Researchers have created a new approach to develop personalised gene therapies for patients with retinitis pigmentosa (RP), a leading cause of vision loss.
The approach, the first of its kind, takes advantage of induced pluripotent stem cell technology to transform skin cells into retinal cells, which are then used as a patient-specific model for disease study and preclinical testing.
Using this approach, researchers from Columbia University Medical Center (CUMC) showed that a form of RP caused by mutations to the gene MFRP (membrane frizzled-related protein) disrupts the protein that gives retinal cells their structural integrity.
They also showed that the effects of these mutations can be reversed with gene therapy. The approach could potentially be used to create personalised therapies for other forms of RP, as well as other genetic diseases.
"The use of patient-specific cell lines for testing the efficacy of gene therapy to precisely correct a patient's genetic deficiency provides yet another tool for advancing the field of personalised medicine," said Stephen H Tsang, the Laszlo Z Bito Associate Professor of Ophthalmology and associate professor of pathology and cell biology.
While RP can begin during infancy, the first symptoms typically emerge in early adulthood, starting with night blindness. In later stages, RP destroys photoreceptors in the macula, which is responsible for fine central vision.
In the current study, the CUMC team used iPS technology to transform skin cells taken from two RP patients - each with a different MFRP mutation - into retinal cells, creating patient-specific models for studying the disease and testing potential therapies.
By analysing these cells, the researchers found that the primary effect of MFRP mutations is to disrupt the regulation of actin, the protein that makes up the cytoskeleton, the scaffolding that gives the cell its structural integrity.
The researchers also found that MFRP works in tandem with another gene, CTRP5, and that a balance between the two genes is required for normal actin regulation.
In the next phase of the study, the CUMC team used adeno-associated viruses (AAVs) to introduce normal copies of MFRP into the iPS-derived retinal cells, successfully restoring the cells' function.
The researchers also used gene therapy to "rescue" mice with RP due to MFRP mutations.
According to Tsang, the mice showed long-term improvement in visual function and restoration of photoreceptor numbers.
"This study provides both in vitro and in vivo evidence that vision loss caused by MFRP mutations could potentially be treated through AAV gene therapy," said coauthor Dieter Egli, an assistant professor at CUMC.
The paper was published in Molecular Therapy, the official journal of the American Society for Gene & Cell Therapy.