Programming Circulating Cells as a Therapy for Age-related Macular Degeneration

Michael Boulton, PhD
University of Florida (Gainesville, FL)
Year Awarded:
2011
Grant Duration:
July 1, 2011 to June 30, 2013
Disease:
Macular Degeneration
Award Amount:
$100,000
Grant Reference ID:
M2011017
Award Type:
Standard
Award Region:
US Northeastern

Co-principal Investigators

Maria E Grant, MD
University of Florida

Preprogrammed Bone Marrow Cells as a Systemic Therapy for Dry AMD

Summary

Age-related macular degeneration is the leading cause of irreversible blindness in the elderly. Dry AMD, which represents 85% of AMD, is associated with retinal pigment epithelial (RPE) dysfunction and death for which there is currently no treatment. The development of a minimally invasive cellular therapy that can be given systemically will a) overcome the need for invasive ocular surgery and b) offer the potential for prevention rather than intervention since this therapy can be given much earlier in the disease. Successful development of this approach will offer an important treatment for the 1.7 million plus Americans who are threatened with visual loss from dry AMD, improve quality of life and reduce social and healthcare costs. We predict that the BrightFocus funding for this proposed preclinical study will provide the necessary data to confirm the efficacy of this cellular therapy and allow this pioneering research to translate into phase 1 and 2 clinical trials.

Details

Dry age‐related macular degeneration (AMD) represents 80 to 90 percent of the population currently diagnosed with AMD, yet there is no effective disease‐modifying treatment. Retinal pigmented epithelial (RPE) cells— important for waste recycling and delivery of nutrients to the light‐detecting cells—are mysteriously killed‐off in dry AMD. Therefore, there is much promise in replacing the damaged RPE cells with healthy ones.

In previous studies, Drs. Michael Boulton, Maria Grant and colleagues made the exciting discovery that changing the expression of one gene in isolated bone marrow‐derived plasma cells (BMPCs)—a type of adult stem cell— transforms them into RPE‐like cells. When these cells are injected back into the blood of mice with physically damaged eyes, they go to the retina, renew the single‐layer of RPE cells, and re‐establish normal vision. Drs. Boulton and Grant plan to test this RPE‐replacement treatment in mice with AMD. If this treatment is proven to be effective in these mice, it could lead to human clinical trials and treatment possibilities without the need for invasive eye surgery or injections.

Research Updates

Age-related macular degeneration (AMD) is the leading cause of irreversible blindness in the elderly. Dry AMD, which represents 85% of AMD, is associated with retinal pigment epithelial (RPE) dysfunction and death for which there is currently no treatment. The development of a minimally invasive cellular therapy that can be given systemically will: a) overcome the need for invasive eye surgery; and b) offer the potential for prevention rather than intervention since this therapy can be given much earlier in the disease. Having shown that genetically reprogrammed bone marrow progenitor cells (BMPCs) can repair the RPE and reverse blindness in an acute damage model, Dr. Boulton’s team hypothesizes that preprogrammed BMPCs, when administered systemically into the bloodstream, have the capacity to repair and regenerate the RPE in in a mouse model of AMD.

During the first year of the study, this team has injected genetically-modified BMPCs into the bloodstream of the mice at one and two months after the induction of AMD to study prevention of the disease. They successfully reprogrammed isolated BMPCs in a culture dish by genetically modifying them with the RPE differentiation marker, called RPE65. Systemic delivery of these genetically-modified cells via the tail vein in the mice prevented the progression of early AMD. Introduction of these genetically-modified BMPCs maintained visual function, retained retinal thickness, and prevented degeneration of the retina in AMD mice which was not observed in AMD mice receiving “control” treatments, including being given bone marrow progenitors which were programmed with an irrelevant gene. This team is now evaluating the effect of administering genetically-modified BMPCs at 3 and 6 months after induction of AMD to investigate the best time for treatments. The data obtained in the first year validate Dr. Boulton’s hypothesis and provides an experimental paradigm that could become the basis for cell-based therapies in the clinic for not only AMD but also for retinal degenerative diseases such as Best disease, Stargardt's disease and forms of retinitis pigmentosa.