Project Description Narrative:
Vision restoration is a priority for Wisconsin with a large target population: Over 100,000 adults and 6,000 children (<18 years) currently living in Wisconsin have a visual impairment severe enough to qualify as a “visual disability” – numbers that are predicted to increase 116% by 2050 – and the associated cost of treating visual impairment and blindness in the state exceeds $2.6 billion annually. In addition to the direct socioeconomic burdens associated with severe visual impairment – including a reduced ability to participate in daily life and frequent costly visits to the doctor – the inability to see carries with it increased risk of other medical complications, with 39% of adults aged >65 years reporting having experienced a fall in the previous year as a result of visual impairment.
The long-term goal of this project is to develop translatable, life-long gene therapy treatments to preserve or restore vision in patients with neurodegenerative or vascular diseases affecting the eye. In the majority of such diseases, blindness occurs due to an underlying genetic abnormality that triggers the progressive degeneration of both rod and cone photoreceptor cells. Critically, this process typically spares inner retinal neurons and ganglion cells, whose axons comprise the optic nerve and project to the brain, raising the possibility that vision might be restored if only the residual dormant inner retinal neurons might be stimulated or rendered light sensitive. Whilst several approaches to vision restoration have already been explored, including prosthetic retinal implants, photoreceptor transplantation, and optogenetics, each has substantial technological shortcomings that severely limit their clinical utility.
The objective of this project is to assess whether vision can be more efficiently and safely restored using a novel strategy whereby residual inner retinal neurons are driven to undergo direct lineage reprogramming into cone photoreceptor-like cells. The researchers’ overall hypothesis is that conversion of inner retinal neurons into cone photoreceptors can be achieved through targeted over-expression of specific transcription factors known to be involved in photoreceptor development duringretinogenesis. Completion of this project aiming to restore vision in patients with severe impairment or blindness has the potential to directly impact the health and wellbeing of Wisconsin residents. Specifically, in the short term any human trials of vision restoration therapies would be expected to take place at the Medical College of Wisconsin and enroll Wisconsin residents first.