Gene therapies are a promising method to treat all forms of Usher syndrome. The goal is to deliver a healthy copy of a gene - or tools to repair it - into cells, usually using a harmless virus called AAV (adeno-associated virus). But many Usher genes are very large, and AAV has a strict size limit on the amount of DNA it can carry. This means most Usher genes do not fit into a single AAV.
To address this problem in USH1F, which is caused by mutations in the PCDH15 gene, researchers tested a “dual-AAV” strategy. They split the PCDH15 gene into two smaller segments, each packaged into its own AAV. When cells were given both AAVs, the two pieces rejoined within the cell to form a full-length, functional PCDH15 protein.
The results were impressive: in mice missing normal PCDH15 protein, this therapy restored both hearing and balance. The approach also worked in human retinal organoids (lab-grown eye tissues that mimic the human retina) and even in the retina of a monkey, showing the protein was correctly produced in different models.
What this means for the Usher syndrome community: This “dual-AAV method” could be used for any large USH gene that doesn’t fit into one AAV. Other researchers are already testing this approach for USH1B (MYO7A), another very large gene. As more studies show success, this strategy could expand to more USH genes, bringing hope for future treatments that could work across many subtypes of the disease.
