FFB-Funded Researchers Make Key Advances in Gene Therapy for Usher 1B

The laboratories of David S. Williams, Ph.D., University of California at San Diego, and Xian-Jie Yang, University of California at Los Angeles, have successfully used gene therapy to treat mice with the same genetic defect that causes Usher syndrome 1B (Usher 1B) in humans.

Though substantial preclinical investigation remains to be carried out, Williams reports in the January 18, 2007 online issue of Gene Therapy that the success with mice is a major step in developing a treatment for humans with Usher 1B.

Usher syndrome — the most common form of combined deaf-blindness — affects 10,000-15,000 people in the U.S. Individuals with Usher 1B are born deaf or with profound hearing impairment, and gradually lose their sight to retinitis pigmentosa.

In 1995, FFB-funded investigators participated in the fi nding that mutations in the gene called myosin VIIa (MYO7A) are responsible for both visual and auditory symptoms, as well as problems with balance.

MYO7A is crucial to the function of cilia — tiny hair-like structures — which are present in both the retina and the cochlea of the inner eye.

Williams notes that one of the biggest challenges of developing the Usher 1B gene therapy was designing a delivery mechanism that could transport the very large MYO7A gene to targeted retinal cells. In this study, researchers used a lentivirus — a manmade virus designed for therapeutic purposes — to deliver MYO7A to the retina.

Another challenge is to control the “expression” of the newly delivered, therapeutic gene. When genes tell cells which proteins, and how much of them to produce, the action is known as expression. If a gene expresses too much or too little protein, problems often occur (i.e., loss of retinal function and vision).

The investigators have found that the retinal cells are especially sensitive to the expression level of MYO7A. In ongoing studies, they are developing methods to fine-tune gene expression, so that MYO7A instructs cells to make just the right amount of protein for proper functioning of the retina.

Williams is also working with Ulrich Mueller, Ph.D., Scripps Research Institute (La Jolla, California), to develop MYO7A gene therapy to treat hearing impairment associated with Usher 1B.

Williams and Yang are collaborating with Samuel Jacobson, Ph.D., University of Pennsylvania, to coordinate approaches to future human clinical trials for Usher 1B gene therapy.