Hope for Better Treatments for AMD

By Sondra Forsyth

According to a release from the Medical University of South Carolina (MUSC), one approach that researchers have explored to treat retinal diseases such as age-related macular degeneration (AMD) involves transplantation of retinal pigment epithelium cells (RPE) derived from induced pluripotent stem cells (iPSCs). Induced pluripotent stem cells are cells that have the potential to regenerate any cell or tissue in the body, as shown in a landmark paper published by Takahashi K et al in Cell (Aug 25, 2006).

However, life-long immune suppression drugs are necessary to avoid rejection because the “mother” cells are obtained from donors unrelated to the patient. To find an iPSC alternative that does not trigger rejection, researchers have used a patient’s own skin cells to generate iPSCs, but the process uses viruses to introduce the desired reprogramming factors. Currently, the U.S. FDA has not allowed clinical trials using virally generated iPSC. Now MUSC scientists, led by Lucian V. Del Priore, M.D., Ph.D., Pierre Gautier Jenkins Professor in the Department of Ophthalmology, have demonstrated that cells that are produced using a successful alternative to viral induction–exposing skin cells to human proteins– will mimic the function of the RPE. The team, including Ernesto Moreira, M.D.; Jie Gong, M.D., Ph.D.; Mark Fields, Ph.D., MPH; and Zsolt Ablonczy, Ph.D., reported their results in the PLOS ONE.

The release quotes Del Priore as saying, “This works because ultimately the DNA leads to creation of a protein inside the cell, which then affects the cell’s behavior.” The efficiency is low; only about 1% of cells become transformed, he reports, but the research establishes that these cells can then be turned into RPE and that these cells function normally in the Petri dish. Specifically, the work demonstrates that the generated RPE can ingest outer segments from the retina, which is important in the normal maintenance of this delicate neural tissue.

Successful transplantation of RPE cells will depend upon repair of the damaged Bruch’s membrane (BM) beneath the cells, and Del Priore and ihis collaborators also have reported on the effects of doing a “chemical peel” of this substrate in Translational Vision Science and Technology. BM explants were dissected from young and old donor eyes. A combination of cleaning and then coating the explants with extracellular matrix ligands removed the abnormal protein deposits and rejuvenated the tissue. These results demonstrate that the detrimental effects of aging BM can be reversed by reengineering the BM surface with this approach.

The main application of this potential therapy is for treatment of the dry form of AMD. Ninety percent of AMD patients have the dry form, as opposed to the wet. Clinical trials for therapies that arise from this human protein-induced pluripotent stem cell research and BM reengineering are still several years away, says Del Priore. It is hoped that MUSC will be a principal site for these landmark studies.

Photo credit: Brennan Wesley, MUSC