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Stem cells restore sight in mouse model of retinitis pigmentosa

25.02.2010
Findings could affect future treatments for macular degeneration, stargardt disease & other forms of retinal disease

An international research team led by Columbia University Medical Center successfully used mouse embryonic stem cells to replace diseased retinal cells and restore sight in a mouse model of retinitis pigmentosa.

This strategy could potentially become a new treatment for retinitis pigmentosa, a leading cause of blindness that affects approximately one in 3,000 to 4,000 people, or 1.5 million people worldwide. The study appears online ahead of print in the journal Transplantation (March 27, 2010 print issue).

Specialized retinal cells called the retinal pigment epithelium maintain vision. Retinitis pigmentosa results from the death of retinal cells on the periphery of the retina, leading to "tunnel vision," where the field of vision is narrowed considerably and everything outside the "tunnel" appears blurred or wavy.

"This research is promising because we successfully turned stem cells into retinal cells, and these retinal cells restored vision in a mouse model of retinitis pigmentosa," said Stephen Tsang, M.D., Ph.D., assistant professor of ophthalmology, pathology and cell biology, Columbia University Medical Center, and lead author of the paper. "The transplanted cells not only looked like retinal cells, but they functioned like them, too."

In Dr. Tsang's study, sight was restored in one-fourth of the mice that received the stem cells. However, complications of benign tumors and retinal detachments were seen in some of the mice, so Dr. Tsang and colleagues will optimize techniques to decrease the incidence of these complications in human embryonic stem cells before testing in human patients can begin.

"Once the complication issues are addressed, we believe this technique could become a new therapeutic approach for not only retinitis pigmentosa, but age-related macular degeneration, Stargardt disease, and other forms of retinal disease that also feature loss of retinal cells," said Dr. Tsang.

In age-related macular degeneration, retinal cells in the center of the retina degenerate and cause the center part of vision to become blurry or wavy. In 2010, macular degeneration is prevalent in nine million Americans and its incidence is expected to double by 2020. It is estimated that 30 percent of the population will have some form of macular degeneration by the time they reach the age of 75.

Replacement of damaged retinal cells in patients with macular degeneration is currently offered in some hospitals, but the therapy is limited by a shortage of donor retinal pigment epithelium cells. By using stem cells and turning them into retinal pigment epithelium cells, the supply is virtually unlimited.

Similar approaches to macular degeneration have demonstrated efficacy in other rodent models, but since these models are of rare, unique pathophysiologies of retinal degeneration, they may not be generalizable to most human forms of retinal degeneration, e.g., age-related macular degeneration, retinitis pigmentosa or Stargardt disease.

"It's a good thing that more models are being tried, as this shows there may be real potential for stem cells to treat different causes of the loss of retinal pigment epithelium in humans," said Dr. Tsang.

Research Used Highly Technical Methods Developed at Columbia

The research methods used in this study were developed by Columbia researchers, past and present, including:

Dr. Peter Gouras (ophthalmology) pioneered retinal cell transplantation where stem cells are placed underneath the retina. Co-authors on this paper, Drs. Nan-Kai Wang (a former retinal fellow now at the Chang Gung Memorial Hospital, the Chang Gung University College of Medicine and National Taiwan University in Taiwan) and Joaquin Tosi (ophthalmology) used this technique to place transplanted stem cells underneath the retina.

Dr. Gouras also developed many of the non-invasive methods used to assess neuronal function in mouse visual system, such as electroretinography, which measures the retina's response to light.

The strategies for embryonic stem cell use were developed at Columbia by Dr. Elizabeth J. Robertson (now at Oxford). In collaboration with Dr. Pamela L. Schwartzberg (now at the National Institutes of Health), and Dr. Stephen P. Goff (biochemistry, molecular biophysics and microbiology), Dr. Robertson combined embryonic stem cells with homologous recombination to achieve gene targeting, producing the first gene-targeted mice.

The techniques employed to engineer stem cells were developed at Columbia by Drs. Goff and Virginia E. Papaioannou (genetics).

Co-author Dr. Victor Chyuan-Sheng Lin (pathology) tapped Dr. Martin Chalfie's (biological sciences) Nobel Prize winning work on green fluorescent protein, to turn the stem cells used in this research yellow, enabling the team to use imaging to see them non-invasively in the mice.

Dr. Takayuki Nagasaki (ophthalmology) developed an advanced imaging technique, known as fundus autofluorescence imaging, which enabled the researchers to examine the mouse eye using non-invasive methods.

"I am fortunate that this diverse expertise exists at the same university – Columbia is one of the few places in the world where this research could be conducted," said Dr. Tsang. "And our multidisciplinary approach to basic science research is unique."

This research was supported by grants from the National Institutes of Health, Research to Prevent Blindness, New York, NY, the Foundation Fighting Blindness, the Dennis W. Jahnigen Career Development Scholars Award Program of American Geriatics Society, the Schneeweiss Stargardt Fund, and Professor Gertrude Neumark Rothschild.

Columbia University's Department of Ophthalmology at the Edward S. Harkness Eye Institute is a leader in neurosciences. Ophthalmic studies at Columbia, sometimes undertaken in collaboration with other departments, use multiple approaches to reach an understanding of retinal disease. Research activities include: identifying genes linked to macular degeneration, seeking ways to stop the progress of diabetic retinal disease, and developing interventions that can save the sight of premature infants during their first few months of life. Although it most often threatens the sight of older adults, retinal disease puts all ages at risk. http://www.columbiaeye.org/

Columbia University Medical Center provides international leadership in basic, pre-clinical and clinical research, in medical and health sciences education, and in patient care. The medical center trains future leaders and includes the dedicated work of many physicians, scientists, public health professionals, dentists, and nurses at the College of Physicians and Surgeons, the Mailman School of Public Health, the College of Dental Medicine, the School of Nursing, the biomedical departments of the Graduate School of Arts and Sciences, and allied research centers and institutions. Established in 1767, Columbia's College of Physicians and Surgeons was the first institution in the country to grant the M.D. degree and is now among the most selective medical schools in the country. Columbia University Medical Center is home to the most comprehensive medical research enterprise in New York City and state and one of the largest in the United States.

Elizabeth Streich | EurekAlert!
Further information:
http://www.columbia.edu

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