FUTURE FILE: Highlighting innovative early-stage and preclinical concepts in retina


Future File is a Retinal Physician feature designed to highlight new and innovative early-stage and preclinical concepts that could one day help to advance the everyday practice of retina specialists.

Protein May Be Key Factor in Triggering AMD

■ Researchers have identified a new protein linked to AMD that could offer new hope for the diagnosis and treatment of the disease. A European research team found significantly higher levels of a protein called factor H-related protein 4 (FHR-4) in the blood of AMD patients. Further investigation, using eye tissue donated for medical research, showed the presence of the protein within the macula. The results of this study open up new routes for early diagnosis, by measuring FHR-4 levels in the blood, and suggest that therapies targeting this protein could provide future treatment options.

FHR-4 regulates the complement system, which plays a critical role in inflammation and the body’s defense against infection. Previous studies have linked the complement system to AMD, showing that genetically inherited faults in key complement proteins are strong risk factors for the condition. In this large-scale study, the researchers used a genome-wide association study to identify specific changes in the genome related to the increased levels of FHR-4 found in AMD patients. They found higher blood FHR-4 levels were associated with changes to genes that code for proteins belonging to the factor H family, which clustered together within a specific region of the genome. The identified genetic changes also overlapped with genetic variants first found to increase the risk of AMD more than 20 years ago. Together, the findings suggest that inherited genetic changes can lead to higher blood FHR-4 levels, which results in uncontrolled activation of the complement system within the eye and drives disease.

Primitive Stem Cells May Be Key to Retinal Regeneration

■ Johns Hopkins Medicine researchers have transformed adult human cells to a primitive state, giving them the potential to replace and repair damage to blood vessels in the retina caused by diabetes. The findings from this mouse study, the researchers say, advance regenerative medicine techniques aimed at reversing the course of diabetic retinopathy and other blinding eye diseases. Results of experiments using human cells and mice were published in Nature Communications.

“Our study results bring us a step closer to using stem cells more widely in regenerative medicine, without the historical problems our field has encountered in getting such cells to differentiate and avoid becoming cancerous,” says Elias Zambidis, MD, PhD, an oncologist and member of Johns Hopkins’ Institute for Cell Engineering.

The Johns Hopkins team reprogrammed fibroblast cells to revert to a state that is even more primitive than that of conventional human induced pluripotent stem cells — more like the state of embryonic cells about 6 days after fertilization. To do this, the scientists bathed the cells in a mixture of nutrients and chemicals, including a popular anticancer drug used to treat a variety of cancers including those of the ovaries and breast.

Dr. Zambidis says the drugs worked to wind back the cells’ biological clock. The scientists also found that the stem cells did not have abnormal changes in factors that can alter core DNA, called epigenetics, that typically plague other lab-made versions of naive stem cells.

The research team injected cells called vascular progenitors, which were made from the naive stem cells and are capable of making new blood vessels, into the eyes of mice bred to have a form of diabetic retinopathy that results from blood vessels closing off in the retina. They found that the naive vascular progenitors migrated into the retina’s innermost tissue layer that encircles the eye, with higher efficiencies than have been reported with vascular cells made from conventional stem-cell approaches. The naive vascular cells took root, and most survived in the retina for the duration of the 4-week study. Dr. Zambidis said that the reprogramming appeared to erase disease-associated epigenetics in the donor cells, and brought them back to a healthy nondiabetic stem cell state.

Cell Transplantation Effective at 5-Month Mark

■ ProtoKinetix has developed and patented a family of hyper stable, potent glycopeptides (AAGP) that enhance both engraftment and protection of transplanted cells, organs, and tissues used in regenerative medicine. Pluripotent stem-cell therapy guided into retinal cells could potentially cure blindness even in the late stages of disease, the company says. However, until now, studies in animals have shown that too few transplanted retinal cells survive the hostile local environment long enough to integrate correctly into the retina’s complex neural circuitry. The AAGP molecule in this study has overcome this considerable obstacle for stem-cell treatments that aim to replace retinal cells.

At the 5-month timepoint, the tests show that AAGP preserved and allowed these cells to mature without compromise. These studies are a critical component of the preclinical testing required to advance this program into clinical trials. The study is being conducted by the Gregory-Evans Retinal Therapeutic Lab at the University of British Columbia. RP