In simple terms, genes are like recipes for making proteins. All the cells in our bodies “read” genetic information so they can make the critical proteins necessary to stay healthy and function properly. If there is a mistake in a gene — that is, a misspelling — a protein might not be made correctly and cells in the retina might degenerate and cause vision loss.
These misspellings are called mutations, and just like a mistake in a recipe, some mutations are more devastating than others. For example, when baking a cake, let’s say there is an error in the recipe. It incorrectly calls for a quarter cup of sugar, when the right amount is a half of a cup. The cake may not taste great, but it is still edible. But let’s say the instruction for adding flour is omitted entirely. Then the cake will be a complete failure and go uneaten.
Well, the same concept applies to genetic mutations in inherited retinal diseases. Some mutations can lead to devastating vision loss while others cause less severe, slower progressing impairment. So, a doctor or scientist is not only interested in which gene is defective in a patient, but how the defect affects vision. Identifying mutations cannot only help deliver a prognosis for a patient, it can direct them to clinical trials for therapies to save their vision.
Jason Comander, M.D., Ph.D., an FFB-funded clinical researcher from Massachusetts Eye and Ear Infirmary, presented the results of his work in cataloguing 190 mutations in the gene rhodopsin (RHO) at the RD2016 meeting, held September 19-24, 2016 in Kyoto, Japan. It’s the world’s largest semi-annual conference focused exclusively on retinal degenerative diseases, and supported in-part by FFB.
RHO is critical for vision, because it expresses a protein that enables rods — the photoreceptors that provide vision in dark settings — to absorb light. Mutations in RHO are also a leading cause of autosomal dominant retinitis pigmentosa (RP). About 100,000 people around the world have RP due to RHO defects.
Dr. Comander says that knowing the mutation can be very informative for patients and families by giving them a prognosis for vision loss.
Dr. Comander and other investigators are studying the details of these mutations in the laboratory. He notes that knowing a mutation’s implications is critical to interpreting genetic test results.
“Certain changes in rhodopsin can be ‘red herrings.’ That is, they cause no problems at all and the real mutation, the mutation causing vision loss, could be in a different gene,” says Dr. Comander.
“Because of this complexity, when you get genetic testing, it is better to use an institution that specializes in retinal disease and understands which DNA changes are truly important. You want an accurate diagnosis, especially when you rely on that information for seeking gene-based treatments.”
In the end, knowledge of a patient’s mutation may directly determine which potential future clinical trials of emerging therapies might be most relevant.
For example, the global biopharmaceutical company Shire is developing a drug known as SHP630 that addresses mis-folded RHO protein caused by a few mutations including P23H, T17M, and R135W. The drug is intended to stabilize the mis-folded RHO protein so that it can function properly in photoreceptors.
Spark Therapeutics and researchers from the University of Florida are each developing gene therapies that are designed to work by shutting down mutant copies of RHO and, at the same time, delivering healthy copies. These approaches are designed to work regardless of the RHO mutation.
“These strategies are targeted toward rescuing rods, which is usually most relevant for younger patients or those with milder disease. Those patients and families who can successfully identify their mutations can position themselves to take advantage of future clinical trials using these treatment strategies,” says Dr. Comander. “We are at a very exciting time in the development of potential therapies for people with RHO mutations.”