Translational Research

Translational research transforms scientific discoveries arising from laboratory, clinical or population studies into clinically relevant applications to improve health by reducing disease incidence, morbidity and mortality. Owing to a dramatically increased understanding of disease mechanisms, NEI’s translational research program has made significant progress

Gene Transfer: A pioneering, NEI-funded phase I clinical trial published in 2008 found that gene transfer for Leber congenital amaurosis (LCA) resulted in modest visual improvement. This ongoing clinical trial is the result of years of translational research.

  • In 1993, NEI intramural investigators studying the visual cycle isolated RPE65, a gene expressed in the retinal pigment epithelium
  • The development of a RPE65 knockout mouse helped determine that RPE65 transports vitamin A to neural retina to enable phototransduction.
  • In 1997, NEI investigators identified mutations in RPE65 as the cause of a form of LCA.
  • In 1998, NEI investigators identified RPE65 mutations in Briard dogs with early onset visual impairment.
  • Clinical studies of patients with LCA and animal model work established that retinal architecture remains normal for some period before photoreceptor cells degenerate, providing a window of opportunity to intervene in the disease with gene transfer.
  • In a 2001, NEI investigators established that RPE65 gene transfer restored vision in Briard dogs.
  • NEI next supported an R24 grant to conduct necessary pre-clinical toxicity studies to gain regulatory approval.
  • In 2005, the Recombinant Advisory Committee granted approval to begin a phase I clinical trial of RPE65 gene transfer for LCA.
  • In 2008, NEI investigators reported that RPE65 gene transfer was well-tolerated and resulted in statistically significant increases in visual sensitivity.
  • In 2009, NEI investigators reported that visual improvements measured at three months have persisted for one year.
  • This ongoing clinical trial will next evaluate gene transfer in younger patients with less advanced disease.
  • Based on this breakthrough study, NEI grants support efforts to develop gene therapy for a number of eye diseases.

Neurotrophic Agents: During the early 1990s, NEI investigators began evaluating the use of neurotrophic agents in animal models of retinitis pigmentosa (RP), a family of retinal degenerative diseases. These naturally occurring proteins had been previously evaluated in a variety of neurodegenerative diseases. These early laboratory studies established that ciliary neurotrophic factor (CNTF) resulted in photoreceptor cell protection in a variety of animal models of RP. In 2011, Neurotech Pharmaceuticals reported positive results from a phase II clinical trial with the use of ciliary neurotrophic factor (CNTF) in age-related macular degeneration. These encouraging results were made possible with robust support from NEI.

  • In 1994, NEI investigators reported that CNTF delayed retinal degeneration in a rodent model of retinal injury.
  • In 1997, NEI investigators reported that CNTF is upregulated in animal models of retinal injury, providing evidence that CNTF is directly implicated in the protection of photoreceptor cells.
  • In 1998, NEI investigators found that CNTF preserved photoreceptor function in a wide variety of animal models of RP.
  • Although CNTF exhibited therapeutic potential, further progress was inhibited by drug delivery to the retina.
  • During this period, Neurotech Pharmaceuticals licensed CNTF for use in its proprietary drug delivery device, encapsulated cell technology (ECT).
  • ECT is an implantable device consisting of a semi-permeable encapsulated membrane containing transfected cells that produce CNTF. This device offered a viable method to deliver CNTF. However, Neurotech lacked funding to evaluate the utility of its drug delivery device.
  • In 2002, NEI provided funding to evaluate the ECT device in canine models of RP. These studies established proof-of-concept that the ECT device was an effective drug delivery method for CNTF.
  • NEI provided funding necessary to gain regulatory approval for ECT with CNTF.
  • NEI also funded the phase I clinical trial to establish the safety of CNTF in patients with RP. Results from this study, published in 2006, established that ECT delivery with CNTF was well-tolerated.
  • Preliminary data suggested that patients in the trial experienced two to three lines of visual improvement on an eye chart. The trial also demonstrated that the ECT device might be a viable drug delivery device for a variety of therapeutic proteins and other drugs.
  • A subsequent Phase II clinical trial evaluating ECT delivery of CNTF found that this treatment approach was effective in treating geographic atrophy, an advanced form of age-related macular degeneration.
  • While awaiting results from the phase I clinical trial for ECT in RP, subsequent NEI-supported animal model studies, published in 2010, found that CNTF regenerates cone photoreceptor cell outer segments. Outer segments are essential to phototransduction, the biochemical process that converts light into an electrical signal.

Cell Therapy\Regenerative Medicine: Another promising therapy for eye disease is cell transplantation. Some of these approaches have already led to standard, state-of-the-art treatments, such as corneal transplantation. Other investigational treatments are being developed through NEI’s translational research efforts.

  • During the early 1990s, NEI supported retinal cell transplantation studies in animal models. These early studies, using fetal or adult cells, found that implantation of donor cells delayed retinal degeneration in animal models of RP. However, transplanted cells could not migrate to integrate with the host retina.
  • In more recent studies, NEI supported investigators have developed RPE cells from induced pluripotent stem cells (iPS). These cells have delayed retinal degeneration in animal models of retinal disease.
  • Based on this and other work, in November 2010, the FDA granted approval to Advanced Cell technology to evaluate their proprietary iPS RPE cells in the treatment of Stargardt disease and age-related macular degeneration.
  • Efforts to replace lost cell function require that donor cells integrate with the host. Recent NEI work has focused on developing new tissue or organ structures rather than disassociated single cell types. In a recent NEI supported study, investigators implanted animal pole cells isolated from blastula stage embryos of Xenopus laevis in the eye bed. These precursor cells formed an entire eye, with appropriate neural structure and connectivity. ERGs in iPS induced eyes were similar to normal eyes. Importantly these could guide vision based behavior.
  • These and other studies are providing important clues in the development of regenerative medicine.

Last Reviewed: December 2011