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.

A major advance in gene therapy for Retinitis Pigmentosa

A paper published in Nature Communications sheds light on why, until now, it has not been possible to effectively restore vision in rd1 mice – the world’s major model for retinitis pigmentosa (RP). This research also demonstrates how a particular type of mutation in this mice was the cause of failure of previous gene therapy attempts.

Is a whole eye transplant possible?

When we talk about an eye transplant, we usually refer to a cornea transplant, in the present day scenario. No one so far has been able to remove a complete eye from a donor, and transplant it into a recipient and make the eye function. But it looks like this is about to change...

New animal model may help develop new treatments for RP

Developing new treatments for diseases such as RP have been difficult for many reasons. Apart from the fact that it was difficult to pinpoint the genetic defect in the disease, lack of an adequate animal model that could be used to test any new treatment to study its effect and follow the effect for a few months has been an underlying problem for many years now.   

Hence the recent publication in IOVS of success in creating a genetically modified mini-pig may help in the development of newer and improved treatment paradigms, and may eventually help lead us to a cure diseases such as retinitis pigmentosa (RP), which is the most common inherited retinal disease in India. The researchers used miniature pigs, weighing about 150 pounds at full growth, instead of the larger pig, since managing the smaller pigs was much more easier. 

This model has been developed by researchers in the Department of Ophthalmology & Visual Sciences at the University of Louisville, along with researchers from the National Swine Resource and Research Center, University of Missouri.

For those from the scientific background, here's the abstract from IOVS. " ... describes the creation of an inbred, transgenic mini-pig that carries a mutant human rhodopsin gene which is expressed in the retina and is associated with progressive loss of light-evoked ERG responses. This is a significant achievement of considerable practical value in an era in which translational activity for retinal diseases is burgeoning. The rationale for generating this pig is laid out well, and the design appears to have multiple advantages over the existing retinal dystrophic pig. There are many rodent models of retinitis pigmentosa (RP) and conditions resembling RP, but what has been lacking is a large animal model that more accurately mimics the situations encountered when treating human patients. One potential animal model is the pig. There is an existing pig model of retinal degeneration (RD); however, a number of factors have made this model difficult to use, including the large size of the animals at the time of degeneration as well as molecular genetic considerations. The article describes the successful development of a genetically accurate RP-like condition in a mini-pig.

This model should prove quite valuable to people working on treatment of RD, including traditional pharmacologic approaches and regenerative strategies, such as stem cell transplantation. The authors evaluated six transgenic founders whose retinal function was studied with full-field electroretinography from three months through two years. Progeny from one founder were generated and genotyped to determine the transgene inheritance pattern. Retinal mRNA was isolated and the ratio of P23H to wild-type pig RHO measured. The result is a powerful new tool for retinal degeneration research that should be of interest to a wide range of workers in that field."

The Pro23His (P23H) rhodopsin (RHO) mutation is the cause for the most common form of human autosomal dominant retinitis pigmentosa (adRP), with a high propensity for disease characteristics to pass to the next generation. This study was focused on establishing a transgenic miniature swine model of RP using this human P23H RHO gene. 

Animal models are used to screen for safety and efficacy of new treatment paradigms for diseases such as RP, which includes newer treatment modalities such as medications, stem cell therapies, gene therapy, and the artificial retinal prosthesis.

The prevalence of RP in India is considered to be significantly higher compared to other nations. With some small sample studies indicating that RP may affect about 1 in 1000 in some areas, to almost 1 in 500 in some rural areas in India, we potentially have a population of about a million RP patients. 

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