Reprogramming Stem Cells and Genome Surgery to Treat Retinal Diseases

At a Glance

  • Columbia University Medical Center researcher, Dr. Stephen H. Tsang is using induced pluripotent stem (iPS) cells to better understand inherited and degenerative retinal disorders.
  • He believes patients suffering from these conditions could potentially benefit from the ability to regenerate cells and tissues from iPS cells.
  • Dr. Tsang’s laboratory was the first restore visual function in a pre-clinical retinitis pigmentosa mouse model using patient iPS cells.

“The recent marriage of iPS cell technology with a technique called CRISPR genome surgery makes possible the correction and transplantation of stem cells derived from the patients themselves. Hence, we will soon be able to replace diseased cells with healthy ones by re-engineering the patient’s cells.”

— Stephen H. Tsang, MD, PhD

Stephen H. Tsang, MD, PhD, an alumnus of Columbia University Medical Center, is an internationally recognized clinician and geneticist specializing in the treatment of retinal degenerative disorders at NewYork-Presbyterian/Columbia University Medical Center. Dr. Tsang is investigating the link between genome engineering and precision medicine within ophthalmology and, in particular, retinal diseases. He is one of a handful of NIH-supported clinicians directing the full spectrum of bench-to-bedside research.

Dr. Stephen H. Tsang

Dr. Stephen H. Tsang

Dr. Tsang explores cell-based treatments for retinal diseases examines embryonic stem cells to model and replace diseased human retinal cells, and creates patient-specific disease models relevant to drug development. “The eye is an ideal testing ground for stem cell therapies because of its relative immune privilege and its ready accessibility for monitoring and imaging purposes,” explains Dr. Tsang.

“Various assays can be used to quantify transplanted tissue at multiple time points noninvasively,” he adds.

Using induced pluripotent stem cells (iPS cells), Dr. Tsang is expanding ophthalmic research into inherited and degenerative retinal disorders. His laboratory was the first to restore visual function in a pre-clinical retinitis pigmentosa mouse model using patient iPS cells and to do so without inducing tumor formation. Preoperatively, these mutant mice exhibited an early onset of blindness characterized by profoundly reduced activity on the electroretinogram, proving to be an ideal recipient in which to study the efficacy of stem cell therapy for retinal pigment epithelial-related diseases.

To collect iPS cells from patients, Dr. Tsang obtains a 2mm skin biopsy from which he isolates fibroblasts to be reprogrammed into pluripotent cells, or cells that are not fixed regarding their developmental possibilities. The process requires manipulating the cell’s specific properties to ensure their transplantation will help regenerate cells anywhere they are used in the body. Reprogramming the iPS cells allows Dr. Tsang to minimize the chance of cell rejection after transplantation.

Induced pluripotent stem cells

Induced pluripotent stem cells

“This is not a transplant in the conventional sense, in which an organ comes from another donor,” says Dr. Tsang. “You are not in danger of rejecting the donor cells; they are your cells, taken from your body. All we have done is reprogram your cells in a way that provides the missing link that may cure whatever is ailing you.”

In one study, Dr. Tsang obtained iPS cells from two patients, each with retinitis pigmentosa. Retinitis pigmentosa has multiple genetic sources, but one of the gene mutations associated with the disease has an unknown function. Dr. Tsang studied this particular gene – known as membrane frizzled-related protein (MFRP). In addition to retinitis pigmentosa, its mutations have been associated with nanophthalmos, posterior microphthalmia, foveoschisis, and optic disc drusen in young children. Dr. Tsang’s research sought to investigate the defects this gene creates in cells.

With a goal to reverse these flaws, Dr. Tsang collected iPS cells and altered them using gene therapy. In doing so, he managed to interfere with the process of gene mutation and discovered that the specific defects that MFRP triggers can be reversed. This finding was a major step forward in the treatment of blinding diseases, including glaucoma and macular degeneration, although it also has significant implications for other degenerative disorders of the central nervous system, such as Alzheimer’s and Parkinson’s diseases. Patients suffering from these conditions could potentially benefit from the ability to regenerate cells and tissues from iPS cells. Now, a new technique called CRISPR genome surgery will make the gene editing process even more efficient, which will allow for greater application of iPS cell technology in the future.

Retinal cells derived from human iPS cells

Retinal cells derived from human iPS cells

“Using iPS cells is like having a patient in a dish,” says Dr. Tsang. The culture dish is a cost-effective and controlled space in which he can conduct experiments to test the success of gene therapy. The alternative, conducting these initial experiments in vivo or live patients, is expensive and often unreliable. While the process of generating new cells from iPS cells has not yet been perfected, these discoveries are remarkable breakthroughs that represent precision medicine’s potential to eliminate human diseases.

Related Links