Research

Our research focus

RNU4-2 and RNU6 are genes that code for spliceosome RNA that help retinal cells edit the mRNA's that are precursors of the proteins cells need to do their job. When variants disrupt these genes, the retina degenerates and vision is lost. Understanding exactly how this happens — and how to interrupt it — is the central scientific challenge facing CURE4/6.

Effective treatment of any disease is the result of quality research that is reproducible. CURE4/6 supports three major areas of research. The most important is discovering treatments that can slow, stop or even reverse RP. But any therapy that has a chance of success must be grounded in good science. To that end, CURE4/6 is engaged in studies with animal models, human tissue and human retinal organoids to further understand the nature of the RNU4-2 and RNU6 disease mechanism. The results of these studies will guide next steps which will include the development of treatments that slow or halt the progression of this type of RP. These therapies might include ASO (antisense oligonucleotide) or gene therapies.

In addition to research about the mechanism and potential treatment of this type of RP, CURE4/6 supports research in two additional areas that we believe have great benefit, Incomplete Penetrance and Variants of Uncertain Significance (VUSs)

Incomplete Penetrance: When a Variant Doesn't Always Cause Disease Most people assume that inheriting a disease-causing genetic variant means you will develop the disease. With RNU4-2 and RNU6-related retinitis pigmentosa, that isn't always true. Some people carry the same variant that causes severe vision loss in their relatives, yet reach adulthood with little or no symptoms. Geneticists call this incomplete penetrance. We saw this directly in the families described in our research. Among individuals known to carry a disease-causing RNU4-2 variant, nine were obligate carriers — their position in the family tree guarantees they carry the change — who had no visual symptoms at all. In some cases, careful testing did reveal subtle, subclinical findings (for example, a mildly reduced electroretinogram, narrowed retinal vessels, or quiet atrophic changes in the periphery) even when the person had no complaints. In others, the eye appeared entirely normal. This is one of the most important and hopeful questions in our field. If two people carry the same variant and one loses their sight while the other keeps it, something is making the difference — a second genetic factor, a protective modifier, a difference in how the variant is expressed, or a mechanism we haven't yet identified. Understanding what protects the unaffected carriers could point directly toward a therapy for those who are affected. CURE4/6 is studying incomplete penetrance to answer three questions: Why do some carriers escape disease? Can we predict who is at risk and who is protected? And can the protective mechanism be turned into a treatment? Identifying and following carriers — both affected and unaffected — within the same families is central to that work.

Variants of Uncertain Significance (VUS): The Genetic Answers We Don't Have Yet When a family pursues genetic testing for retinitis pigmentosa, the hardest result is not a "no." It's a "maybe." A variant of uncertain significance, or VUS, is a change in the DNA that we can see clearly but cannot yet classify as either disease-causing or harmless. The laboratory is being honest: the evidence isn't there yet to call it either way. These are not rare. In screening of the RNU4-2 gene, alongside the recurrent variants confirmed as disease-causing, the discovers of these variants also found 24 additional unique DNA changes across 27 families that had to be classified as VUS. In the related RNU6 genes, they identified 66 more. Because RNU4-2 and RNU6 retinal disease was only recently discovered, many variants in these genes are still being classified. Behind each of those numbers is a family left without a definitive answer. A VUS is not a permanent verdict — it's a placeholder for missing evidence. Variants get reclassified as new data arrives: more families found carrying the same change, laboratory experiments showing what the variant does to the spliceosome, or careful tracking of who within a family is affected and who is not. With enough evidence, a VUS can become a confirmed diagnosis or be cleared as benign. The CURE4/6 VUS program aims to help affected families and their clinicians make sense of these results and contribute to the research that reclassifies them. By gathering families who share these VUS's, connecting their genetic and clinical information, and pairing that with functional laboratory testing, we can build the evidence needed to move variants out of the "uncertain" column. For many families, that is the difference between an open question and a real diagnosis.