinopathy, a relatively common retinal disease associated with fluid detachment of the macula and significant visual impairment
  • MVRF funding of successful gene therapy clinical trials for Leber Congenital Amaurosis, a severe retinal degenerative disease in which children have little or no vision.
  • Preclinical gene therapy trials for achromatopsia, an inherited retinal disease associated with loss in cone photoreceptor function and associated loss in color vision and visual acuity.
  • Identification of new genetic variants responsible for age-related macular degeneration
  • Determining the molecular and cellular basis for juvenile and age-related macular degeneration
  • Development of new imaging tools for the diagnosis of age-related macular degeneration
  • Evaluation of neurotropic factors which important in photoreceptor cell survival