Converting rods into cones in a model of retinitis pigmentosa (RP) rescues retinal degeneration

Heritable retinal degeneration is a common cause of visual impairment and blindness, affecting millions of people worldwide. Many research groups have focused on targeted gene therapy as a treatment for these diseases. However, inherited retinal diseases can be caused by mutations in any one of more than 200 genes, and the pathogenic mechanisms of various mutations differ greatly. This was the motivating factor in the work by Dr James C Corbo and his team at the Washington University School of Medicine to develop gene-independent therapies that would be more widely applicable. This work has been published in the Proceedings of the National Academy of Sciences.


It is estimated that almost 200 distinct genes are the causative agent behind one or more inherited retinal pathologies. Retinitis pigmentosa (RP) accounts for approximately 50% of known inherited retinal degeneration cases. RP is probably one of the most heterogeneous diseases recorded to date, arising from mutations in more than 50 genes with over 3,000 mutations reported by mid-2013. In addition, many syndromic forms of RP also exhibit genetic heterogeneity which, when combined with incomplete penetrance and clinical heterogeneity, result in a significant medical challenge in terms of devising optimized clinical care strategies.

While RP can be initiated (literally) in thousands of different ways, the course of disease generally progresses through an increasing level of rod photoreceptor cell loss followed by cone photoreceptor degeneration. Retinitis pigmentosa is a subtype of retinal degeneration that might be particularly amenable to a gene-independent approach. Here, mutations in rod-enriched genes initiate a progressive sequence of rod cell death followed by cone loss. Cone dysfunction is particularly debilitating for patients, yet it appears to be secondary to rod death; studies in animal models suggest that collapse of the outer nuclear layer (ONL) during rod degeneration may generate an oxidative, nutrient-deficient environment that is toxic to cones. In this case, preservation of rod cell bodies may be sufficient to forestall secondary cone death. the researchers hypothesized that converting adult rods into cones could make the cells resistant to the effects of mutations in rod-specific genes, thereby preventing ONL collapse and secondary cone loss. Although conversion of rods into cones would be expected to result in a loss of rod function and consequent night blindness, this disability is generally well tolerated by patients and might be considered an acceptable risk if coupled with significant cone rescue.

The researchers (headed by Dr Joseph C Corbo (left in pic), credit: Washington Univ School of Medicine) report the rescue of  retinal degeneration by the reprogramming of rods into cones (photo on top credit: Corbo Lab). The study used a well-characterized retinal transcription factor to re-direct rods to a cone cell fate. The principle itself of course is not new. Conversion of one differentiated cell type into another has been carried out in other contexts, including the conversion of pancreatic exocrine cells into β-cells or, auditory endothelial cells into hair cells and fibroblasts into neurons. Of course rod reprogramming is quite different in that the conversion itself would result in a loss of rod function followed by consequent night blindness. However, most individuals might agree that night blindness is an acceptable risk in the context of maintaining a healthy cone cell population and functional photopic vision. The result of the cellular reprogramming in this case reduced rod photoreceptor cell death in a rhodopsin knock-out model of retinitis pigmentosa (RP). The loss of the rod cell population has a deleterious impact on the cones which subsequently degenerate leaving patients with both reduced or absent photopic and scotopic vision. The results of the research suggest that maintaining a rod photoreceptor cell architecture may be sufficient to slow or halt cone cell degeneration.

To achieve their results, the research team exploited the biology of the neural retina-specific leucine zipper (Nrl) transcription factor, known from many previous studies to determine photoreceptor cell fate in the retina. Under normal conditions, photoreceptor precursors expressing Nrl become rods whereas those without Nrl progress to a cone photoreceptor lineage. To knock out Nrl in a model of retinitis pigmentosa the research team generated a conditional Nrl knock out controlled through a tamoxifen inducible promoter. A daily injection of 4-hydroxyl-tamoxifen (4-OHT), between postnatal day 42 and 44, caused inactivation of the Nrl transcription factor resulting in the reprogramming of rods to a cone cell fate. Assays of the reprogrammed pseudo-cones demonstrated a significant decrease in the scotopic ERG response suggesting a loss of rod function, while genetic analysis indicated a loss of expression of rod-specific genes, including rhodopsin, with a parallel activation of cone specific genes.

The work resulted in partial reprogramming of rods into cells with a variety of cone-like molecular, histologic, and functional properties. While the reprogramming was dependent on the timing of Nrl knock-out, the strategy nevertheless rescued the cone cell population within a model of RP. Keeping the rod cells alive, even dysfunctional rods harboring mutations that cause RP, appeared to be sufficient to maintain the retinal architecture and thereby support cone cell survival. In concluding their research, the authors commented that apart from providing insights into the plasticity and maintenance of rod photoreceptor identity, the study demonstrated that partial rod-to-cone reprogramming can forestall retinal degeneration in the Rho−/− model of retinitis pigmentosa. Although these cells are not true cones, they exhibit sufficient down-regulation of rod-specific genes to resist the deleterious effects of a rod-specific mutation. Thus, rod reprogramming may represent a unique therapeutic strategy for retinal disease caused by mutations in rod-enriched genes.

In addition, the research team suggests that the re-programming approach may also be employed to generate a novel cone cell population that could serve to rescue other retinal degenerative conditions, including age-related macular degeneration. While the results indicate the potential for this strategy in the rhodopsin knock-out model, other models of RP, including dominant forms, will need to be tested.

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