NIH/NEI – NEI Audacious Goals Initiative: Preliminary Studies for Translation-Enabling Models of the Visual System (R21 Clinical Trial Not Allowed)

The National Eye Institute (NEI) Audacious Goal Initiative (AGI) was launched in 2012 with an open competition for bold, new ideas to stimulate innovation in establishing a national vision research agenda. A single audacious goal emerged from this process, namely, restoring usable vision in humans by regenerating neurons and neural connections in the eye and visual system. The National Advisory Eye Council further recommended that photoreceptor cells and retinal ganglion cells are the most compelling targets for regeneration through this initiative because the loss of either cell type by disease or injury leads to severe visual disability and blindness.

The NEI has hosted workshops and town hall events to elicit information from the vision community as part of the AGI. The principal objective of these meetings was to identify gaps in knowledge, barriers to progress, and promising strategies for achieving regeneration of photoreceptors, retinal ganglion cells and their connections. A recurring theme that emerged from these meetings is the importance of improved model systems in understanding the fundamental biology of regenerative processes.

The diversity and unique characteristics of existing animal models have contributed greatly to our understanding the biology of neural regeneration. The ability of zebrafish to regenerate central neurons into adulthood and the ability to control genetic expression in mice are two examples where the characteristics of the model system have been exploited to produce a wealth of knowledge. Ultimately these discoveries must be translated into the ability to restore function in human patients with blinding diseases. The proof-of-concept studies for translation-enabling models sought in the current FOA are expected to bring us closer to that goal.

Advancing toward the treatment of human eye disease introduces many challenges, including the degree to which the animal model emulates critical aspects of human disease, the presence of a cone-dominant retina and fovea, and differences in the types of retinal ganglion cells and their regenerative capacity. There is a clear need for models that more closely emulate the human visual system and critical aspects of human disease as we move from laboratory investigation to clinical medicine. The ultimate goal of this FOA is to develop new experimental models that could move the field closer to translation by generating pre-clinical data of the type that might be used to support an application for a human clinical trial aimed at restoring vision through regenerative medicine.

The NEI AGI previously solicited [RFA-EY-17-003] and funded projects addressing the development and characterization of animal models that emulate critical aspects of a human blinding disease that might be amenable to cell-replacement or other regenerative therapies, and allow evaluation of cell survival, integration and restored visual function. Applications to this FOA must aim to generate preliminary data that could support the efficacy of a new model.

Funded grants will support proof-of-principle data collection to demonstrate adequate initial characterization of the proposed translation-enabling model. Programmatic priorities include:

  • Innovation of the model system (e.g., transgenic primate model, inducible cell-specific ablation model)
  • Closer alignment to human retina anatomy and physiology (e.g., cone dominance or fovea-like cone density, similarity in ganglion cell types) than existing models
  • Capture of critical biological and pathophysiological aspects of human eye disease that are amenable to regenerative medicine approaches
  • Potential to inform development or validation of therapies for human disorders
  • Allowance for functional testing of restored visual function

The resultant preliminary data will allow investigators to be poised to incorporate the model in response to a subsequent larger scale translational FOA.

Scientific Scope

Applications to this FOA must address the collection of preliminary data to support the development and characterization of models that emulate critical aspects of a human blinding disease, cell-replacement strategies using endogenous or exogenous strategies, and evaluation of cell survival, integration and restored visual function. Applications focusing solely on gene therapy, neuroprotection, or other non-regenerative approaches will be considered non-responsive to this FOA. Applications evaluating paracrine effects of stem cells that are not expected to integrate into the retinal circuitry, or examining only neurotrophic factors, and applications focusing solely on optic nerve regeneration without replacement of RGC cell bodies will also be considered non-responsive.

Projects will be prioritized on their scientific merit and their collective potential to advance the AGI. Given the emphasis on translation, development of non-human primate models is encouraged, although other mammalian models will be accepted. In vitro retina organoid models may also be appropriate. Low priority will be given to applications proposing to refine existing models, or to develop rodent models with insufficient justification for relevance. Applicants are strongly encouraged to contact NIH staff prior to submission.

Deadline:  February 8, 2019 (letters of intent); March 8, 2019 (full proposals)