by Lindy Keane Carter
Severe vision loss associated with retinal diseases such as age-related macular degeneration (AMD) is caused by dysfunction of the retinal pigment epithelium (RPE) – a layer of cells under the retina – and damage to the substrate under the RPE cells, Bruch’s membrane (BM). Transplantation of RPE cells derived from induced pluripotent stem cells (iPSCs) is one therapeutic approach that researchers are exploring to treat this blinding disease.
Induced pluripotent stem cells are cells that have the potential to regenerate any cell or tissue in the body, as shown in a 2006 landmark paper published in Cell.1 Clinical studies have demonstrated that RPE cells derived from other stem cells are safe and may be effective at improving vision, but life-long immune suppression drugs are necessary because the “mother” cells are derived from donors unrelated to the patient. To find an iPSC alternative that does not trigger transplant rejection, researchers at MUSC and elsewhere 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 does not allow clinical trials using virally generated iPSCs.
MUSC scientists led by Lucian V. Del Priore, M.D., Ph.D., Pierre Gautier Jenkins Professor in the Department of Ophthalmology, have demonstrated a successful alternative to viral induction: exposing skin cells to human proteins. “This works because ultimately the DNA creates a protein inside the cell, which then affects the cell’s behavior,” explains Del Priore. 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 demonstrated that the generated RPE can ingest outer segments from the retina, which is important in the normal maintenance of this delicate neural tissue. Work on this project involved a collaborative research team that included Ernesto Moreira, M.D.; Jie Gong, M.D., Ph.D.; Mark Fields, Ph.D., MPH; and Zsolt Ablonczy, Ph.D. Their primary findings were published November 25, 2015 in PLoS ONE.2
Successful transplantation of RPE cells will depend upon repair of the damaged BM beneath and Del Priore and investigators also have reported on the effects of doing a “chemical peel” of this substrate.3 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.
1 Takahashi K, Yamanaka S. Cell 2006 Aug 25;126(4):663-676.
2 Gong J, et al. PLoS One 2015 Nov 25;10(11):e0143272
3 Moreira EF, et al. Translational Vision Science and Technology 2015 Oct 30;4(5):10.